10 of The Most Functional Foods In The World Which Destroy Cancer Cells

10 of The Most Functional Foods In The World Which Destroy Cancer Cells

Many specific proteins, enzymes and coding within our immune system may be activated to kill cancer cells. There is no such thing as a cancer cell that cannot be defeated by the human immune system. The difference between cancers that grow and those that don't are what we put in our bodies to prohibit their growth. Proteins can be rendered ineffective if cells experience uncontrolled growth though damage or mutations to DNA or if toxins through food and chemical pollution override the immune system's natural function. Here are 10 functional foods which suppresses tumour development during immune surveillance in the human body.

Scientists have found that healthy cells damaged by chemotherapy secreted more of a protein which boosts cancer cell survival. Chemotherapy has been proven to cause cancer cells to interact with nearby tumour cells and cause them to grow, invade, and importantly, resist subsequent therapy. Where conventional medical treatment fails cancer patients, natural foods succeed.

In a study published in the journal Science Translational Medicine, scientists identified a molecule, known as TIC10, which activates a protein that helps fight the disease. The protein, called TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand) suppresses tumour development it can actually cross the blood-brain barrier, which separates the main circulatory system from the brain.

Through the body's infinite wisdom, its systems recognize foreign invaders and poisons such as chemotherapy which are not beneficial for the brain. Many cancer drugs are consequently blocked from passing the blood-brain barrier. However, TRAIL is permitted passage due to its beneficial effects on the immune system. 

Another positive is that TIC10 does not just activate the TRAIL gene in cancerous cells, but also in healthy ones. This is known as the 'bystander effect' - i.e. where cells near cancerous cells are also killed.

Nearby healthy cells are also given a boost to increase the number of cancer-killing TRAIL receptors on their cell surface.

10 FUNCTIONAL FOODS THAT INHIBIT TUMORS 

1. TurmericCurcumin, possibly the most powerful antioxidant known from the popular Indian spice Turmeric, has countless health benefits. A recent study led by a research team in Munich showed that it can also inhibit formation of metastases.

Curcumin exerts anti-inflammatory and anti-oxidative effects by inhibiting tumor necrosis factor-alpha (TNF-alpha), suggesting that its effect on endothelial function may be mediated by the suppression of inflammation and/or oxidative stress via down-regulation of TNF-alpha. 

One of the most comprehensive summaries of a review of 700 turmeric studies to date was published by the respected ethnobotanist James A. Duke, Phd. He showed that turmeric appears to outperform many pharmaceuticals in its effects against several chronic, debilitating diseases, and does so with virtually no adverse side effects. 

2. Sea Vegetables

Nori, hijiki, wakame, arame, kombu and kelp are just a few of several varieties of sea vegetables with potent effects on cancer. They are a rich source of many wonderful minerals, including magnesium, calcium, iron, and bioavailable iodine. 

But since chronic, unwanted inflammation and chronic oxidative stress are both risk factors for development of cancer, it would be quite natural for scientists to be interested in sea vegetables are anti-cancer foods not only in the case of colon cancer, but for other types of cancer as well. Sea vegetables are well-researched as containing a variety of anti-inflammatory and antioxidant compounds, and this nutrient combination delivers some risk-lowering benefits in the case of colon cancer and other cancer types.

Of special note in this area of cancer and sea vegetables is the issue of estrogen-related cancers, especially breast cancer. Intake of sea vegetables appears able to modify various aspects of a woman's normal menstrual cycle in such a way that over long periods of time (tens of years) the total cumulative estrogen secretion that occurs during the follicular phase of the cycle gets reduced.

3. Grapes and Resveratrol

Resveratrol is a phenolic compound that contributes to the antioxidant potential of red grapes.

Resveratrol is not only an antioxidant and antimutagen, but also reduces oxidant-caused cell death. Resveratrol has been shown to inhibit production of nitric oxide and tumor necrosis factor alpha (TNF-A) by lipopolysaccharide-stimulated Kuppfer cells. Kuppfer cells are macrophages fixed in place in the liver. Their chronic overproduction of nitric oxide and TNF-A due to chronic infection can cause severe liver damage. 

Perhaps Resveratrol's most important property is its ability to inhibit cyclooxygenase-2 (CoX-2). CoX-2 is related to cancers and abnormal growths in the intestinal tract. Natural CoX-2 inhibitors such as resveratrol have been shown to reduce the occurrence of cancers and pre-cancerous growths. So while pharmaceutical companies race to find complex agents that inhibit CoX-2, the ingredient is already present in red grapes which if consumed daily (or via organic grape juice) will protect against tumors naturally. 

4. Chlorella and Spirulina 

Scientists in South Korea recently found that carotenoids from chlorella may be effectively used to prevent cancer in humans. They discovered the primary carotenoid from C. ellipsoidea is violaxanthin, while the major carotenoid from C. vulgaris is lutein. They examined the activity of semi-purified extracts of these carotenoids against human cancer and found they inhibited cancer cell growth in a dose-dependent manner.

Chlorophyll neutralizes environmental toxins and pollutants. It helps the blood carry oxygen to all cells and tissues. Cancer cannot thrive in cells that are fully oxygenated. Chlorophyll plays a part in chlorella's ability to detoxify heavy metals, and is a natural wound healer. There is evidence that chlorophyll reduces the ability of carcinogens to bind with DNA in major organs. Its anti-mutagenic properties make it protective against toxins such as pharmaceutical drugs.

Spirulina simply is unable to remove heavy metals like chlorella does, as it lacks a cell membrane, however it shows significant immune-boosting properties. It is is made of a spiral strand which gives it its name. Spirulina is rich in vitamins B, E, K and beta carotene as well as iron and magnesium and essential fatty acids. It contains amino acids that promote improved mental functioning, vitality and energy, and balanced blood sugar. According to a study done in China, selenium-infused spirulina inhibited the growth of breast cancer cells.

5. Green TeaThe health benefits of green tea are due to the presence of a group of plant flavonoids called catechins. Of particular interest to researchers is epigallocatechin-3-O-gallate (EGCG), the primary catechin in green tea. For example, South Korean researchers have found that EGCG blocks TNF naturally by interfering with the ability of certain pro-inflammatory chemicals to bind to cells of smooth muscle tissue of the vascular system. In a 2009 study conducted by the Chonbuk National University Medical School, it was noted that the specific mechanism of action of EGCG in terms of blocking TNF is the suppression of fractalkine, an inflammatory agent specifically involved in the development of arteriosclerosis, or hardening of the arteries.

6. Cruciferous Vegetables

Cruciferous vegetables contain vitamins, minerals, other nutrients, and chemicals known as glucosinolates. These chemicals break down into several biologically active compounds that are known to possess anticancer effects. Arugula, broccoli, cabbage, cauliflower, kale, turnips and collard greens are a few among many different types of cruciferous vegetables which are rich in nutrients, including several carotenoids (beta-carotene, lutein, zeaxanthin); vitamins C, E, and K; folate; and minerals. Biologically active compounds such as indoles, nitriles, thiocyanates, and isothiocyanates in these vegetables prevent cancer by protecting cells from DNA damage, helping inactivate carcinogens, inducing cell death of carcinogens and inhibiting tumor blood vessel formation (angiogenesis) and tumor cell migration (needed for metastasis). For total glucosinolate content, turnip greens outscore cabbage, kale, cauliflower, and broccoli among the most commonly eaten cruciferous vegetables. 

7. Tomatoes 

Regular consumption of tomato and its products is being consistently associated with lower risk of several types of cancer and, to a lesser extent, coronary heart disease. Among the many tomato components credited with healthful properties, carotenoids and particularly lycopene are being actively investigated. 

Modest effects of the regular intake of a tomato juice provides small amounts of carotenoids which were found on the production of inflammatory mediators, such as TNF-alpha. TNF-alpha production by whole blood was found to be more than 30% lower after almost a month of consuming raw tomato juice.

8. Medicinal MushroomsMushrooms have been used for at least 5000 years for nutritional and medicinal purposes. Anti-viral and anti-cancer effects have been demonstrated in more than 50 species through animal and in vitro studies. Six components of these mushrooms have been investigated for their activity in human cancers: the lentinan component of shiitake, schizophyllan, active hexose correlated compound (AHCC), maitake D-fraction and two components of Coriolus versicolor. 

Coriolus versicolor is an extremely common polypore mushroom which can be found throughout the world.Versicolor means 'of several colours' and it is true that this mushroom is found in a wide variety of different colours as depicted in the image above. It is also recognized as a medicinal mushroom in Chinese medicine under the name yun zhi.

Polysaccharide-K (PSK), is a protein-bound polysaccharide isolated from Trametes versicolor, which is used as an immune system boosting agent in the treatment of cancer in some European countries as well as China and Japan. In Japan, PSK is approved as an adjuvant for cancer therapy and is covered by government health insurance. 

PSK displays anticancer activity from preliminary laboratory assessments in vitro, in vivo and in human clinical trials. Preliminary research has shown that the PSK might reduce mutagen-induced, radiation-induced, and spontaneously-induced development of experimental cancer cell preparations.

9. GarlicThe study, published online in the journal Cancer Prevention Research, notes that Chinese medicine has used garlic since 2000 BCE. The authors suggest compounds such as diallyl sulfide--that are released when a garlic bulb breaks into cloves--may contribute to the herb's potential preventative powers.

A number of studies on garlic have appeared dealing with diallyl sulfide and cancer. One from the Republic of Korea cites diallyl disulfide (DADS) as the most prevalent oil-soluble sulfur compound in garlic, inhibiting cell proliferation in many cell lines. Scientists there examined DADS ability to kill cells in a process involving free radical production. They found that the famous tumor suppressor gene, p53, arrested the cell cycle when DADS treatment was present. Cancer cells died following 24 hour DADS treatment that activated the p53 gene. They also found that DADS induced cell death was prevented by treatment with a compound known to prevent p53 dependent cell death by reducing free radical levels in the mitochrondria, the cellular furnaces. Their results showed that mitochrondrial free radicals may serve as second messengers in DADS-induced cell death, which requires activation of p53. That study was found in the Journal of Biochemical and Molecular Toxicology.

Allicin - which gives garlic its aroma and flavour - acts as the world's most powerful antioxidant. Allicin compound has to decompose in order to generate a potent antioxidant. The reaction between the sulfenic acid and radicals is as fast as it can get, limited only by the time. Garlic oil and powder supplements are produced by distilling fresh garlic, and then diluting it with other substances rendering them ineffective. This process destroys the majority of allicin in garlic. AlliMAX is the only nutraceutical with a difference as it is the only one to provide the body with a guaranteed 100% yield of pure stabilized allicin extract. 

10. Hemp
Hemp oil promotes full body healing and raises melatonin levels thousands of times higher than normal. When the pineal gland produces vast amounts of melatonin, it causes no harm to the body but it is very hard on the condition you are suffering from and indeed can eliminate it.

Melatonin has been shown to slow or stop the growth of several types of cancer cells and even treat cancer. Some of the studies have suggested that melatonin may extend survival and improve quality of life for patients with certain types of untreatable cancers such as advanced lung cancer and melanoma. Some studies reported that a small number of cancers went into total or partial remission

Peer-reviewed and published research has shown melatonin offers particularly strong protection against reproductive cancers. Cells throughout your body -- even cancer cells -- have melatonin receptors. So when melatonin makes its nightly rounds, cell division slows. When this hormone latches onto a breast cancer cell, it has been found to counteract estrogen's tendency to stimulate cell growth.

For almost a decade, Rick Simpson has been showing people how to cure cancer with hemp oil. Both the commercial legal type of hemp oil and the illegal THC laden hemp oil are the most power-packed protein sources available in the plant kingdom. Its oil can be used in many nutritional and transdermal applications. 

Hemp oil is one of the richest sources of essential amino acids and essential fatty acids, providing an excellent balance between omega-3, -6 and -9 fatty acids. All of these substances are currently being discussed, not only in the alternative health scene, but also by the food industry, which is searching for suitable ingredients to create so called 'functional foods'.

Sources:cancer.gov 
nutraingredients.com
phoenixtears.ca 
cancer.org 
sacredearth.com 
preventdisease.com
purehealthsystems.com 
whfoods.com

Dave Mihalovic is a Naturopathic Doctor who specializes in vaccine research, cancer prevention and a natural approach to treatment.

Turmeric's 'Smart Kill' Properties Put Chemo & Radiation To Shame

Turmeric's 'Smart Kill' Properties Put Chemo & Radiation To Shame

Posted on:   Sunday, March 22nd 2015   Written By: Sayer Ji, Founder

The ancient Indian spice turmeric strikes again! A new study finds turmeric extract selectively and safely killing cancer stem cells in a way that chemo and radiation can not.

A groundbreaking new study published in the journal Anticancer Research reveals that one of the world's most extensively researched and promising natural compounds for cancer treatment: the primary polyphenol in the ancient spice turmeric known as curcumin, has the ability to selectively target cancer stem cells, which are at the root of cancer malignancy, while having little to no toxicity on normal stem cells, which are essential for tissue regeneration and longevity.

Titled, "Curcumin and Cancer Stem Cells: Curcumin Has Asymmetrical Effects on Cancer and Normal Stem Cells," the study describes the wide range of molecular mechanisms presently identified by which curcumin attacks cancer stem cells (CSCs), which are the minority subpopulation of self-renewing cells within a tumor colony, and which alone are capable of producing all the other cells within a tumor, making them the most lethal, tumoriogenic of all cells within most if not all cancers.  Because CSCs are resistant to chemotherapy, radiation, and may even be provoked towards increased invasiveness through surgical intervention, they are widely believed to be responsible for tumor recurrence and the failure of conventional treatment.

