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[46]
[44]
were significantly reduced. Wang et al. showed that proteins. In the nucleus, β-catenin binds to the T-cell factor/
treatment with curcumin resulted in the activation of Chk1 lymphocyte enhancer factor, transcription factors and
mediated G2 checkpoint which caused the induction of activates the expression of target genes like c-myc, VEGF,
G2/M arrest and resistance of cancerous cells to curcumin- cyclin -D1, that results in cell proliferation. Curcumin has
[52]
induced apoptosis. In hepatoma cell lines Chk1-mediated been shown to interrupt this pathway and thus suppress
activation of G2 checkpoint was required for curcumin the expression of β-catenin target genes like c-myc, VEGF,
induced G2/M arrest. Chk1 inhibition reversed this arrest cyclin-D. Curcumin has been reported to suppress cell
significantly and sensitizes curcumin resistant cells to proliferation and induced apoptosis by interrupting wnt
apoptosis. Single knockdown of Chk1 in Hep3B cells signaling via decreasing β-catenin activity. Curcumin
[53]
caused the abrogation of curcumin-induced G2/M arrest and its reduced analogue tetrahydrocurcumin showed
[54]
and decreased phosphorylation of Cdk1. Thus G2/M arrest anti-proliferative effects on HepG2 cell lines. HepG2
is Chk1-mediated and may be responsible for the resistance cells (hepatoma cell line) when treated with novel
of cancer cells to curcumin-induced apoptosis. [46] curcumin derivative and mesenchymal stem cells showed
a significantly decrease of proliferation rate as compared
Caspase-3 is the key member of caspase family proteins to the control group. Xu et al. found that curcumin
[51]
[53]
that are crucial in apoptosis. The pro-apoptotic effect significantly suppressed the cell proliferation, decreased
of curcumin was assessed by measurement of caspase-3 the β-catenin accumulation and induced apoptosis in
[47]
activity. Dai et al. demonstrated that curcumin human HCC cell lines BEL-7402 and QGY-7703 in a dose
significantly elevated the activity of caspase-3. dependent manner. A dose dependent decrease in the
expressions of c-myc and VEGF was also reported. Thus
Tumor necrosis factor-related apoptosis inducing ligand curcumin attenuated wnt signals in HCC cells.
(TRAIL) can induce apoptosis in cancer cells by binding
to four types of membrane bound death receptors (DR4, Blockade of the Hedgehog pathway
DR5, DcR1 and DcR2). Jung et al. established that The Hedgehog pathway is another potential target for
[48]
curcumin sensitizes human renal cancer cells to TRAIL cancer stem cell eradication. In liver cells, the suppression
mediated apoptosis. Membrane bound death receptors of the Sonic Hedgehog pathway by small interfering RNA
DR4 and DR5 have a conserved cytoplasmic region called decreased HCC cell proliferation also chemosensitized the
the death domain which is necessary for TRAIL-induced cells to 5-fluorouracil and induction of cell apoptosis.
[55]
apoptosis. TRAIL induces apoptosis only in the cancer In HB, blocking the Hh Hedgehog signaling pathway
[48]
cells without any toxicity to normal cells because normal with an antagonist cyclopamine strongly inhibited cell
cells have decoy receptors on their surface. [49] proliferation of HB cell lines. A significant decrease in
[56]
expression of Notch1, Hes1 and cyclin D1 was observed in
Notch signaling can either behave as an oncogene or as HepG2 cells upon treatment of hepatoma cell lines (HepG2)
a tumor suppressor. When the pathway is unregulated, with mesenchymal stem cells conditioned medium (MSCs
it behaves as an oncogene and hence it results in CM) and novel curcumin derivative (NCD). Pre-treatment
[51]
increased cell proliferation, prevention of differentiation of MSCs with NCD resulted in a more significant decrease
and inhibition of apoptosis. Aziz et al. proved that in the expression of these genes. Thus NCD and MSCs had
[50]
[51]
curcumin has inhibitory effects on Notch1 signaling and synergistic effect in suppression of Notch1 signaling. [51]
its target genes (Hes1 and cyclin D1).
Induce differentiation of cancer stem cell
Cytotoxic/anti-proliferation activity of curcumin Cancer stem cells comprising a small proportion of cancer
Curcumin has been demonstrated to inhibit the cells sustain tumor growth and are more resistant to
proliferation of HepG2 cells (Hepatoma cell line) in a dose conventional chemotherapy than other more differentiated
and time dependent manner in in vitro studies. Curcumin cancer cells. Malignancy may thus be treated by inducing
[47]
demonstrates anti-proliferative action by blocking two the differentiation of cancer stem cells and thus making
important pathways; the Wnt signaling pathway and the them lose their self-renewal property. Curcumin has been
Hedgehog pathway. Both these pathways affect the cancer shown to induce differentiation of embryonic stem cells
stem cells. through possible modulation of nitric oxide-cyclic GMP
pathway. [57]
Blockade of the Wnt signaling pathway
Wnt signaling pathways have important role in Anti-antiangiogenic effects of curcumin
carcinogenesis as well as embryonic development. Wnt Active neovascularisation is a predominant feature in HCC
proteins can activate different pathways but canonical and supports tumor growth. Angiogenesis starts when
wnt/β-catenin pathway is the most studied. In the absence tumor cells start sending signals to the nearby surrounding
of wnt proteins, β-catenin is targeted to the destruction normal host tissue and encourage the release of signaling
complex for its phosphorylation at specific sites, β-catenin molecules that initiate and promote angiogenesis. This
accumulates and recruited to the nucleus by Bcl-9 adaptor angiogenesis provides the tumor cells with oxygen and

66 Hepatoma Research | Volume 2 | March 9, 2016