Linkage of Curcumin-Induced Cell Cycle Arrest and Apoptosis by Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1

Srivastava, Rakesh K.; Chen, Qinghe; Siddiqui, Imtiaz A.; Sarva, Krishna; Shankar, Sharmila

doi:10.4161/cc.6.23.4951

Cited by 160 publications

(122 citation statements)

References 84 publications

(103 reference statements)

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“…Multiple mechanisms of action are likely responsible for Curcumin various effects on cancer cells: G1/S arrest and apoptosis induction have been observed other than the mitotic block in different tumor cell lines [18][19][20]. Experimental evidence reveals a multitude of molecular targets, including transcription factors, cell cycle proteins, enzymes, cell surface adhesion protein and cytokines [21,22].…”

Section: Introductionmentioning

confidence: 99%

Curcumin derivatives: Molecular basis of their anti-cancer activity

Basile

Ferrari

Lazzari

et al. 2009

Biochemical Pharmacology

164

129

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Curcumin, a phenolic compound from the plant Curcuma longa L., has shown a wide-spectrum of chemopreventive, anti-oxidant and anti-tumor properties. Although its promising chemotherapeutic activity, preclinical and clinical studies highlight Curcumin limited therapeutic application due to its instability in physiological conditions. To improve its stability and activity, many derivatives have been synthesized and studied, among which bis-DemethoxyCurcumin (bDMC) and diAcetylCurcumin (DAC). In this report, we show that both bDMC and DAC are more stable than Curcumin in physiological medium. To explore the mechanism of their chemotherapeutic effect, we studied their role in proliferation in the HCT116 human colon cancer cells. We correlated kinetic stability and cellular uptake data to their biological effects. Both bDMC and DAC impair correct spindles formation and induce a p53-and p21 CIP1/WAF1 -independent mitotic arrest, which is more stable and long-lasting for bDMC. A subsequent p53/p21 CIP1/WAF1 -dependent inhibition of G1 to S transition is triggered by Curcumin and DAC as a consequence of the mitotic slippage, preventing postmitotic cells from re-entering the cell cycle. Conversely, the G1/S arrest induced by bDMC is a direct effect of the drug and concomitant to the mitotic block. Finally, we demonstrate that bDMC induces rapid DNA double-strand breaks, moving for its possible development in anti-cancer clinical applications.

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Section: Introductionmentioning

confidence: 99%

Curcumin derivatives: Molecular basis of their anti-cancer activity

Basile

Ferrari

Lazzari

et al. 2009

Biochemical Pharmacology

164

129

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“…During DNA damage, cells are blocked in G2/M phase to provide time to repair damaged DNA (Molinari, 2000;Abraham, 2001), or lead to apoptotic cell death in case of severe DNA damage . Several studies have indicated that curcumin induces cell cycle arrest and apoptosis in various human cancer cells (Park et al, 2006;Tan et al, 2006;Srivastava et al, 2007;Weir et al, 2007;Lin et al, 2008;Mackenzie et al, 2008;Sun et al, 2008). This study investigates the mechanism of DNA damage-mediated cell cycle arrest by curcumin in pancreatic cancer cells.…”

Section: Curcumin Causes Dna Damage and Induces Apoptosismentioning

confidence: 99%

“…Inhibition of cell growth and induction of apoptosis is the common mechanism by which curcumin shows its anticancer effects. Accumulating evidence suggests the involvement of multiple-signaling pathways by which curcumin causes growth suppression of human cancer cells (Cheng et al, 2001;Hidaka et al, 2002;Bharti et al, 2003;Kim et al, 2003;Shishodia et al, 2003;Blasius et al, 2006;Lev-Ari et al, 2006;Mitra et al, 2006;Park et al, 2006;Tan et al, 2006;Aggarwal et al, 2007;Aoki et al, 2007;Deeb et al, 2007;Fahey et al, 2007;Lin et al, 2007Lin et al, , 2008Marín et al, 2007;Shankar and Srivastava, 2007;Srivastava et al, 2007;Weir et al, 2007;Binion et al, 2008;Freudlsperger et al, 2008;Ji et al, 2008;Kasinski et al, 2008;Mackenzie et al, 2008;Shankar et al, 2008;Sun et al, 2008). Phase I clinical trials of curcumin demonstrated encouraging chemopreventive effects in patients with high-risk or pre-malignant lesions.…”