The study identified the following 8 molecular mechanisms by which curcumin targets and kills cancer stem cells:

·         Down-regulation of interleukin-6 (IL-6): IL-6 is classified as a cytokine (a potent biomolecule released by the immune system) and modulates both immunity and inflammation. It's over expression has been linked to the progression from inflammation to cancer. Curcumin inhibits IL-6 release, which in turn prevents CSC stimulation.

·         Down-regulation of interleukin-8 (IL-8): IL-8, another cytokine, is released after tumor cell death, subsequently stimulating CSCs to regrow the tumor and resist chemotherapy. Curcumin both inhibits IL-8 production directly and indirectly.

·         Down-regulation of interleukin-1 (IL-1): IL-1, a family of cytokines, are involved in response to injury and infection, with IL-1 β playing a key role in cancer cell growth and the stimulation of CSCs. Curcumin inhibits IL-1 both directly and indirectly.  

·         Decrease CXCR1 and CXCR2 binding: CXCR1 and CXCR2 are proteins expressed on cells, including CSCs, which respond to the aforementioned cytokines in a deleterious manner. Curcumin has been found to not only block cytokine release, but their binding to these two cellular targets.

·         Modulation of the Wnt signaling pathway: The Wnt signaling pathway regulates a wide range of processes during embryonic development, but are also dsyregulated in cancer. Curcumin has been found to have a corrective action on Wnt signaling.

·         Modulation of the Notch Pathway: The Notch signaling pathway, also involved in embryogenesis, plays a key role in regulating cell differentiation, proliferation and programmed cell death (apoptosis), as well as the functioning of normal stem cells. Aberrant Notch signaling has been implicated in a wide range of cancers. Curcumin has been found to suppress tumor cells along the Notch pathway.

·         Modulation of the Hedgehog Pathways: Another pathway involved in embryogenesis, the Hedgehog pathway also regulates normal stem cell activity. Abnormal functioning of this pathway is implicated in a wide range of cancers and in the stimulation of CSCs and associated increases in tumor recurrence after conventional treatment. Curcumin has been found to inhibit the Hedgehog pathway through a number of different mechanisms.

·         Modulation of the FAK/AKT/FOXo3A Pathway: This pathway plays a key role in regulating normal stem cells, with aberrant signaling stimulating CSCs, resulting once again in tumor recurrence and resistance to chemotherapy. Curcumin has been found

·         in multiple studies to destroy CSCs through inhibiting this pathway.

As you can see through these eight examples above, curcumin exhibits a rather profound level of complexity, modulating numerous molecular pathways simultaneously. Conventional cytotoxic chemotherapy is incapable of such delicate and "intelligent" behavior, as it preferentially targets fast-replicating cells by damaging their DNA in the vulnerable mitosis stage of cell division, regardless of whether they are benign, healthy or cancerous cells.  Curcumin's selective cytotoxicity, on the other hand, targets the most dangerous cells – the cancer stem cells – which leaving unharmed the normal cells, as we will now learn more about below.

Curcumin and Normal Stem Cells

Normal stem cells (NSCs) are essential for health because they are responsible for differentiating into normal cells that are needed to replace damaged or sick ones. If curcumin were to kill normal cells, like radiation and chemotherapy, it would not provide a compelling alternative to these treatments.  The study addressed this point:

"The safety of curcumin has been long established, as it has been used for centuries as a dietary spice. The question arises as to why curcumin does not seem to have the same deleterious effects on normal stem cells (NSCs) as it does on CSCs. There are several possible reasons that curcumin has toxic effects on CSCs, while sparing NSCs."

The study offered three potential explanations for curcumin's differential or selective cytotoxicity:

·         Malignant cells take in much more curcumin than normal cells.

·         Curcumin alters the microenvironment of cells in such a way that is adverse to CSCs and beneficial to NSCs.

·         Curcumin may not only directly attack CSCs, but may encourage them to differentiate into non-lethal, more benign cells.

Concluding Remarks

This study adds growing support to the idea that safe, time-tested, natural substances are superior to synthetic ones. Given the evidence that a safe and effective alternative may already exist, chemotherapy, radiation and even surgery may no longer be justified as the first-line standard of care for cancer treatment. In fact, a significant body of evidence now implicates these treatments in worsening prognosis, and in some cases driving cancer stem cell enrichment in tumors. Radiotherapy, for instance, has been found to induce cancer stem cell like properties in breast cancer cells, essentially increasing their malignancy and tumoriogenicity by 30 fold.  This is hardly progress when one considers the role that CSCs play, especially in contributing to post-treatment secondary cancers.

Turmeric and its components, of course, are not FDA approved drugs, and by definition the FDA will not allow an unapproved substance, natural or synthetic, to prevent, treat, diagnosis or cure a disease.  This means that you will not be seeing it offered by an oncologist as an alternative to chemotherapy or radiation any time soon.  This does not, however, mean that it does not work. We have gathered over 1500 citations from the National Library of Medicine's bibliographic database MEDLINE, accessible through pubmed.gov, and which can be viewed on our database here: Turmeric Research, showing that curcumin and related turmeric components possess significant anti-cancer activity.  Truth be told, the information is so extensive, revealing over 700 possible health benefits, that I believe this plant embodies a form of intelligence and even compassion. You can learn more about this supposition here: Turmeric's Healing Power: A Physical Manifestation of Compassion?  I also discuss this concept in my lecture, Food As Medicine Rebooted, which you can watch below: Of course, the point is not to wait until one has such a severe health problem that taking heroic doses of spices or herbs becomes the focus. It is important to remember that ancient cultures used spices like turmeric mainly in culinary doses, as part of their dietary practices. These smaller amounts, delivered mainly as whole food extracts, likely constituted effective preventive strategies – perhaps preventing the need for radical, heroic intervention later in life. If you read our previous article, Turmeric: A Wellness Promoting Tonic at Low Doses, Research Reveals, you'll see this point explored in greater depth in light of a human clinical study.

For more research on turmeric and cancer, you can view our two database sections on these topics below:

