Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating akt and p38 mAPK

Weir, Nathan M.; Selvendiran, Karuppaiyah; Kutala, Vijay Kumar; Tong, Liyue; Vishwanath, Shilpa; Rajaram, Murugesan V. S.; Tridandapani, Susheela; Anant, Shrikant; Kuppusamy, Periannan

doi:10.4161/cbt.6.2.3577

Cited by 253 publications

(193 citation statements)

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“…Activation of caspase-3 followed by PARP cleavage is critical for triggering apoptosis in many cells (Elmore, 2007). It has been reported that curcumin induces apoptosis in cisplatin-resistant human ovarian cancer cells via activation of caspase-3 and degradation of PARP (Weir et al, 2007). Similarly, our present data revealed that miR-9 overexpression resulted in activation of caspase-3 and cleavage of PARP in SKOV3 cells, which confirmed the pro-apoptotic activity of miR-9 at the molecular level.…”

Section: Discussionsupporting

confidence: 87%

“…Phenethyl isothiocyanate, acting as an inhibitor of EGFR-Akt axis, has been shown to suppress ovarian tumor growth in a preclinical mouse model (Loganathan et al, 2012). Curcumin has been shown to inhibit Akt phosphorylation in ovarian cancer cells (Weir et al, 2007). Consistently, we also observed the inhibitory effects of curcumin on Akt activation in SKOV3 cells.…”

Section: Discussionsupporting

confidence: 85%

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Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Zhao¹,

Zhang²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has shown cytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA) mediators of the anticancer effects of curcumin in ovarian cancer cells. Materials and Methods: SKOV3 ovarian cancer cells were treated with curcumin (10-60 μM) and miR-9 expression, cell proliferation, and apoptosis were assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined. Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpression or curcumin treatment. Results: Curcumin caused a significant and dose-dependent increase of miR-9 expression in SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9 significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled with reduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavage of caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blot analysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) decline in the phosphorylation of Akt and FOXO1, compared to untreated cells. Conclusions: The present study provided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely through upregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identify direct targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 85%

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Zhao¹,

Zhang²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…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.…”

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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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“…This was shown for multidrug resistant myeloid leukemia cells (Lu et al, 2012), cisplatin resistant ovarian cancer cells (Weir et al, 2007), multiple myeloma cells resistant to 4 4 dexamethasone, doxorubicin and melphalan (Sung et al, 2009), as well as hormone independent, multidrug resistant breast cancer cells (Labbozzetta et al, 2009). …”

Section: Introductionmentioning

confidence: 80%

“…The drugs that could be efficient against chemoresistant cells could be of great importance in enhancing effectiveness of cancer treatment. There are some data in the literature that verified anticancer properties of curcumin in drug resistant cells (Labbozzetta et al, 2009;Lu et al, 2012;Sung et al, 2009;Weir et al, 2007). However, these data should be more abundant in order to make more general conclusions about curcumin's activity against drug resistant cells.…”

Section: Discussionmentioning

confidence: 99%

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

Rak

Čimbora‐Zovko

Gajski

et al. 2013

Toxicology in Vitro

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Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating akt and p38 mAPK

Cited by 253 publications

References 48 publications

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

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

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

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