My success with Curing 2007 Stage IV Metastised Prostate Cancer with a PLANT BASED DIET. Also Baking Soda for high pH. MANY have duplicated my success.
Wednesday, March 25, 2015
Turmeric's 'Smart Kill' Properties Put Chemo & Radiation To Shame
Turmeric's 'Smart Kill' Properties Put Chemo &
Radiation To Shame
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.
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.
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:
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,
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kinase D1) (115) ↓ Nanog (260) ↑(255) ↓ SOX-2 (SRY-box2) (260) ↑ miR-145 (260)
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factor B) (262) Table II. continued Effect on Pathway Effect on NSCs
(Reference) ↓ SOD-2 (superoxide dismutase 2, ↑ (261**) mitochodrial) (263) ↓ RB
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14, 2014 Revised October 19, 2014 Accepted October 24, 2014
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