·         Health Guide: Turmeric

·         Health Guide: Cancer Research

 Abstract. Curcumin has been shown to have numerous cytotoxic effects on cancer stem cells (CSCs). This is due to its suppression of the release of cytokines, particularly interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and also to its effects at multiple sites along CSC pathways, such as Wnt, Notch, Hedgehog and FAK. In spite of its multiple actions targeting CSCs, curcumin has little toxicity against normal stem cells (NSCs). This may be due to curcumin’s different effects on CSCs and NSCs. The use of cytotoxic therapies remains the standard treatment for patients with metastatic cancer. The efficacy of these treatments is limited, with recurrence common. According to the cancer stem cell paradigm, cancers contain distinct subpopulations of cancer stem/progenitor cells (CSCs) characterized by self-renewal mechanisms and resistance to conventional treatments (1-3). When CSCs are transferred to an immune-deficient mouse, these cells can reconstitute the original cancer in the animal (4-6). Even a small number of stem cells (as few as 100) can be effective in bringing about the transplantation (7). However, tumors depleted of stem cells do not grow as xenografts (8). These CSCs have been shown to be resistant to chemotherapy (9), radiation (10) and hormone therapy (11). For this reason, metastases from solid tumors, in particular, will re-appear even after initially successful treatments and prolonged periods of complete remission. Further, an unintended consequence of induced cancer cell death is the release of inflammatory cytokines, which can stimulate replication of CSCs (12-14). The percentage of CSCs in the cancer has been shown to increase in patients receiving neoadjuvant chemotherapy (9, 15, 16). Thus, an “equilibrium” may be formed where chemotherapy-induced tumor cell death results in increased stimulation of tumor growth (12). In addition, the cytokines secreted during induced cancer cell death can result in resistance to cytotoxic agents, so that metastases, when they occur, may be refractory to therapy (14, 17, 18). This suggests, for therapy to be effective on a consistent basis, it must eliminate both CSCs and non-stem cell cancer cells. Curcumin and Interleukin-6 (IL-6) IL-6 (also known as interferon (IFN)-β2) is a multi-functional cytokine involved in the immune and inflammatory response and progression from inflammation to cancer. Increased IL-6 activity has been found in multiple cancers, including multiple myeloma, as well as breast, colon and prostate carcinoma, and IL-6 has been associated with decreased survival and more aggressive disease in these patients (19-22). IL-6 signals through a heterodimeric receptor complex that contains the ligand binding IL-6α chain (CD126) and the common cytokine receptor signal-transducing subunit glycoprotein-130 (gp130, CD130) (19, 23). This leads to activation of the JAK family of tyrosine kinases (Janus kinases), which stimulate multiple pathways, including MAPK, STAT-3 and AKT (19, 23-25). IL-6 promotes chemoresistance, angiogenesis and invasion (12, 17, 26-29). Furthermore, IL-6 has been shown to convert regular cancer cells to CSCs in established breast and prostate cancer cell lines (12). When investigators in this latter study added an anti-IL-6 antibody to the culture medium, this did not occur, demonstrating the crucial role of IL-6 in non-stem cell cancer cell to CSC conversion (12). Shi et al. used multiple chemotherapy agents, including 5- fluorouracil, paclitaxel and doxorubicin, standard drugs for the 599 This article is freely accessible online. Correspondence to: Lawrence Helson, MD, SignPath Pharma, Inc., 1375 California Road, Quakertown, PA 18951, U.S.A. Tel: +1 2155389996, Fax: +1 2155381245, e-mail: lhelson@comcast.net Key Words: Curcumin, cancer stem cells, interleukin-6, interleukin- 8, interleukin-1, CXCR1, CXCR2, Wnt pathway, Notch pathway, Hedgehog pathway, FAK pathway, review. ANTICANCER RESEARCH 35: 599-614 (2015) Review Curcumin and Cancer Stem Cells: Curcumin Ηas Asymmetrical Effects on Cancer and Normal Stem Cells PETER P. SORDILLO and LAWRENCE HELSON SignPath Pharma, Inc., Quakertown, PA, U.S.A. 0250-7005/2015 $2.00+.40 treatment of breast cancer, to induce formation of the multidrug-resistant tumor breast cancer cell line MCF-7/R (30). IL- 6 levels were markedly increased in the line previously treated with chemotherapy compared to the untreated line. Suppression of IL-6 and companion cytokine IL-8 in this study was shown to reverse the multi-drug resistance in the treated cell line, while increased expression of IL-6 or IL-8 increased the resistance of the cells to treatment. One mechanism by which curcumin targets CSCs is inhibition of IL-6 release from cells, thus preventing CSC stimulation. Curcumin has been shown to decrease IL-6 levels or inhibit IL-6 function in multiple experimental systems. Jain et al. studied the effects of curcumin on the human promonocytic cell line U937, which had been maintained with a high concentration of glucose. A marked inhibition of IL-6 secretion from the monocytes was noted (31). This effect was dose-dependent. The investigators also studied rats with streptozoticin-induced hyperglycemia. The diabetic animals demonstrated high IL-6 levels compared to controls. Curcumin significantly reduced the previously elevated IL-6 levels (31). In another study, curcumin was found to prevent IL-6 expression in human rheumatoid synovial fibroblasts (32). Moriasi et al. found that IL-6 expression could be suppressed in a colon cancer cell line treated with curcumin (33). Cohen et al. reported that curcumin inhibited IL-6 production in four head and neck squamous cell carcinoma cell lines (34). Of note was the fact that this effect was also dose-dependent, with the more aggressive head and neck carcinoma cell lines demonstrating higher levels of IL-6 before treatment and requiring higher concentrations of curcumin to inhibit IL-6 compared to the less aggressive cell lines. Similarly, a dosedependent decrease in IL-6 levels was found in human pancreatic cell lines after treatment with a nanoparticleencapsulated formulation of curcumin (35). Curcumin was shown to block production of IL-6 in an experimental acute pancreatitis rat model (36). Bharti et al. reported that curcumin was able to block IL-6-induced STAT-3 phosphorylation in a multiple myeloma cell line (37). The curcumin analog FLLL3 was also shown to reduce IL-6-induced STAT-3 phosphorylation (38). Park et al. showed that curcumin increased the activity of bortezomib against human multiple myeloma U266 cells by decreasing IL-6 production and blocking STAT-3 phosphorylation (39). Curcumin and Interleukin-8 (IL-8) IL-8 (CXCL8) is an important cytokine, which increases after tumor cell death, stimulates CSCs and results in tumor regrowth and resistance to chemotherapy (18, 40). IL-8 is a 72- amino-acid protein belonging to the CXC cytokine family. This cytokine has numerous functions including the induction of neutrophil chemotaxis, neutrophil activation, regulation of cell adhesion, promotion of angiogenesis, histamine release and regulation of receptor protein signaling pathways (13, 41- 45). Release of IL-8 can be caused by many stimuli, including infection, trauma, hypoxia, acidosis, corticosteroids, androgens or chemotherapy (18, 46-47). Docetaxel, a commonly-used chemotherapeutic agent for the treatment of prostate, breast, lung and ovarian cancers, has been shown to markedly increase IL-8 levels (48). As with IL-6, elevated levels of IL- 8 have been detected in human cancers and have been associated with a poor prognosis (13, 49-52). IL-8 has been found to increase tumor growth in cancer cell lines and in xenografts (53-57). Curcumin is a potent inhibitor of IL-8 production, as well as of numerous IL-8 cancer-promoting bio-activities. Hidaka et al. measured IL-8 levels in the human pancreatic carcinoma cell line SUIT-2 after incubation with 10-100 μM concentration of curcumin. The magnitude of the decrease in IL-8 production was dose-dependent. The investigators also reported that curcumin markedly reduced IL-8 receptor internalization. These changes were accompanied by marked suppression of tumor cell growth (58). Curcumin prevented the acid-induced production of IL-8 in human esophageal epithelial cells (59) and reduced IL-8 levels in cultured monocytes previously treated with a high concentration glucose (31). Curcumin caused a dose-dependent blockage of IL-8 production in human head and neck carcinoma cell lines (34). Wang et al. reported that curcumin suppressed neurotensin-mediated IL-8 production in the human colon cancer line HCT166, thus blocking colon cancer cell migration (60). It has been reported that curcumin blocked IL-8 release in alveolar epithelial cells (61) and in human peripheral blood monocytes and alveolar macrophages (62). Curcumin was found to reduce chronic non-bacterial prostatitis in rats by blocking IL-8 release (63). Curcumin and Interleukin-1 (IL-1) The interleukin-1 family is a group of proteins intimately involved in the body’s response to injury or infection (64-66) but which also play a key role in the development and spread of tumors (67-70). Voronou et al. have shown that one of these cytokines, IL-1β, is required for tumor angiogenesis (71). Elevated levels of IL-1β have been found in patients with cancer (72), while increased cancer cell growth after IL-1β stimulation has been found in multiple experimental systems (73-75). Li et al. found that this cytokine was effective in stimulating the growth of a subpopulation of cancer cells with characteristics of CSCs (74). As with IL-8, curcumin inhibits the production of IL-1β and other cytokines by monocytes and macrophages (62). Kloesch et al. found that curcumin caused significant antiinflammatory effects against fibroblast-like synoviocytes, by blocking IL-1β and IL-6 (32). Curcumin has been shown to block NF-ĸB activation induced by this cytokine in bone ANTICANCER RESEARCH 35: 599-614 (2015) 600 marrow stromal cells (76), human articular chondrocytes (77- 78) and colonic epithelial cells (79). Kalinski et al. have shown that IL-1β-induced NF-ĸB gene expression could be blocked by curcumin in two human chondrosarcoma cell lines (80). They also showed that curcumin blocked recruitment of the receptor-associated kinase (IRAK) to the IL-1 receptor, thus preventing signaling. Inhibition of IRAK likely occurs because of curcumin’s blockage of IRAK thiols. CXCR1 and CXCR2 Cytokines of the CXC family bind to transmembrane (7-TM) proteins on the target cell, primarily CXCR1 and CXCR2 (81-86). While CXCR2 binds multiple cytokines, including GROα (CXCL1) and GROβ (CXCL2), CXCR1 only binds IL-8 and CXCL6 (87). CXCR1 appears to be the most important mediator of IL-8-stimulated chemotaxis (85). These receptors occur not only on leukocytes but also on tumor cells, as well as on most normal cells (46, 88-89). Increased production of inflammatory cytokines can, thus, result in increased stimulation of CXCR1 and CXCR2 on tumor cells, particularly on CSCs (51, 53, 90). Studies on human cancer cells lines have confirmed that malignant cells respond to the effects of autocrine/paracrine IL-8 signaling, resulting in cell proliferation and metastases (91-95). Therefore, it has been suggested that these receptors may be primary targets for prevention of tumor growth and recurrence (58, 90, 96-98). Ginestier et al. has reported that in both human breast cancer cell lines and human breast cancer cells heterotransplanted into nude mice, the use of an anti-CXCR1 antibody, or of repertaxin, a CXCR1 inhibitor, not only caused a reduction in the number of bulk tumor cells but a major reduction in CSCs as well (48). Likewise, the CXCR2 antagonist A210397767 has been shown to inhibit leukocyte-infiltration into cancerous tissue, thus retarding tumor growth (99). In addition to blocking cytokine release, curcumin inhibits cytokine bioactivities by its actions against CXCR1 and CXCR2 (58, 100). For example, Hidaka et al. have reported that curcumin has major effects on cytokine function by both a reduction of IL-8 production and an effect on CXCR1 and CXCR2. Curcumin was found to regulate the “recycling” of CXCR1 and CXCR2 from the cytoplasm to the cell surface, thus preventing cytokine-induced receptor internalization (58). In another study, by the same investigators, Takahashi et al. reported that curcumin’s prevention of IL-8-induced neutrophil chemotaxis appears to occur because of the regulation by curcumin of the Rab11 trafficking molecule, a low-molecular weight G protein (101, 102), which in malignant cells associates more with CXCR1 and CXCR2. The anti-CSC effect induced by curcumin is caused by the stacking of the Rab 11 vesicle complex with CXCR1 and CXCR2 in the endocytic pathway (41). The Wnt Pathways The Wnt signaling pathways regulate multiple processes during embryonic development, as well as gene transcription, cell migration, cell proliferation and tissue homeostasis in the adult organism (103-107). These pathways occur in multiple species, including drosophila, where much of the original work was done, as well as mice and humans (103). Mutations involving the Wnt pathways have been shown to lead to the development of multiple diseases including type 2 diabetes, Alzheimer’s, autism, osteoporosis and schizophrenia (106, 108-113), as well as to multiple types of cancer (103, 105, 114-118). Wnt signaling regulates levels of the protein β- catenin. Wnt signaling is associated with a decrease in β- catenin phosphorylation, so β-catenin accumulates and, in turn, stimulates the genes for VEGF, cyclin D1 and c-Myc. Aberrant Wnt signaling and excessive levels of β-catenin can result in carcinogenesis and uncontrolled cell proliferation. Kanwar