mentioning

confidence: 99%

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells

2009

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Curcumin has been shown to inhibit the growth of various types of cancer cells; however, at concentrations much above the clinically achievable levels in humans. The concentration of curcumin achieved in the plasma after oral administration in humans was estimated to be around 1.8 mM. Here, we report that treatment of BxPC-3 human pancreatic cancer cells with a low and single exposure of 2.5 mM curcumin for 24 h causes significant arrest of cells in the G2/M phase and induces significant apoptosis. Immunoblot studies revealed increased phosphorylation of H2A.X at Ser-139 and Chk1 at Ser-280 and a decrease in DNA polymerase-b level in curcumin-treated cells. Phosphorylation of H2A.X and Chk1 proteins are an indicator of DNA damage whereas DNA polymerase-b plays a role in the repair of DNA strand breaks. Normal immortalised human pancreatic ductal epithelial (HPDE-6) cells remained unaffected by curcumin treatment. In addition, we also observed a significant increase in the phosphorylation of Chk1 at Ser-345, Cdc25C at Ser-216 and a subtle increase in ATM phosphorylation at Ser-1981. Concomitant decrease in the expressions of cyclin B1 and Cdk1 were seen in curcumin-treated cells. Further, curcumin treatment caused significant cleavage of caspase-3 and PARP in BxPC-3 but not in HPDE-6 cells. Silencing ATM/Chk1 expression by transfecting BxPC-3 cells with ATM or Chk1-specific SiRNA blocked the phosphorylation of ATM, Chk1 and Cdc25C and protected the cells from curcumin-mediated G2/M arrest and apoptosis. This study reflects the critical role of ATM/Chk1 in curcumin-mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells.

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“…First, although a role for bTREK-1 channels in the therapeutic actions of curcumin hasn't been demonstrated, several interesting possibilities exist. Most notably, curcumin shows promise in the treatment of human prostate cancer, where it induces apoptosis of prostate cancer cells [25][26][27]. Remarkably, it has been shown that TREK-1 K + channels are expressed in human prostate cancers, but not in normal prostate cells.…”

Section: Discussionmentioning

confidence: 99%

Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells

Enyeart

Liu

Enyeart

2008

Biochemical and Biophysical Research Communications

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Bovine adrenal zona fasciculata (AZF) cells express bTREK-1 K + channels that set the resting membrane potential. Inhibition of these channels by adrenocorticotropic hormone (ACTH) is coupled to membrane depolarization and cortisol secretion. Curcumin, a phytochemical with medicinal properties extracted from the spice turmeric, was found to modulate both bTREK-1 K + currents and cortisol secretion from AZF cells. In whole-cell patch clamp experiments, curcumin inhibited bTREK-1 with an IC 50 of 0.93μM by a mechanism that was voltage-independent. bTREK-1 inhibition by curcumin occurred through interaction with an external binding site and was independent of ATP hydrolysis. Curcumin produced a concentration-dependent increase in cortisol secretion that persisted for up to 24 h. At a maximally effective concentration of 50 μM, curcumin increased secretion as much as10-fold. These results demonstrate that curcumin potently inhibits bTREK-1 K + channels and stimulates cortisol secretion from bovine AZF cells. The inhibition of bTREK-1 by curcumin may be linked to cortisol secretion through membrane depolarization. Since TREK-1 is widely expressed in a variety of cells, it is likely that some of the biological actions of curcumin, including its therapeutic effects, may be mediated through inhibition of these K + channels.

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Linkage of Curcumin-Induced Cell Cycle Arrest and Apoptosis by Cyclin-Dependent Kinase Inhibitor p21/WAF1/CIP1

Cited by 160 publications

References 84 publications

Curcumin derivatives: Molecular basis of their anti-cancer activity

Curcumin derivatives: Molecular basis of their anti-cancer activity

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells

Curcumin inhibits bTREK-1 K+ channels and stimulates cortisol secretion from adrenocortical cells

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