et al. studied colon carcinoma cells that had been made resistant to FOLFOX chemotherapy and were enriched with CSCs (119). These cells can be made to grow in spheroid colonies called colonospheres. Decreased levels of phosphorylated β-catenin, a marker of β-catenin degradation, and increasing levels of β-catenin were associated with an increased number of cells in the colonosphere that were positive for CD44+. Decreased levels of β-catenin were correlated with a decreased number of CSCs and decreased colonosphere formation. Similar results were found with mammospheres by Korkaya et al. (120). Zhao et al. developed a strain of β-catenin deficient mice and reported that the absence of β-catenin resulted in the impairment of selfrenewal of both normal hematopoetic stem cells and chronic myelogenous leukemia stem cells (121). Curcumin modulates Wnt signaling. Karkarala et al. have shown that curcumin can inhibit Wnt signaling and the formation of mammospheres in breast cancer cell lines, as well as in normal breast cell lines (122). Likewise, curcumin has been shown to cause a marked decrease in cell migration and invasion in a human osteosarcoma cell line (123). This effect was dose-dependent. In this study, no change in the cytosolic β-catenin was seen but there was a marked decrease in nuclear β-catenin with curcumin. Evidence indicates that curcumin can act at multiple points along the Wnt pathway. Xu et al. reported that curcumin induced apoptosis in a human hepatocellular carcinoma cell line by decreasing β-catenin activity, thus reducing stimulation of the β-catenin target genes (124). They suggested this was an effect of the maintenance of the β-catenin destruction complex by curcumin, which prevented axin recruitment to the cell membrane (124). In a human head and neck carcinoma cell line, MDA-1986, curcumin reduced cell growth by increasing activating factor 3, thus causing the inhibition of the receptor Frizzled-1 (125). Prasad studied the effects of curcumin on the human breast Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 601 cancer cell lines MCF-7 and MDA-MB-231 and found that curcumin blocked malignant cell growth at multiple sites along this pathway, causing suppression of β-catenin, cyclinD1, slug and dishevelled and also altering the levels of Ecadherin and GSK3β (126). Derivatives of curcumin have been shown to inhibit colon cancer cells by decreasing the amount of the transcriptional coactivator p300 (127). The Notch Pathway Like the Wnt pathways, the Notch pathway has been conserved among species through evolution. The Notch signaling pathway plays a critical role in regulating cell differentiation, cell proliferation and apoptosis (128-133). Notch signaling is known to regulate the functioning of normal stem cells (134-139). Aberrant Notch signaling has been implicated in the progression from Barrett’s esophagus to esophageal carcinoma (140-141), as well as in the development of carcinomas of the breast, lung and pancreas, of multiple myeloma and of other cancers (142-146). The role of the Notch pathway in the preservation of CSCs has been emphasized (8, 147). A ten-fold increase in mammosphere formation was seen after addition of a Notch activating peptide to a breast cancer cell line (139). Phillips showed that the number of breast cancer stem cells could be increased by the use of recombinant human erythropoetin, which stimulated the Notch pathway by induction of Jagged-1 (148). Curcumin acts to suppress tumor cells at multiple sites along the Notch pathway. Liu et al. showed that increasing doses of curcumin caused increasing inhibition of SMMC- 7721 hepatoma cells in culture and these changes paralleled decreases in NOTCH-1 mRNA and protein expression (149). Subramanian et al. showed that curcumin inhibited the formation of esophagospheres through its actions on the Notch pathway causing capsase 3 activation and reducing Notch-1 activation through reduction of γ-secretase complex proteins (142). Kong showed that curcumin inhibited Notch-1 activity in two prostate cancer cell lines by down-regulating the genes MT1-MMP and its target molecule MMP2 (150). Aziz et al. showed curcumin caused destruction of hepatoma cells through down-regulation of Notch-1 and its target genes HES1 and CyclinD1 (CCND1) (151). The Hedgehog Pathways Like the Wnt and Notch pathways, the Hedgehog pathways have a key role in embryonic development (152-154), as well as the regulation of normal stem cell activity (155-157). Three, closely related, pathways are known but the Sonic Hedgehog pathway (Shh) is the most investigated. Abnormal functioning of the Hedgehog pathways has been implicated in the development of many types of cancer and has been associated with stimulation of CSCs, thus, with an increased risk of tumor recurrence after therapy (158-161). It has also been shown that blockage of the Hedgehog pathway can suppress CSCs and reverse chemoresistance (162-164). Tumorigenesis occurs in these pathways because of the 7-transmembrane protein Smoothened. Smoothened is normally suppressed by the 12-transmembrane proteins Patched-1 and Patched-2. During aberrant Hedgehog signaling, one of the Hh proteins is released and binds to Patched, freeing Smoothened and leading to the activation of the transcription factors Gli2 and Gli3, which cause transcription of the target genes, such as GLI1, cyclinD (CCND1), cyclinE (CCNE), Patched 1 (PTCH1), c-MYC and n-MYC (165-167). Curcumin can inhibit these pathways by multiple mechanisms. Sun et al. studied the effects of curcumin on the pancreatic carcinoma cell line PANC-1 and found a marked inhibition of cell proliferation (168-169). Significant decreases in Shh and Gli1 expression were noted, suggesting one of curcumin’s many effects is through suppression of the Hedgehog pathway. Elamin et al. studied curcumin’s effect on medulloblastoma cells and found cell-cycle arrest at the G2/M phase. Down-regulation of Shh, Gli1 and Patched-1 was seen, as well as of effectors cyclinD1, c-Myc and n-Myc (170). Lim et al. utilized a unique polymeric nanoparticle formulation of curcumin against medulloblastoma and glioblastoma cell lines and found inhibition of the expression of Gli1 and Patched-1, as well as marked reduction in the number of CSCs expressing the stem cell marker CD133 (171). Slusarz reported that curcumin caused major reductions in GLI1 mRNA concentrations in transgenic prostate carcinoma (TRAMP) mice and in prostate carcinoma cell lines (172). The FAK/AKT/FOXO3A Pathway The FAK/AKT/FOXO3A pathway plays an important role in the regulation of normal stem cells (173-174). Aberrant signaling through the pathway can stimulate the formation of CSCs, resulting in tumor recurrence and the conferring of resistance to chemotherapy (175-178). Under normal conditions, activity of this pathway is suppressed by the phosphatase and tensin homolog (PTEN), which acts as a tumor suppressor gene (179-181). Inhibition of PTEN allows for uncontrolled pathway signaling, blocking apoptosis of CSCs. Loss or a deficiency of PTEN has been linked with many diseases, including autism (182). PTEN deficiency has been associated with myeloproliferative disorders and preleukemia (183-184). Loss of PTEN results in increases in CSCs in prostate cell lines (185), while epidemiological studies show that up to 70% of prostate cancer patients have lost a PTEN gene (186). Multiple investigators have shown that curcumin is effective in destroying CSCs by inhibition of this pathway. Shu et al. have shown that addition of curcumin to a human ANTICANCER RESEARCH 35: 599-614 (2015) 602 medulloblastoma cell line resulted in marked decreases in phosphorylated Akt and phosphoinositide 3-kinase (PI3K), markers of FAK/AKT/FOXO3A pathway activity (187). Likewise, Chen et al. have shown that curcumin inhibited focal adhesion kinase (FAK, PTK2) phosphorylation at multiple sites (TYR397, 407, 576, 577, 861 and 925) in HCT- 116 colon carcinoma cells, causing pathway suppression and allowing apoptosis (188). Yu et al. reported similar results (189). Wang et al. showed that curcumin could inhibit this pathway in human bladder carcinoma cells by increasing the activity of PTEN (190). Hussain et al. showed that addition of curcumin to T-cell acute lymphoblastic leukemia caused the de-phosphorylation of Akt and of FOXO transcription factor, thus inhibiting the FAK/AKT/FOXO3A pathway and allowing apoptosis of cancer cells to proceed (191). Wu reported that curcumin caused apoptosis in a nasopharyngeal carcinoma cell line by inducing p53 and FOXO3A, a downstream effector of PTEN (192). Curcumin and Normal Stem Cells The safety of curcumin has been long established, as it has been used for centuries as a dietary spice. The question arises as to why curcumin does not seem to have the same deleterious effects on normal stem cells (NSCs) as it does on CSCs. There are several possible reasons that curcumin has toxic effects on CSCs, while sparing NSCs. Curcumin has been shown to have a much greater uptake by malignant cells compared to normal cells. Kunwar et al. studied the differential uptake of curcumin and the fluorescence spectra of curcumin-loaded cells in two normal cell lines (NIH373 mouse fibroblast cells and a mouse spleen lymphocyte line) and in two malignant cell lines (MCF human breast carcinoma and EL4 murine T-cell lymphoma) (193). Much higher uptake was measured in the malignant lines. In addition, fluorescence intensity was at least 3-8 times greater in the two malignant cell lines. Since curcumin has been shown to accumulate more in cancer cells than in bulk tumor cells, it might be expected as well that it would accumulate more in CSCs compared to NSCs. Another explanation is that curcumin not only directly affects cells but their microenvironment as well. Under normal conditions, there is a delicate balance between proliferationpromoting and proliferation-inhibiting signals from the environment (194). Curcumin appears to shift the microenvironment around these cells to one that is adverse to proliferation of CSCs, but conducive to NSCs. As noted, curcumin has been shown to suppress the release of proinflammatory cytokines (Table I). A third explanation is that curcumin’s direct actions against CSCs may not be solely through its toxic effects. It has been suggested that it is possible to target CSCs not by causing cell death but by inducing these stem cells to differentiate. Many authors have suggested this as a strategy for depleting the CSC population and, thus, preventing recurrence (199-200). Almanaa et al. have suggested that induction of CSC differentiation may be one of the ways curcumin depletes CSCs. They tested cell lines that contained a large number (up to 40.4%) of ALDH1A1-stained cells with curcumin. After treatment, the cells with this stem cell marker were either markedly diminished or gone, suggesting either the destruction of the CSC population or their differentiation into less malignant cells (201). Studies have shown that curcumin indeed causes differentiation of both CSCs and NSCs. Gu et al. showed that curcumin can stimulate rat mesenchymal stem cell differentiation into osteoblasts (202). Likewise, Mujoo et al. showed curcumin could induce the differentiation of human embryonal stem cells (203). In another study, curcumin increased the differentiation rate of neural stem cells in rats (204). Curcumin was also shown to increase differentiation of mesenchymal stem cells in culture by suppression of NF-ĸB, one of the mechanisms by which curcumin attacks CSCs (205). Zhuang et al. showed that curcumin could cause the differentiation of glioblastoma– initiating cells in immunocompromised mice (206). Roy et al. have shown that difluorinated-curcumin could stimulate differentiation of colonic stem cells causing restoration of PTEN (207). Likewise, Batth et al. reported that curcumin could induce differentiation in a murine embryonal carcinoma cell line (208). These factors may help explain why curcumin has a less toxic effect against NSCs than on CSCs. Still, in view of curcumin’s activities at numerous sites along multiple cancer pathways, curcumin’s lack of substantial toxicity to Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 603 Table I. Curcumin: Suppression of key inflammatory cytokines. Cytokine Reference IL-6 (interferon-β2) 31-39, 59, 63 IL-8 (CXCL8) 31, 34, 35, 58-63, 79, 259 IL-1 32, 33, 62, 76-80, 259 TNF-α 31, 35, 36, 62, 63, 76, 78, 196, 259 MCP-1 (monocyte chemotactic protein-1) (CCL2) 31, 62, 257, 258 MIP-1α (macrophage inflammatory protein-α) 62 Interferon-γ 195, 196 IL-12 195, 196 IL-2 196 GROα (CXCL1) 197 GROβ (CXCL2) 197 SDF-1 (stromal cell-derived factor-1, CXCL12) 198 IP-10 (CXCL-10) 258 ANTICANCER RESEARCH 35: 599-614 (2015) 604 Effect on Pathway Effect on NSCs (Reference) Wnt ↓ Nuclear β-catenin (122*, 123, 124, 126, ↑ (204, 222) 127, 170*, 217, 224, 226, 227) ↓ c-Myc (123, 124, 170*, 223, 226, 227, 229, 268) ↓ Wnt 3 (127) ↑ (204, 222) ↓ Matrix metalloprotenase-2 (150, 219) ↓ Matrix metalloprotenase-9 (123, 229) ↑ Axin (124) ↓ (222) ↓ Frizzled-1 (125, 229) ↑ (222) ↓ SLUG (SNAI2) (126, 230, 242*) ↓ Dishevelled (126) ↑ (222) ↓ Transcriptional coactivator p300 (127) ↓ TcF/LeF (223, 226, 227, 229) ↑ (222) ↑ Adenomatous polyposis cell protein (229) ↓ (222) ↓ Nestin (206*) ↑ (222) ↑ β-tubulin (206*); ↓ (225) ↑ (222); ↓ (255) ↑ Wnt inhibitory factor-1 (WIF-1) (228) ↓ (222) ↓ BDNF (273) ↑ (272) ↓ EGFR (HER1) (244*) ↑ Dnmt 1 (DNA methyltransferase) (244*) ND – Neuro D1 ↑ (222) ND – DCX (Doublecortin) ↑ (222) ND – Neurogenin ↑ (222) ND – Neureglin ↑ (222) ND – Neuroligin ↑ (222) ND – Reelin ↑ (222) ND – Serotonin receptor 1A RNA ↑ (272) ND – Pax 6 (Aniridia type II protein) ↑ (222) ND – LRP5/6 ↑ (222) ND – DKK1 (Dickkorf-related protein 1) ↓ (220) ND – Wnt 1 ↔ (222) ND – Wnt 5 ↔ (222) Notch ↓ Notch-1 (142*, 149, 151, 243*, 266*) ↓ Notch-3 (243*) ↓ Jagged-1 (142*) ↑ Caspase 3 (142*, 190, 191, 215, ↓ (205, 232, 271+) 235, 236, 243*) ↑ Caspase 7 (239, 246*) ↑ Caspase 8 (235, 236) ↑ Caspase 9 (235, 239) ↓ (271+) ↑ PARP cleavage (215*, 235, 236, 239, ↓ (232) 243*, 245*) ↓ miR-21 (142*, 207*, 246*) ↓ miR-34a (142*) ↑ let 7a (142*) ↓ HES 1 (142*, 150, 151, 226*); ↔ (171*) ↔ HES 5 (171*) ↔ HEY 2 (171*) ↑ BAX (142*, 216) ↓ (270+) ↓ Presenilin 1 (142*) ↓ Presenilin 2 (142*) ↓ Nicastrin (142*) ↓ APH 1 (142*) ↓ PEN 2 (142*) ↑ p53 (192, 251); ↓ (267, 268) ↑ (233) ↑ p21/WAF1 (142*) ↑ (233) Effect on Pathway Effect on NSCs (Reference) Hedgehog ↓ Shh (168, 169, 170*) ↓ Gli-1(168, 169, 170*, 171*, 172) ↑ (222) ↓ Cyclin D1 (39, 123, 126, 142*, 151, 170*, 221, 224, 226, 229, 230, 239, 243*) ↓ Vimentin (169, 242*) ↓ Patched-1 (170*, 171*) ↑ Olig 2 (206*) ↑ E-cadherin (161, 188, 242*) ↑ GSK3β (126, 189, 191, 224, 234) ↓ (222) FAK ↓ Phosphorylation of Akt (170*, 171*, ↑ (269+) 187, 188, 189, 191, 207*) ↓ PI3K (187) ↓ VEGF (31, 219, 229, 230, 246*, 269) ↑ (269+); ↓(261**) ↓ VEGFR (269) ↑ (269+) ↓ Phosphorylated m-Tor/m-Tor (189, 269) ↑ (269+, 271+) ↓ HIF1α (hypoxia-inducible factor 1α) (269) ↑ (269+) ↓ Signal tranducer CD24 (188) ↑ Acetylation histone H1 (247*) ↔ Acetylation histone H2 (247*) ↑ Acetylation histone H3 (247*) ↓ (248) ↑ Acetylation histone H4 (247*) ↓ (248, 249) ↑ Acetylation histone H8 (247*) ↓ Bcl-2 (B-cell lymphoma 2) (142*, 170*, ↑ (270+) 171*, 190, 209, 215*, 216, 230, 239, 243*) ↓ Bcl- xL (142*, 170*, 217, 221, 235, 239, 243*, 266*, 268) ↓ SRC (241) ↑ (205) ↓ IGF-1 (insulin-like growth factor 1) (171*) ↓ IGF-2 (171*) ↓ IGF-1R (171*) ↓ P-IGF1Rβ (171*) ↑ IGFBP (250) ↓ (261**) ↑ Heme oxigenase-1 (214) ↑ (202, 261**) ↓ β-integrin (237) ↑ (205) ↓ Fibronectin (242*) ↑ PTEN (190, 207*, 246*) ↓ Conversion of LC3-1 (microtubule- ↑ (271+) associated protein-1 light chain 3) to LC3-11 (235) ↑ FOXO3a (192) ND – mlc 2 (myosin light chain 2) ↑ (233) ND – Homebox protein Nkx-2.5 ↑ (233) MAPK ↑ p38 MAPK (189, 209, 210, 211) ↑ (231) ↓ Survivin (BIRC5) (123, 209, 219, 220, 229, 241, 243*, 263) ↑ ERK (210, 212, 213) ; ↑ (205, 231); ↔(171*, 211) ↓ (233) ↑ JNK (210, 211, 212, 213, 233) ↓ (232, 261**) ↑ ATF 3 (Activating transcription factor 3) (125) ↓ ABCG2 (214*, 253*) ↓ ABCC1 (254*) ↓ Oct-4 (260) ↑ (255) ↓ GPX (glutamate peroxidase) (264) ↑ (261**) ↓ Cyclin B1 (219) Table II. continued Table II. Curcumin: Major actions against molecular targets along key CSC pathways. ormal tissues is significant. Table II lists important targets of curcumin along key CSC pathways. The assignment of these targets is somewhat arbitrary as many of these biomolecules are situated along the intersection of multiple pathways. It is clear, however, that curcumin often has different effects on CSCs and NSCs in these crucial pathways. For example, studies on CSCs have demonstrated that part of curcumin’s toxicity to CSCs involves suppression of molecular abnormalities in the Wnt pathway, such as its inhibition of β-catenin (122, 125-126). Curcumin has opposite effects on neural stem cells as it stimulates neurogenesis. Curcumin increases β-catenin, cyclin D1, dishevelled and frizzled but reduces expression of the components of the β-catenin destruction complex, including the tumor suppressors GSK-3β, APC (adenomatous polyposis cell protein) and axin. Curcumin has contrary, but doubly-beneficial, actions like inhibiting CSCs, while at the same time stimulating normal NSC function (204, 222). Acknowledgements The Authors wish to thank Diana C. Sordillo, M.S. for her review of the manuscript and her helpful suggestions. References 1 Gangemi R, Paleari L, Orengo AM, Cesario A, Chessa L, Ferrini S and Russo P: Cancer stem cells: A new paradigm for understanding tumor growth and progression and drug resistance. Curr Med Chem 16: 1688-1703, 2009. Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 605 Effect on Pathway Effect on NSCs (Reference) ↑ PKD1 (protein kinase D1) (115) ↓ Nanog (260) ↑(255) ↓ SOX-2 (SRY-box2) (260) ↑ miR-145 (260) ↓ EZH2 (Zesle homolog 2) (210, 230) ↓ beclin-1 (235) ↑ (271+) ↑ c-jun (211, 213, 241) ↓ AP-1 (activator protein-1) (256) ↓ (76) ↓CCL2 (MCP-1) (257) ↓ (76) ↓ pp2A (protein phosphatase 2A) (212) ↓ pp5 (protein phosphatase 5) (212) ↑ jun-B (213) ↑ ROS (reactive oxygen species) (235) ↓ (232, 261**) ↑ PPAR γ (peroxisome proliferator- ↓ (202) activated receptor γ) (238) ↓ Transcription factor sp-1 (188) ↓ Calmodulin (188) ↓ EphB2 (Ephrin type-B receptor 2) (188) ↓ AIP-1/Alix protein (230) ↓ PCNA (proliferating cell nuclear antigen) (230) ↓ Ki67 (230) ↑ GFAP (glial fibrillary acidic protein) (206*) ↑ C/EBPα (Ccaat-enhancer binding protein α) ↓ (202) (250) ND – RUNX 2 (Runt-related transcription ↑(202, 265) factor 2) ND – CSPG (chondroitin sulfate ↑ (205) proteoglycan) JAK/ ↓ DNA replication licensing STAT3 factor MCM2 (218, 219) ↓ STAT3-p (39, 171*, 218, 219, 221, 243*) ↓PDGFB (platelet-derived growth ↓ (261**) factor B) (262) Table II. continued Effect on Pathway Effect on NSCs (Reference) ↓ SOD-2 (superoxide dismutase 2, ↑ (261**) mitochodrial) (263) ↓ RB phosphorylation (243*) ↓ ICAM-1 (intercellular adhesion molecule; CD54) (219) ↓ CKD4 protein (39) ↔ STAT 1 (243*) ↔ STAT 6 (243*) ↓ Nitric oxide synthase (252) ↑ (233) ↑ SOCS 1 protein (247*) ↑ SOCS 3 protein (247*) ND – CXCL10 (IP-10) ↓ (258) NF-ĸB ↓ NF-ĸB (170*, 201*, 239, 246*, 268) ↓ (76, 205) ↓ Iĸ-Bα (239) ↓ (205) ↓ TNFα (35, 196, 263) ↓ (76) ↓ IL-1α (256) ↓ (76) ↓IL-1β (80) ↓ (205) ↓ IL-6 (239, 242*) ↓ s IL-6R (242*) ↓ SOX-9 (242*) ↓ ADAM 17 (ADAM metallopeptidase domain 17; TNF-α converting enzyme) (242*) ↓ Hsp90 (heat shock protein 90) ↓ COX2 (234, 236, 246*) ↑ (205) ↑ Cytochrome-C release (235, 236) ↓ c-FLIP (CFLAR) (235) ↓ X-linked IAP (BIRC4) (235), ↔ (215*) ↓ (205) ↓ cIAP-2 (BIRC3) (235) *Study done on lines with high proportion of CSCs. **Study done on induced pluripotent stem cell line. +Study done on human umbilical vein endothelial cells, not progenitor cells. ND- No data on curcumin’s effect on cancer cell lines. 2 Boman BM and Huang E: Human colon cancer stem cells: A new paradigm in gastrointestinal oncology. J Clin Oncol 26: 2826-2838, 2008. 3 Singh AK, Arya RK, Maheshwari S, Singh A, Meena S, Pandey P, Dormand O and Datta D: Tumor heterogeneity and cancer stem cell paradigm: Updates in concept, controversies and clinical relevance. Int J Cancer doi: 10.1002/ijc.28804, 2014. 4 Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkleman RM, Cusimano MD and Dirks PB: Identification of human brain tumor initiating cells. Nature 432: 396-401, 2004. 5 Rao G, Liu H, Li B, Hao J, Yang Y, Wang M, Wang X, Wang J, Jin H, Du L and Chen Q: Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemotherapeutic drugs. Acta Pharmacologica Sinica 34: 793- 804, 2013. 6 Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, Fiocco R, Foroni C, Dimeco F and Vescovi A: Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64: 7011-7021, 2004. 7 Ebben JD, Treisman DM, Zorniak M, Kutty RG, Clark PA and Kuo JS: The cancer stem cell paradigm: A new understanding of tumor development and treatment. Expert Opin Ther Targets 14: 621-632, 2010. 8 Fan X, Khaki L, Zhu T, Soules M, Talsma C, Gul N, Koh C, Zhang J, Li Y, Maciaczyk J, Nikkhah G, DiMeco F, Piccirillo S, Vescovi A and Eberhart C: Notch pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28: 5-16, 2010. 9 Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J and Chang JC: Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100: 672-679, 2008. 10 Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL and Clarke MF: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458: 780-783, 2009. 11 Kabos P, Haughian JM, Wang X, Dye WW, Finlayson C, Elias A, Horwitz KB and Sartorius CA: Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat 128: 45-55, 2010. 12 Iliopoulos D, Hirsch HA, Wang G and Struhl K: Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL-6 secretion. Proc Natl Acad Sci USA 108: 1397-1402, 2011. 13 Singh J, Simoes B, Howell S, Farnie G and Clarke R: Recent advances reveal IL-8 signaling as a potential key to targeting breast cancer stem cells. Breast Cancer Res 15: 210-218, 2013. 14 Korkaya H, Liu S and Wicha MS: Regulation of cancer stem cells by cytokine networks: Attacking cancer’s inflammatory roots. Clin Cancer Res 17: 6125-6129, 2011. 15 Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y and Noguchi S: Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 15: 4234-4241, 2009. 16 Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM and Chang JC: Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 106: 13820-13825, 2009. 17 Wang Y, Li LZ, Ye L, Niu XL, Liu X, Zhu YQ, Sun WJ and Liang YJ: Chemotherapy resistance induced by interlukin-6 in ovarian cancer cells and its signal transduction pathways. Zhonghua Fu Chan Ke Za Zhi 45: 691-698, 2010. 18 Waugh DJJ and Wilson C: The interleukin-8 pathway in cancer. Clin Cancer Res 14: 6735-6741, 2008. 19 Waldner MJ, Foersch S and Neurath MF: Interleukin-6 - A key regulator of colorectal cancer development. Int J Biol Sci 8: 1248-1253, 2012. 20 Goswami B, Mittal P and Gupta N: Correlation of levels of IL-6 with tumor burden and receptor status in patients of locally advanced carcinoma breast. Indian J Clin Biochem 28: 90-94, 2013. 21 Gado K, Domjan G, Hegyesi H and Falus A: Role of interleukin- 6 in the pathogenesis of multiple myeloma. Cell Biol Int 24: 195- 209, 2000. 22 Smith PC, Hobisch A, Lin DL, Culig Z and Keller ET: Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev 12: 33-40, 2001. 23 Leonard M, Ryan MP, Watson AJ, Schramek H and Healy E: Role of MAP kinase pathways in mediating IL-6 production in human primary mesangial and proximal tubular cells. Kidney Internat 56: 1366-1377, 1999. 24 Scheller J, Chalaris A, Schmidt-Arras D and Rose-John S: The pro- and anti-inflammatory properties of the cytokine interleukin- 6. BBA- Mol Cell Res 1813: 878-888, 2011. 25 Hodge DR, Hurt EM and Farrar WL: The role of IL-6 and STAT3 in inflammation and cancer. Eur. J. Cancer 41: 2502- 2512, 2005. 26 Rattigan Y, Hsu J-M, Mishra PJ, Glod J and Banerjee D: Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. Exp Cell Res 316: 3417-3424, 2010. 27 Ancrile B, Lim KH and Counter CM: Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev 21: 1714-1719, 2007. 28 Guthrie GJK, Roxburgh CSD, Richards CH, Horgan PG and McMillan DC: Circulating IL-6 concentrations link tumour necrosis and systemic and local inflammatory responses in patients undergoing resection for colorectal cancer. Brit J Cancer 109: 131-137, 2013. 29 Wang Y, Li L, Guo X, Jin X, Sun W, Zhang X and Xu RC: Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine 59: 228-236, 2012. 30 Shi Z, Yang WM, Chen LP, Yang DH, Zhou Q, Zhu J, Chen JJ, Huang RC, Chen ZS and Huang RP: Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res Treat 135: 737-747, 2012. 31 Jain SK, Rains J, Croad J, Larson B and Jones K: Curcumin supplementation lowers TNF-α, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-α, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid Redox Signal 11: 241–249, 2009. ANTICANCER RESEARCH 35: 599-614 (2015) 606 2 Kloesch B, Becker T, Dietersdorfer E, Kiener H and Steiner G: Anti-inflammatory and apoptotic effects of the polyphenol curcumin on human fibroblast-like synoviocytes. Int Immunopharmacol 15: 400-405, 2013. 33 Moriasi CM, Trevino C, Subramaniam D, Ramalingam S, Awasthi V, Shanjana A and Anant S: Curcumin regulates Interleukin-6 expression in colon cancer cells Cancer Res 71: 4606-4606, 2011. 34 Cohen AN, Veena MS, Srivatsan ES and Wang MB: Suppression of interleukin 6 and 8 production in head and neck cancer cells with curcumin via inhibition of Iĸβ kinase. Arch Otolaryngol Head Neck Surg 135: 190-197, 2009. 35 Bisht S, Feldmann G, Soni S, Ravi R, Karikar C, Maitra A and Maitra A: Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): A novel strategy for human cancer therapy. J Nanobiotechnol 5: 3, 2007. 36 Gulcubuk A, Altunatmaz K, Sonmez K, Haktanir-Yatkin D, Uzun H, Gurel A and Aydin S: Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis. J Vet Med A Physiol Pathol Clin Med 53: 49- 54, 2006. 37 Bharti AC, Donato N and Aggarwal BB: Curcumin (diferuloylmethane) inhibits constitutive and IL-6- inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 171: 3863-3871, 2003. 38 Liu Y, Fuchs J, Li C and Lin J: IL-6, a risk factor for hepatocellular carcinoma : FLLL32 inhibits IL-6 induced STAT3 phosphorylation in human hepatocellular cancer cells. Cell Cycle 9: 3423-3427, 2010. 39 Park J, Ayyappan V, Bae EK, Lee C, Kim BS, Kim BK, Lee YY, Ahn KS and Yoon SS: Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells. Mol Oncol 2: 317-326, 2008. 40 Wang Y, Qu Y, Niu XL, Sun WJ, Zhang XL and Li LZ: Autocrine production of interleukin-8 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cytokine 56: 365-375, 2011. 41 Takahashi M, Ishiko T, Kamohara H, Hidaka H,Ogawa M and Baba H: Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1, 6- heptadiene-3,5-dione) blocks the chemotaxis of neutrophils by inhibiting signal transduction through IL-8 receptors. Mediators Inflamm 2007: 10767, 2007. 42 Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, Elner SG and Strieter RM: Interleukin-8 as a macrophage-derived mediatior of angiogenesis. Science 258: 1798-1801, 1992. 43 Holmes WE, Lee J, Kuang WJ, Rice GC and Wood WI: Structure and functional expression of a human interleukin-8 receptor. Science 253: 1278-1280, 1991. 44 Abraham RT: Chemokine to the rescue: Interleukin-8 mediates resistance to PI3K-pathway-targeted therapy in breast cancer. Cancer Cell 22: 703-705, 2012. 45 Chuntharapai A and Kim KJ: Regulation of the expression of IL- 8 receptor A/B by IL-8: Possible functions of each receptor. J Immunol 155: 2587-2594, 1995. 46 Brat DJ, Bellail AC and Van Meir EG: The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7: 122-133, 2005. 47 Vlahopoulos S, Boldogh I, Casola A and Brasier AR : Nuclear factor-ĸβ-dependent induction of interleukin-8 gene expression by tumor necrosis factor α: Evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation. Blood 94: 1878-1889, 1999. 48 Ginestier C, Liu S and Wicha MS: CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 120: 485-487, 2010. 49 Yao C, Lin Y, Chua MS, Ye CS, Bi J, Li W, Zhu YF and Wang SM: Interleukin-8 modulates growth and invasiveness of estrogen receptor- negative breast cancer cells. Int J Cancer 121: 1949- 1957, 2007. 50 Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, Vermeulin PB and Dirix LY: Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival . Clin Cancer Res 10: 7157-7162, 2004. 51 Shi Q, Abbruzzese JL, Huang S, Fidler IJ, Xiong Q and Xie K: Constitutive and inducible interleukin-8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5: 3711-3721, 1999. 52 Freund A, Chauveau C, Brouillet JP, Lucas A, Lacroix M, Licznar A, Vignon F and Lazennec G: IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells. Oncogene 22: 256-265, 2003. 53 Inoue K, Slaton JW, Kim SJ, Perrotte P, Eve BY, Bar-Eli M, Radinsky R and Dinney CP: Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Res 60: 2290-2299, 2000. 54 Seaton A, Scullin P, Maxwell PJ, Wilson C, Pettigrew J, Gallagher R, O’Sullivan JM, Johnston PG and Waugh DJ: Interleukin-8 signaling promotes androgen independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. Carcinogenesis 29: 1148- 1156, 2008. 55 Zhu YM, Webster SJ, Flower D and Woll PJ: Interleukin- 8/CXCL8 is a growth factor for human lung cancer cells. Br J Cancer 91: 1970-1976, 2004. 56 Kitadai Y, Takahashi Y, Haruma K, Naka K, Sumii K, Yokozaki H, Yasui W, Mukaida N, Ohmoto Y, Kajiyama G, Fidler IJ and Tahara E: Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice. Br J Cancer 81: 647-653, 1999. 57 Singh S, Sadanandam A, Nannuru KC, Varney ML, Mayer-Ezell R, Bond R and Singh RK: Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival and angiogenesis. Clin Cancer Res 15: 2380-2386, 2009. 58 Hidaka H, Ishiko T, Furuhashi T, Kamohara H, Suzuki S, Miyazaki M, Ikeda O, Mita S, Setoguchi T and Ogawa M: Curcumin inhibits interleukin 8 production and enhances interleukin 8 receptor expression on the cell surface: Impact on human pancreatic carcinoma cell growth by autocrine regulation. Cancer 95: 1206-1214, 2002. 59 Raflee P, Nelson VM, Manley S, Wellner M, Floer M, Binion DG and Shaker R: Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): Role of PKC, MAPKs, and NF-ĸB. Am J Physiol Gastrointest Liver Physiol 296: G388-G398, 2009. 60 Wang X, Wang Q, Ives KL and Evers BM: Curcumin inhibits neurotensin-mediated interleukin-8 production and migration of HCT116 human colon cancer cells. Clin Cancer Res 12: 5346- 5355, 2006. Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 607 61 Biswas SK, McClure D, Jimenez LA, Megson IL and Rahman I: Curcumin induces glutathione biosynthesis and inhibits NF-ĸB activation and interleukin-8 release in alveolar epithelial cells : Mechanism of free radical scavenging activity. Antioxid Redox Signal 7: 32-41, 2005. 62 Abe Y, Hashimoto S and Horie T: Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39: 41-47, 1999. 63 Zhang QY, Mo ZN and Liu XD: Reducing effect of curcumin on expressions of TNF-alpha, IL-6 and IL-8 in rats with chronic nonbacterial prostatitis. Nat J Andrology 16: 84-88, 2010. 64 Weber A, Wasiliew P and Kracht M: Interleukin-1 (IL-1) pathway. Sci Signal 3:cm1.doi:10.1126/scisiggnal.3105cm1, 2010. 65 Dinarello CA: Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117: 3720-3732, 2011. 66 Contassot, E, Beer HD and French LE: Interleukin-1, inflammasomes, autoinflammation and the skin. Swiss Med Wkly 142: w13590.doi:10.4414/smw.2012.13590, 2012. 67 McKenzie RC, Oran A, Dinarello CA and Sauder DN: Interleukin-1 receptor antagonist inhibits subcutaneous B16 melanoma growth in vivo. Anticancer Res 16: 437-441, 1996. 68 Chirivi RG, Garofalo A, Padura IM, Mantovani A and Giavazzi R: Interleukin-1 receptor antagonist inhibits the augmentation of metastasis induced by interleukin-1 or lipopolysaccharide in a human melanoma/nude mouse system. Cancer Res 53: 5051- 5054, 1993. 69 Anasagasti MJ, Alvarez A, Martin JJ, Mendoza L and VidalVanaclocha F: Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4 mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice. Hepatology 25: 840- 846, 1997. 70 Vidal-Vanaclocha F., Amezaga C, Asumendi A, Kaplanski G and Dinarello CA: Interleukin-1 receptor blockade reduces the number and size of murine B16 melanoma hepatic metastases. Cancer Res 54: 2667-2672, 1994. 71 Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA and Apte RN: IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 100: 2645-2650, 2003. 72 Colasante A, Mascetra N, Brunetti M, Lattanzio G, Diodoro M, Caltagirone S, Musiani P and Aiello FB : Transforming growth factor beta 1, interleukin-8 and interleukin-1, in nonsmall cell lung tumors. Am J Respir Crit Care Med 156: 968- 973, 1997. 73 Jedinak A, Dudhgaonkar S and Silva D: Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 215: 242-249, 2010. 74 Li Y, Wang L, Pappan L, Galliher-Beckley A and Shi J: IL-1β promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Molecular Cancer 11: 87-94, 2012. 75 Kaler P, Augenlicht L and Klampfer L: Macrophage-derived IL- 1beta stimulates Wnt signaling and growth of colon cancer cells: A crosstalk interrupted by vitamin D3. Oncogene 28: 3892-3902, 2009. 76 Xu YX, Pindolia KR, Janakiraman N, Chapman RA and Gautam SC: Curcumin inhibits IL-1α and TNF-α induction of AP-1 and NF-ĸB DNA-binding activity in bone marrow stromal cells. Hematopathol Mol Hematol 11: 49-62, 1997-1998. 77 Henrotin Y, Clutterbuck AL, Allaway D, Lodwig EM, Harris P, Mathy-Hartert M, Shakbaei M and Mobasheri A: Biological actions of curcumin on articular chondrocytes. Osteoarthritis Cartilage 18: 141-149, 2010. 78 Shakibaei M, John T, Schulze-Tanzil G, Lehmann I and Mobasheri A: Suppression of NF-ĸβ activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloprotreinase-9 in human articular chondrocytes. Biochem Pharmacol 73: 1434-1445, 2007. 79 Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA and Sartor RB: Curcumin blocks cytokine-mediated NF-ĸβ activation and proinflammatory gene expression by inhibiting inhibitory factor I-ĸβ kinase activity. J Immunol 163: 3474-3483, 1999. 80 Kalinski T, Sel S, Hutten H, Ropke M, Roessner A and Nass N: Curcumin blocks interleukin-1 signaling in chondrosarcoma cells. PloS ONE 9: e99296, 2014. 81 Rossi D and Zlotnik A: The biology of chemokines and their receptors. Annu Rev Immunol 18: 217-242, 2000. 82 Lee J, Horuk R, Rice GC, Bennett GL, Camarato T and Wood WI: Characterization of two high affinity human interleukin-8 receptors. J Biol Chem 160: 16283-16287, 1992. 83 Holmes WF, Lee J, Kuang WI, Rice GC and Wood WI: Structure and functional expression of a human interleukin-8 receptor. Science 253: 1278-1280, 1991. 84 Murphy PM and Tiffany HL: Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253: 1280-1283, 1991. 85 Hammond MEW, Lapointe GR, Feucht PH, Hilt S, Gallegos CA, Gordon LA, Gieden MA, Mullenbach G and Tekamp-Olson P: IL-8 induces neutrophil chemotaxis predominantly via type I IL- 8 receptor. J Immunol 155: 1428-1433, 1995. 86 Rose JJ, Foley JF, Murphy PM and Venkatesan S: On the mechanism and significance of light-induced internalization of human neutrophil chemokine receptors CXCR1 and CXCR2. J Biol Chem 279: 24372-24386, 2004. 87 Ahuja SK and Murphy PM: The CXC chemokines growthregulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor. J Biol Chem 271: 20545-20550, 1996. 88 Murdoch C, Monk PN and Finn A: CXC chemokine receptor expression on human endothelial cells. Cytokine 11: 704-712, 1999. 89 Flynn G, Maru S, Loughlin J, Romero IA and Male D: Regulation of chemokine receptor expression in human microglia and astrocytes. J Neuroimmunol 136: 84-93, 2003. 90 Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, Brown M, Viens P, Xerri L, Bertucci F, Stassi G, Dontu G, Birnbaum D and Wicha MS: Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular structure. Cancer Res 69: 1302-1313, 2009. 91 Brew R, Erikson JS, West DC, Kinsella AR, Slavin J and Christmas SE: Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. Cytokine 12: 78-85, 2000. 92 Lang K, Niggeman B, Zanker KS and Entschladen F: Signal processing in migrating T24 human bladder carcinoma cells: ANTICANCER RESEARCH 35: 599-614 (2015) 608 ole of the autocrine interleukin-8 loop. Int J Cancer 99: 673- 680, 2002. 93 De Larco JE, Wuertz BRK, Rosner KA, Erickson SA, Gamache DE, Manivel JC and Furcht LT: A potential role for interlaukin- 8 in the metastatic phenotype of breast carcinoma cells. Am J Pathol 158: 639-646, 2001. 94 Kamohara H, Takahashi M, Ishko T, Ogawa M and Raha H: Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-α and leukemia inhibitory factor in pancreatic carcinoma cells: Impact of CXCL-8 as an autocrine growth factor. Int J Oncol 31: 627-632, 2007. 95 Takamori H, Oades ZG, Hoch OC, Burner M and Schraufstatter IU: Autocrine growth effect of IL-8 and GROα on a human pancreatic cancer cell line, Capan-1. Pancreas 21: 52-56, 2000. 96 Wu D, LaRosa GJ and Simon MI : G protein-coupled signal transduction pathways for interleukin-8. Science 261: 101-103, 1993. 97 Wang S, Wu Y, Hou Y, Guan X, Castelvetere MP, Oblak JJ, Banerjee S, Filtz TM, Sharkar F., Chen X, Jena B and Li C: CXCR2 macromolecular complex in pancreatic cancer: A potential therapeutic target in tumor growth. Transl Oncol 6: 216- 225, 2013. 98 Campbell LM, Maxwell PJ and Waugh DJJ: Rational and means to target pro-inflammatory interleukin-8 (CXCL8) signaling in cancer. Pharmaceuticals 6: 929-959, 2013. 99 Tazzyman S, Barry ST, Ashton S, Wood P, Blakey D, Lewis CE and Murdoch C: Inhibition of neutrophil infiltration into A549 lung tumors in vitro and in vivo using a CXCR2-specific antagonist is associated with reduced tumor growth. Int J Cancer 129: 847-858, 2011. 100 Shishodia S, Chaturvedi MM and Aggarwal BB: Role of curcumin in cancer therapy. Curr Probl Cancer 31:243-305, 2007. 101 Fan G, Lapierre LA, Goldenring JR, Sai J and Richmond A: Rab11 family interacting protein 2 and myosin Vb are required for CXCR2 recycling and receptor mediated chemotaxis. Mol Biol Cell 15: 2456-2469, 2004. 102 Stenmark H and Olkkonen VM: The Rab GTPase family. Genome Biol 2: Reviews 3007- Reviews 3007.7, 2001. 103 Nusse R: Wnt signaling and stem cell control. Cell Research 18: 523-527, 2008. 104 Komiya Y and Habas R: Wnt signal transduction pathways. Organogenesis 4: 68-75, 2008. 105 Klaus A and Birchmeier W: Wnt signaling and its impact on development and cancer. Nature Reviews Cancer 8: 387-398, 2008. 106 Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20: 781-810, 2004. 107 Rao T and Kuhl M: An updated overview on Wnt signaling pathways: A prelude for more. Circulation Research 106: 1798- 1806, 2010. 108 Welters HJ and Kulkarni RN: Wnt signaling: Relevance to betacell biology and diabetes. Trends Endocrinol Metab 19: 349-355, 2008. 109 Zhai L, Ballinger SW and Messina JL: Role of reactive oxygen species in injury-induced insulin resistance. Mol Endocrinol 25: 492-502, 2011. 110 Yoon JC, Ng A, Kim BH, Bianco A, Xavier RJ and Elledge SJ: Wnt signaling regulates mitochondrial physiology and insulin sensitivity. Genes Dev 24: 1507-1518, 2010. 111 Wan W, Xia S, Kalionis B, Liu L and Li Y: The role of Wnt signaling in the development of Alzheimer’s disease: A potential therapeutic target? BioMed Res Int 2014: 301575, 2014. 112 MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Developmental Cell 17: 9-26, 2009. 113 Inestrosa NC, Montecinos-Oliva C and Fuenzalida M: Wnt signaling: Role in Alzheimer’s disease and schizophrenia. J Neuroimmune Pharmacol 7: 788-807, 2012. 114 Howe L and Brown A: Wnt signaling and breast cancer. Cancer Biol Ther 3: 36-41, 2004. 115 Sundhram V, Chauhan SC, Ebeling M and Jaggi M: Curcumin attenuates β-catenin signaling in prostate cancer cells through activation of protein kinase D1. PLoS ONE 7 e35368, 2012. 116 Giles RH, Van Es JH and Clevers H: Caught up in a Wnt storm :Wnt signaling in cancer. Biochim Biophys Acta 1653: 1-24, 2003. 117 Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suarez A and Armas A: Beta-catenin expression in pattern in stage I and II ovarian carcinomas: Relationphip with beta-catenin gene mutations, clinicopathological feature, and clinical outcome. Am J Pathol 155: 527-536, 1999. 118 Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML and Rimm DL : Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res 59: 1811-1815, 1999. 119 Kanwar SS, Yu Y, Nautiyal J, Patel BB and Majumdar APN: The Wnt/β-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer 9: 212-224, 2010. 120 Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J and Clouthier SG: Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol 7: e1000121, 2009. 121 Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, Lagoo A and Reya T: Loss of β-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell 12: 528-541, 2007. 122 Kakarala M, Brenner DE, Khorkaya H, Cheng C, Tazi K, Ginestier C, Liu S, Dontu G and Wicha MS : Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122: 777-785, 2010. 123 Leow PC, Tian Q, Ong ZY, Yang Z and Ee PL: Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells. Invest New Drugs 28: 766-782, 2010. 124 Xu MX, Zhao L, Deng C, Yang L, Wang Y, Guo T, Li L, Lin J and Zhang L: Curcumin suppresses proliferation and induces apoptosis of human hepatocellular carcinoma cells via the Wnt signaling pathway. Int J Oncol 43: 1951-1959, 2013. 125 Yan C, Jamaluddin MS, Aggarwal B, Myers J and Boyd DD: Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther 4: 233-241, 2005. 126 Prasad CP, Rath G, Mathur S, Bhatnagar D and Ralhan R: Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 181: 263-271, 2009. 127 Ryu MJ, Cho M, Song JY, Yun YS, Choi IW, Kim DE, Park BS and Oh S: Natural derivatives of curcumin attenuate the Wnt/β- catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 377: 1304- 1308, 2008. Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 609 128 Miele L: Notch signaling. Clin Cancer Res 12: 1074-1079, 2006. 129 Nickoloff BJ, Qin JZ, Chaturvedi V, Denning MF, Bonish B and Miele L: Jagged-1 mediated activation of Notch signaling induces complete maturation of human keratinocytes through NF-ĸB and PPARγ. Cell Death Differ 9: 842-855, 2002. 130 Wilson A and Radtke F: Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Letts 580: 2860-2868, 2006. 131 Dievart A, Beaulieu N and Jolicoeur P: Involvement of Notch1 in the development of mouse mammary tumors. Oncogene 18: 5973-5981, 1999. 132 Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: Cell fate control and signal integration in development. Science 284: 770-776, 1999. 133 Mumm JS and Kopan R: Notch signaling: From the outside in. Develop Biol 228: 151-165, 2000. 134 Ohlstein B, Kai T, Decotto E and Spradling A: The stem cell niche: Theme and variations. Curr Opin Cell Biol 16: 693-699, 2004. 135 Ohlstein B and Spradling A: Multipotent drosophilia intestinal stem cells specify daughter cell fates by differential Notch signaling. Science 315: 988-992, 2007. 136 Joseph NM and Morrison SJ: Toward an understanding of the physiological function on mammalian stem cells. Dev Cell 9: 173-183, 2005. 137 Ohlstein B and Spradling A: The adult Drosophilia posterior midgut is maintained by pluripotent stem cells. Nature 439: 470- 474, 2006. 138 Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R and McKay RDG: Notch signaling regulates stem cell numbers in vitro and in vivo. Nature 442: 823-826, 2006. 139 Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM and Wicha MS: Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6: R605-R615, 2004. 140 Masuda S: Dysfunctional transforming growth factor-beta signaling with constitutively active Notch signaling in Barrett’s esophageal adenocarcinoma. Cancer 118: 1956-1957, 2012. 141 Peters JH and Avisar N: The molecular pathogenesis of Barrett’s esophagus: Common signaling pathways in embryogenesis metaplasia and neoplasia. J Gastrointest Surg 14(Suppl 1): S81- S87, 2010. 142 Subramaniam D, Ponnurangam S, Ramamoorthy P, Standling D, Battafarano RJ, Anant S and Sharma P: Curcumin induces cell death in esophageal cancer cells through modulating notch signaling. PloS One 7: e30590, 2012. 143 Collins BJ, Kleeberger W and Ball DW: Notch in lung development and lung cancer. Semin Cancer Biol 14: 357-364, 2004. 144 Wang Z, Li Y, Banerjee S and Sarkar FH: Emerging role of Notch in stem cells and cancer. Cancer Lett 279: 8-12, 2009. 145 Allenspach EJ, Maillard I, Aster JC and Pear WS: Notch signaling in cancer. Cancer Biol Ther 1: 466-476, 2002. 146 Houde C, Li Y, Song L, Barton K, Zhang Q, Godwin J, Nand S, Toor A, Aikan S, Smadia NV, Avet-Loiseau H, Lima CS, Miele L and Coignet LJ: Overexpression of the Notch ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104: 3697-3704, 2004. 147 Wang Z, Ahmad A, Li Y, Azmi A, Miele L and Sarkar FH: Targeting Notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Res 31: 1105-1113, 2011. 148 Phillips TM, Kim K, Vlashi E, McBride WH and Pajonk F: Effects of recombinant erythropoietin on breast cancer-initiating cells. Neoplasia 9: 1122-1129, 2007. 149 Liu ZC, Yang ZX, ZhouJS, Zhang HT, Huang QK, Dang LL, Liu GX and Tao KS: Curcumin regulates hepatoma cell proliferation and apoptosis through the Notch signaling pathway. Int J Clin Exp Med 7: 714-718, 2014. 150 Kong T, Wang Y, Xiao L and Liao L: Curcumin inhibits cell survival and migration by suppression of Notch-1 activity in prostate cancer cells. Int J Urol Nephrol 1: 35-39, 2013. 151 Aziz MTA, Khaled HM, Hindawi AE, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, Taha F and Ali WI: Effect of mesenchymal stem cells and a novel curcumin derivative on Notch-1 signaling in hepatoma cell line. BioMed Res Int 2013: e129629, 2013. 152 Ingham PW and McMahon AP: Hedgehog signaling in animal development: Paradigms and principles. Genes Dev 15: 3059- 3087, 2001. 153 Hooper JE and Scott MP: Communicating with Hedgehogs. Nat Rev Mol Cell Biol 6: 306-317, 2005. 154 McMahon AP, Ingham PW and Tabin CJ: Developmental roles and clinical significance of Hedgehog signaling. Curr Top Dev Biol 53: 1-114, 2003. 155 Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN and Bhatia M: Sonic hedgehog induces the proliferation of primitive human hematopietic cells via BMP regulation. Nature Immunol 2: 172-180, 2001. 156 Ahn S and Joyner AL: In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 437: 894-897, 2005. 157 Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P and Wicha MS: Hedgehog signaling and Bmi-1 regulate selfrenewal of normal and malignant human mammary stem cells. Cancer Res 66: 6063-6071, 2006. 158 Izrailit J and Reedijk M: Developmental pathways in breast cancer and breast tumor-initiating cells: Therapeutic inplications. Cancer Letters 317: 115-126, 2012. 159 Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M, Van Arsdale T, Beachy PA and Reya T: Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature 458: 776-779, 2009. 160 Karamboulas C and Ailles L: Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta 1830: 2481-2495, 2013. 161 Takezaki T, Hide T, Takanaga H, Nakamura H, Kuratsu J and Kondo T: Essential role of the Hedgehog signaling pathway in human glioma-intiating cells. Cancer Sci 102: 1306-1312, 2011. 162 Li SH, Fu J, Watkins DN, Srivastava RK and Shankar S: Sulforaphane regulates self-renewal of pancreatic cancer stem cells through the modulation of Sonic hedgehog-GLI pathway. Mol Cell Biochem 373: 217-227, 2013. 163 Huang FT, Zhuan-Sun YX, Zhuang YY, Wei SL, Tang J, Chen WB and Zhang SN: Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance. Int J Oncol 41: 1707-1714, 2012. ANTICANCER RESEARCH 35: 599-614 (2015) 610 164 Tang SN, Fu J, Nall D, Rodova M, Shankar S and Srivastava RK: Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics. Int J Cancer 131: 30-40, 2012. 165 Riobo NA, Saucy B, DiLizio C and Manning DR: Activation of heterotrimeric G proteins by Smoothened. PNAS 103: 12607- 12612, 2006. 166 Shen F, Cheng L, Douglas AE, Riobo NA and Mannig DR: Smoothened is a fully competent activator of the heterotrimeric G protein Gi. Mol Pharmacol 83: 691-697, 2013. 167 Varjosalo M and Taipale J: Hedgehog: Functions and mechanisms. Genes Dev 22: 2454-2472, 2008. 168 Sun XD and Liu XE: Curcumin induces apoptosis of pancreatic cancer cells by inhibiting Ras-ERK and Shh-Gli1 signal pathways. Chin J Pathophysiol 28: 996-1000, 2012. 169 Sun XD, Liu XE and Huang DS: Curcumin reverses the epithelial-mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep 29: 2401- 2407, 2013. 170 Elamin MH, Shinwari Z, Hendrayani SF, Al-Hindi H, Al-Shail E, Khafaga Y, Al-Kofide A and Aboussekhra A: Curcumin inhibits the Sonic Hedgehog signaling pathway and triggers apoptosis in medulloblastoma cells. Mol Carcinog 49: 302-314, 2010. 171 Lim KJ, Bisht S, Bar EE, Maitra A and Eberhart CG: A polymeric nanoparticle formulation of curcumin inhibits growth, clonogenicity and stem-like fraction in malignant brain tumors. Cancer Biol Ther 11: 464-473, 2011. 172 Slusarz A, Shenouda NS, Sakla MS, Drenkhahn SK, Narula AS, MacDonald RS, Besch-Williford CL and Lubahn DB: Common botanical compounds inhibit the Hedgehog signaling pathway in prostate cancer. Cancer Res 70: 3382-3390, 2010. 173 Song G, Ouyang G and Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9: 59-71, 2005. 174 Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, ArdenKC, Blenis J and Greenberg ME: Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857-868, 1999. 175 Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ and Bernards R: A functional genetic approach identifies the PI3K pathway as a major determinat of trastuzumab resistance in breast cancer. Cancer Cell 12: 395-402, 2007. 176 Han Z, Hong L, Han Y, Wu K, Han S, Shen H, Li C, Yao L, Qiao T and Fan D: Phospho Akt mediates multidrug resistance resistance of gastric cancer cells through regulation of P-gp, Bcl- 2 and Bax. J Exp Clin Cancer Res 26: 261-268, 2007. 177 Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, Stanbridge EJ and Lee EY: Cancer stem cells contribute to cisplatin resistance in BRAC1/p53-mediated mouse mammary tumors. Cancer Res 68: 3243-3250, 2008. 178 Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, Camponovo A, Etienne LL, Cavalli F and Mazzucchelli L: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97: 1139-1145, 2007. 179 Chu EC and Tarnawski AS: PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 10: RA235-RA241, 2004. 180 Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP: PTEN is essential for embryonic development and tumour suppression. Nat Genet 19: 348-355, 1998. 181 Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P and Pavletich NP: Crystal structure of the PTEN tumor suppressor: Implications for its phosphoinositide phosphatase activity and membrane association. Cell 99: 323-334, 1999. 182 Napoli E, Ross-Inta C, Wong S, Hung C, Fujisawa Y, Sakaguchi D, Angelastro J, Omanska-Klusek A, Schoenfeld R and Giulivi C: Mitochondrial dysfunction in Pten haplo-insufficient mice with social deficits and repetitive behavior: Interplay between Pten and p53. PLoS ONE 7: e42504, 2012. 183 Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, Haug JS, Rupp D, Porter-Westpfahl KS, Wiedemann LM, Wu H and Li L: PTEN maintains haematopoietic stem cells and acts in lineage choice and leukemia prevention. Nature 441: 518-522, 2006. 184 Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H and Morrison SJ: PTEN dependence distinguishes haemotopoietic stem cells from leukemia-initiating cells. Nature 441: 475-482, 2006. 185 Wang S, Garcia AJ, Wu M, Lawson DA, Witte ON and Wu H: PTEN deletion leads to the expression of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci USA 103: 1480-1485, 2006. 186 Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C and Pandolfi PP: Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725-730, 2005. 187 Shu M, Misi H, Guiyan L, Xiong Z, Yu L and Li T: Curcumin suppresses proliferation and induces apoptosis in human medulloblastoma cell via P13K/AKT signaling pathway. J Third Mil Med Univ 35: 518-522, 2013. 188 Chen CC, Sureshbabul M, Chen HW, Lin YS, Lee JY, Hong QS, Yang YC and Yu SL: Curcumin suppresses metastasis via Sp-1, FAK inhibition, and E-Cadherin upregulation in colorectal cancer. Evid Based Complement Alternat Med 2013: 541695, 2013. 189 Yu S, Shen G, Khor TO, Kim JH and Kong AN: Curcumin inhibits Akt/mTOR signaling through protein phosphatasedependent mechanism. Mol Cancer Ther 7: 2609-2620, 2008. 190 Wang J, Wang Z, Wang H, Zhao J and Zhang Z: Curcumin induces apoptosis in EJ bladder cancer cells via modulating CMyc and P13K/Akt signaling pathway. World J Oncol 2: 113- 122, 2011. 191 Hussain AR, Al-Rasheed M, Manogaran PS, Al-Hussain KA, Platanias LC, Al Kuraya K and Uddin S: Curcumin induces apoptosis via inhibition of P13-kinase/AKT pathway in acute Tcell leukemias. Apoptosis 11: 245-254, 2006. 192 Wu J, Tang Q, Zhao S, Zheng F, Wu Y, Tang G and Hahn SS: Extracellular signal-related kinase signaling-mediated induction and interaction of FOXO3a and p53 contribute to the inhibition of nasopharyngeal carcinoma cell growth by curcumin. Int J Oncol 45: 95-103, 2014. 193 Kunwar A, Bank A, Mishra B, Rathinasamy K, Pandey R and Priyadarsini KI: Qunatative cellular uptake, localization and cytoxicity of curcumin in normal and tumor cells. Biophysica Acta 1780: 673-679, 2008. Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 611 94 Li L and Neaves WB: Normal stem cells and cancer cells: The niche matters. Cancer Res 66: 4553-4557, 2006. 195 Fahey AJ, Robins RA and Constantinescu CS: Curcumin modulation of IFN-β and IL-12 signaling and cytokine induction in human T cells. J Cell Mol Med 11: 1129-1137, 2007. 196 Gao X, Kuo J, Jiang H, Deeb D, Liu Y, Divine G, Chapman RA, Dulchavsky SA and Gautam SC: Immunomodulatory activity of curcumin: Suppression of lymphocyte proliferation, development of cell-mediated cytotoxity, and cytokine production in vitro. Biochem Pharmacol 68: 51-61, 2004. 197 Bachmeier BE, Mohrenz IV, Mirisola V, Schleicher E, Romeo F, Hohneke C, Jochum M, Nerlich AG and Pfeffer U: Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis 29: 779-789, 2008. 198 Xiaoling MU, Jing Z, Fang X and Liangdan T: Curcumin inhibits invasion and metastasis in the human ovarian cancer cells SKOV3 by CXCL12-CXCR4 axis. African J Biotechnol 9: 8230- 8234, 2010. 199 Shekhani MT, Jayanthy AS, Maddodi N and Setaluri V: Cancer stem cells and tumor transdifferentiation: Implications for novel therapeutic strategies. Am J Stem Cell 2: 52-61, 2013. 200 Pham PV, Phan NLC, Nguyen NT, Truong NH, Duong TT, Le DV, Truong KD and Phan NK: Differentiation of breast cancer stem cells by knockdown of CD44: Promising differentiation therapy. J Transl Med doi.10.1186/1479-5876-9-269 2011. 201 Almanaa TN, Geusz ME and Jamasbi RJ: Effects of curcumin on stem-like cells in human esophageal squamous carcinoma cell lines. BMC Complementary and Alternative Medicine 12: 195, 2012. 202 Gu Q, Cai Y, Huang C, Shi Q and Yang H: Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation. Pharmacogn Mag 8: 202-208, 2012. 203 Mujoo K, Nikonoff LE, Sharin VG, Bryan NS, Kots AY and Murad F: Curcumin induces differentiation of embryonic stem cells through possible modulation of nitric oxide-cyclic GMP pathway. Protein Cell 3: 535-544, 2012. 204 Chen F, Wang X, Xiang X, Yuan J, Chu W, Xue X, Zhu H, Ge H, Zou M, Feng H and Lin J: Curcumin increased the differentiation rate of neurons in neural stem cells via Wnt singnaling in vitro study. J Surg Res doi:10.1016/j.jss.2014.06.026, 2014. 205 Buhrmann C, Mobasheri A, Matis U and Shakibaei M: Curcumin mediated suppression of nuclear factor-ĸB promotes chondrogenic differentiation of mesenchymal stem cells in a high-density co-culture microenvironment. Arthritis Res Ther 12: R127, 2010. 206 Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q and Liang Z: Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Science 103: 684-690, 2012. 207 Roy S, Yu Y, Padhye SB, Sarkar FH and Majumdar APN: Difluorinated-curcumin (CDF) restores PTEN expression downregulating miR-21. PLoS ONE 8:e68543, 2013. 208 Batth BK, Tripathi R and Srinivas UK: Curcumin-induced differentiation of mouse embryonal carcinoma PCC4 cells. Differentiation 68: 133-140, 2001. 209 Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA and Hoskin DW: Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling. Mol Carcinog 49: 13-24, 2010. 210 Hua WF, Fu YS, Liao YJ, Xia WJ, Chen YC, Zeng YX, Kung HF and Xie D: Curcumin induces down-regulation of EZH2 expression through the MAPK pathway in MDA-MB-435 human breast cancer cells. Eur J Pharmacol 637: 16-21, 2010. 211 Collett GP and Campbell FC: Curcumin induces c-jun Nterminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis 25: 2183-2189, 2004. 212 Han X, Xu B, Beevers CS, Odaka Y, Chen L, Liu L, Luo Y, Zhou H, Chen W, Shen T and Huang S: Curcumin inhibits protein phosphatase 2A and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells. Carcinogenesis 33: 868- 875,2012. 213 Yang CW, Chang CL, Lee HC, Chi CW, Pan JP and Yang WC: Curcumin induces the apoptosis of human monocytic leukemia THP-1 cells via the activation of JNK/ERK pathways. BMC Complementary and Alternative Medicine 12: 22, 2012. 214 Zhang H, Yu T, Wen L, Wang H, Fei D and Jin C: Curcumin enhances the effectiveness of cisplatin by suppressing CD133+ cancer stem cells in laryngeal carcinoma treatment. Exp Ther Med 6: 1317-1321, 2013. 215 Rao J, Xu DR, Zheng FM, Long ZJ, Huang SS, Wu X, Zhou WH, Huang RW and Liu Q: Curcumin reduces expression of Bcl-2, leading to apotosis in daunorubicin-insensitive CD34+ acute myeloid leukemia cell lines and primary sorted CD34+ acute myeloid leukemia cells. J Transl Med 9: 71, 2011. 216 Liu TY, Tan ZJ, Jiang L, Gu JF, Wu XS, Cao Y, Li ML, Wu KJ and Liu YB: Curcumin induces apoptosis in gallbladder carcinoma cell line GBC-SD cells. Cancer Cell International 13: 64, 2013. 217 Yallapu MM, Maher DM, Sundram V, Bell MC, Jaggi M and Chauhan SC: Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth. J Ovarian Res 3: 11, 2010. 218 Alexandrow MG, Song LJ, Altiok S, Gray J, Haura EB and Kumar NB: Curcumin: A novel Stat3 pathway inhibitor for chemoprevention of lung cancer. Eur J Cancer Prev 21: 407-412, 2012. 219 Yang CL, Liu YY, Ma YG, Xue YX, Liu DG, Ren Y, Liu XB, Li Y and Li Z: Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through janus kinase-STAT3 signaling pathway. PLoS ONE 7: e37960, 2012. 220 Glienke W, Maute L, Milz E, Bauer N and Bergmann L: Curcumin inhibits constitutive STAT3 phosphorylation in human pancreatic cancer cell lines and down-regulates survivin/BIRC5 gene expression. J Clin Oncol 25: 15030, 2007. 221 Mackenzie GG, Queisser N, Wolfson ML, Fraga CG, Adamo AM and Oteiza PI: Curcumin induces cell-arrest and apoptosis in association with the inhibition of constitutively active NF-ĸB and STAT3 pathways in Hodgkin’s lymphoma cells. Int J Cancer 123: 56-65, 2008. 222 Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK and Gupta KC: Curcumin-loaded manoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/β-catenin pathway. ACS Nano 8: 76-103, 2014. 223 Jaiswal AS, Marlow BP, Gupta N and Narayan S: β-cateninmediated transactivation and cell-cell adhesion pathways are ANTICANCER RESEARCH 35: 599-614 (2015) 612 mportant in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 21: 8414-8427, 2002. 224 He M, Li Y, Zhang L, Li L, Shen Y, Lin L, Zheng W, Chen L, Bian X, Ng HK and Tang L: Curcumin suppresses cell proliferation through inhibition of the Wnt/β-catenin signaling pathway in medulloblastoma. Oncol Rep 32: 173-180, 2014. 225 Gupta KK, Bharne SS, Rathinasamy K, Naik NR and Panda D: Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding. FEBS Journal 273: 5320-5332, 2006. 226 Qi LL, Wang JB, Wang HZ, Luo YT and Wu TX: Curcumin induces cleavage of β-catenin by activation of caspases and downregulates the β-catenin/Tcf signaling pathway in HT-29 cells. African J Biotechnol 8: 5527-5533, 2009. 227 Park CH, Hahm ER, Park S, Kim HK and Yang CH: The inhibitory mechanism of curcumin and its derivative against β- catenin/Tcf signaling. FEBS Letters 579: 2965-2971, 2005. 228 Liu YL, Yang HP, Gong L, Tang CL and Wang HJ: Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines. Mol Med Rep 4: 675-679, 2011. 229 Mimeault M and Batra SK: Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy. Chinese Med 6: 31, 2011. 230 Liu D and Chen Z: The effect of curcumin on breast cancer cells. J Breast Cancer 16: 133-137, 2013. 231 Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP and Lee J: Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 283: 14497-14505, 2008. 232 Hsuuw YD, Chang CK, Chan WH and Yu JS: Curcumin prevents methylglyoxal-induced oxidative stress and apoptosis in mouse embryonic stem cells and blastocysts. J Cell Physiol 205: 379- 386, 2005. 233 Mujoo K, Nikonoff LE, Sharin VG, Bryan NS, Kots AY and Murad F: Curcumin induces differentiation of embryonic stem cells through possible modulation of nitric oxide-cyclic GMP pathway. Protein Cell 3: 535-544, 2012. 234 Goel A, Boland CR and Chauhan DP: Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. Cancer Lett 172: 111-118, 2001. 235 Khan MA, Gahlot S and Majumdar S: Oxidative stress induced by curcumin promotes the death of cutaneous T-cell lymphoma (HuT-78) by disrupting the function of several molecular targets. Mol Cancer Ther 11: 1873, 2012. 236 Anto RJ, Mukhopadhyay A, Denning K and Aggarwal BB: Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: Its suppression by ectopic expression of Bcl-2 and Bcl-xl. Carcinogenesis 23: 143-150, 2002. 237 Kim HI, Huang H, Cheepala S, Huang S and Chung J: Curcumin inhibition of integrin (alpha6beta4)-dependent breast cancer cell motility and invasion. Cancer Prev Res (Phila) 1: 385-391, 2008. 238 Chen A and Xu J: Activation of PPAR{gamma} by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am J Physiol Gastrointest Liver Physiol 288: G447-G456, 2005. 239 Bharti AC, Donato N, Singh S and Aggarwal BB: Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101: 1053-1062, 2003. 240 Wu SY, Lee YR, Huang CC, Li YZ, Chang YS, Yang CY, Wu JD and Liu YW: Curcumin-induced heme oxygenase-1 expression plays a negative role for its anti-cancer effect in bladder cancers. Food Chem Toxicol 50: 3530-3536, 2012. 241 Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, Yamamura S, Ueno K and Dahiya R: Curcumin modulates micrRNA-203 mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila) 4: 1698-1709, 2011. 242 Yu CC, Tsai LL, Wang ML, Yu CH, Lo WL, Chang YC, Chiou GY, Chou MY and Chiou SH: miR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6- mediated paracrine effects in head and neck cancer. Cancer Res 73: 3425-3440, 2013. 243 Lin L, Liu Y, Li H, Fuchs J, Shibata H, Iwabuchi Y and Lin J: Targeting colon cancer stem cells using a new curcumin analogue, GO-YO30. Br J Cancer 105: 212-220, 2011. 244 Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH and Majumdar AP: Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl Oncol 4: 32-328, 2009. 245 Charpentier MS, Whipple RA, Vitolo MI, Boggs AE, Slovic J, Thompson KN, Bhandary L and Martin SS: Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote reattachment. Cancer Res 74: 1250, 2013. 246 Bao B, Ali S, Kong D, Sarkar SH, Wang Z, Banerjee S, Aboukameel A, Padhye S, Philip PA and Sarkar FH: Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer. PLoS ONE 6: e17850, 2011. 247 Chen CQ, Yu K, Yan QX, Xing CY, Chen Y, Yan Z, Shi YF, Zhao KW and Gao SM: Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases. Carcinogenesis 34: 1442-1449, 2013. 248 Kang SK, Cha SH and Jeon HG: Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev 15: 165-174, 2006. 249 Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, Hammer RE and Hsieh J: The master negative regulator REST/NRSF controls adult neurogenesis by restraing the neurogenic program in quiescent stem cells. J Neurosci 31: 9772-9786, 2011. 250 Chang KW, Hung PS, Lin IY, Hou CP, Chen LK, Tsai YM and Lin SC: Curcumin up-regulates insulin-like growth factor binding protein-5 (IGFBP-5) and C/EBPα during oral cancer suppression. Int J Cancer 127: 9-20, 2010. 251 Bae YH, Ryu JH, Park HJ, Kim KR, Wee HJ, Lee OH, Jang HO, Bae MK, Kim KW and Bae SK: Mutant p53-Notch signaling axis in involved in curcumin-induced apoptosis of breast cancer cells. Korean J Physiol Pharmacol 17: 291-297, 2013. 252 Song MY, Yim JY, Yim JM, Kang IJ, Rho HW, Kim HS, Yhim HY, Lee NR, Song EK, Kwak JY, Sohn MH and Yim CY: Use of curcumin to decrease nitric oxide production during the induction of antitumor responses by IL-2. J Immunother 34: 149-164, 2011. 253 Chearwae W, Shukla S, Limtrakul P and Ambudkar SV: Modulation of the function of the multidrug resistance-linked ATPbinding cassette transporter ABCG2 by the cancer chemopreventive agent curcumin. Mol Cancer Ther 5: 1995-2006, 2006. Sordillo and Helson: Curcumin and Cancer Stem Cells (Review) 613 54 Chearwae W, Wu CP, Chu HY, Lee TR, Ambudkar SV and Limtrakul P: Curcuminoids purified from turmeric powder modulate the function of human multidrug resistance protein 1 (ABCC1). Cancer Chemother Pharmacol 57: 376-388, 2006. 255 Yanes O, Clark J, Wong DM, Patti GJ, Sanchez-Ruiz A, Benton HP, Trauger SA, Desponts C, Ding S and Siuzdak G: Metabolic oxidation regulates embryonic stem cell differentiation. Nature Chem Biol 6: 411, 2010. 256 Das L and Vineyak M: Curcumin attenuates carcinogenesis by down regulating proinflammatory cytokine interleukin-1 (IL- 1αand IL-1β) via modulation of AP-1 and NF-IL6 in lymphoma bearing mice. Int Immunopharmacol 20: 141-147, 2014. 257 Herman JG, Stadelman HL and Roselli CE: Curcumin blocks CCL2-induced adhesion, motility and invasion, in part, through down-regulation of CCL2 expression and proteolytic activity. Int J Oncol 34: 1319-1327, 2009. 258 Xu YX, Pindolia KR, Janakiraman N, Noth CJ, Chapman RA and Gautam SC: Curcumin, a compound with anti-inflammatory and anti-oxidant properties, down regulates chemokine expression in bone marrow stromal cells. Exp Hematol 25: 413- 422, 1997. 259 Ahmed MM, Khan A and Rainsford KD: Synthesis of thiophene and NO-curcuminoids for anti-inflammatory and anti-cancer activities. Molecules 18: 1483-1501, 2013. 260 Tahmasebi Mirgani M, Isacchi B, Sadeghizadeh M, Marra F, Bilia AR, Mowla SJ, Najafi F and Babaei E: Dendrosomal curcumin nanoformulation downregulates pluripotency genes via miR-145 activation in U87MG glioblastoma cells. Int J Nanomedicine 9: 403-417, 2014. 261 Chang YC, Chang WC, Hung KH, Yang DM, Cheng YH, Liao YW, Woung LC, Tsai CY, Hsu CC, Lin TC, Liu JH, Chiou SH, Peng CH and Chen SH: The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: Identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress. Front Aging Neurosci doi:10.3389/fnagi.2014.00191, 2014. 262 Utpadel D, Goldbrunner R, Lange M, Shan B, Schaaf C, Curic S, Onofri C, Stalla GK and Renner U: Studies on the role of platelet-derived growth factor (PDGF) in human meningiomas. Exp Clin Endocrinol Diabetes 116: N22, 2008. 263 Aravindan S, Natarajan M, Herman TS, Awasthi V and Aravindan N: Molecular basis of ‘hypoxic’ breast cancer cell radio-sensitization: Phytochemicals converge on radiation induced Rel signaling. Rad Oncol 8: 46, 2013. 264 Aziza SAH, Abdel-Aal SA and Mady HA: Chemopreventive effect of curcumin on oxidative stress, antioxidant status, DNA fragmentation and caspase-9 gene expression in 1,2- dimethylhydrazine-induced colon cancer in rats. American J Biochem Mol Biol 4: 22-34, 2014. 265 Gu QL, Cai Y, Huang C and Yang HL: Effect of curcumin on osteogenic differentiation of rat bone marrow mesenchymal stem cells. Chinese J Tissue Eng Res 16: 5057-5061, 2012. 266 Wang Z, Zhang Y, Banerjee S, Li Y and Sarkar FH: Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106: 2503-2513, 2006. 267 Moos PJ, Edes K, Mullaly JE and Fitzpatrick FA: Curcumin impairs tumor suppressor p53 function in colon cancer cells. Carcinogenesis 25: 1611-1617, 2004. 268 Han SS, Chung ST, Robertson DA, Ranjan D and Bondada S: Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. Clin Immunol 93: 152-161, 1999. 269 Fan S, Xu Y, Li X, Tie L, Pan Y and Li X: Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models : in silico, in vitro and in vivo studies. Biochimica et Biophysica Acta 1842: 1742-1754, 2014. 270 Hua WM, Liang ZQ, Fang Y, Gu ZL and Guo CY: Mechanisms of curcumin protecting endothelial cells against ischemia and reperfusion injury. Chinese Pharmacol Bull 8: 13,2009. 271 Han J, Pan XY, Xu Y, Xiao Y, An Y, Tie L, Pan Y and Li XJ: Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy 8: 812-825, 2012. 272 Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC and Ogle WO: Curcumin reverses impaired hippocampal neurogenesis and increases seratonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res 1162: 9-18, 2007. 273 Wang YD, Hu Y and Sun CY: Inhibitory effect of curcumin on angiogenesis induced by brain derived neurotrophic factor from multiple myeloma cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi 14: 70-74, 2006. Received September 14, 2014 Revised October 19, 2014 Accepted October 24, 2014