Induction of apoptosis by metformin in epithelial ovarian cancer: Involvement of the Bcl-2 family proteins

Yasmeen, Amber; Beauchamp, Marie‐Claude; Piura, Ettie; Segal, Eric; Pollak, Michael; Gotlieb, Walter H.

doi:10.1016/j.ygyno.2011.02.021

Cited by 116 publications

(130 citation statements)

References 38 publications

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“…Finally, CDDP alone does not decrease Bcl-2 levels, but in combination with metformin, Bcl-2 is downregulated in OVCa cells. 21 In the present study, in A2780p cells and primary tissue cultures, CDDP treatment decreased Bcl-2 mRNA and protein levels. Likely, the downregulation of Bcl-2 is enhanced by proteasomal degradation.…”

Section: Cancer Cell Biologysupporting

confidence: 51%

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

Mir

Tortosa

Martínez‐Soler

et al. 2012

Intl Journal of Cancer

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Ovarian cancer (OVCa) is the leading cause of death from gynecological malignancies. Although treatment for advanced OVCa has improved with the introduction of taxane-platinum chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the reduced ability to undergo apoptosis. Cisplatin is a genotoxic drug that leads cells to apoptosis through the activation of the p53 pathway. Defective signaling in this pathway compromises p53 function, and thus cisplatin does not induce apoptosis. A new group of nongenotoxic small molecules called Nutlins have been developed to inhibit p53-Mdm2 binding, inducing apoptosis in chemoresistant tumors through the activation of the p53 pathway. The wild-type p53 cisplatin-resistant ovarian cancer cell-line A2780cis was used to test the effect of Nutlin-3a (Nut3a) on apoptosis response. The results showed that Nut3a synergized with cisplatin, inducing cell-cycle arrest in G2/M and potentiating apoptotic cell death. Increased apoptosis was also induced in wild-type TP53 primary OVCa cultures by double cisplatin-Nut3a treatment. In conclusion, Nut3a appears to sensitize chemoresistant OVCa cells to cisplatin, inducing apoptosis. As increased response was generalized in primary tumors, this cisplatin-Nut3a combination could be useful for the treatment of patients harboring wild-type TP53 who do not respond to standard chemotherapy.Ovarian cancer (OVCa) kills~115,000 women annually worldwide. The majority of patients with OVCa are diagnosed with advanced disease and managed with surgical cytoreduction followed by platinum and taxane-based chemotherapy, 1 but the majority of them will eventually recur and die as a consequence of metastatic spread. Crystalline cis-dichlorodiammine platinum (II) [cisplatin (CDDP)] is the cytotoxic agent used as therapy, but it leads to chemoresistance, the largest obstacle in treating patients with recurrent disease. Multidrug resistance, DNA mismatch repair and alterations in the p53 pathway are examples of tumor-cell features that may lead to CDDP resistance. 2Defects in apoptosis are one of the mechanisms that can lead to chemoresistance. The p53 protein is recognized as an important cell-regulatory element that arrests the growth of cells containing damaged DNA. Cell-cycle control and activation of apoptosis appear to be tightly linked functions of p53. The importance of p53 in human malignances was highlighted by the detection of abnormal p53 in more than 50% of human cancers. 3,4 Mutations in TP53 are associated with a lack of response to high-dose CDDP therapy in OVCa patients. 5The short-lived protein p53 and its cellular levels are controlled by the rate at which it is degraded. Although several U3 ubiquitin ligases have been implicated in p53

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Section: Cancer Cell Biologysupporting

confidence: 51%

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

Mir

Tortosa

Martínez‐Soler

et al. 2012

Intl Journal of Cancer

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“…The anticancer activities of metformin are also similar to * This work was supported, in whole or in part, by National Institutes of Health that observed after knockdown of Sp1 or all three Sp proteins by RNA interference in cancer cells, and this includes growth inhibition, induction of apoptosis, reversal of epithelial to mesenchymal transition, and decreased migration/invasion (32)(33)(34)(35)(36). Metformin also inhibits NFB and decreases cyclin D1 and ErbB2 in cancer cell lines (13,20,27,28), and these gene products are also decreased after Sp1, Sp3, and Sp4 silencing by RNAi or by other drugs that down-regulate Sp proteins (32)(33)(34)(35)(36). However, the relationship between metformin-induced down-regulation of Sp1, Sp3, and Sp4 and modulation of mTOR signaling has not been reported, except that total mTOR protein expression was unaffected by silencing of Sp transcription factors in pancreatic cancer cells (31).…”

supporting

confidence: 60%

“…The antineoplastic activities of metformin in cancer cell lines includes the inhibition of several pathways and genes that are important for cancer cell proliferation, survival, migration, and invasion (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Metformin down-regulates expression of Sp1, Sp3, and Sp4 and several pro-oncogenic Sp-regulated genes, and this study shows that inhibition of mTOR signaling and RAS activation by metformin in pancreatic cancer cells is also due to decreased expression of the Sp-regulated upstream receptor tyrosine kinases (RTKs) IGF-1R and EGFR, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…The potential clinical applications for metformin in cancer chemotherapy also stems from studies on the anticancer activities of this drug in cancer cells in culture and in in vivo models (1)(2)(3)(4)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Metformin inhibits growth and induces apoptosis and other antineoplastic responses in multiple cancer cell lines, and this is accompanied by modulation of different pathways and genes.…”

mentioning

confidence: 99%

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Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

Nair

Sreevalsan

Basha

et al. 2014

Journal of Biological Chemistry

119

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Background: Metformin inhibits pancreatic cancer cell and tumor growth and down-regulated Sp transcription factors. Results: Inhibition of mTOR and Ras signaling by metformin is due to decreased expression of Sp-regulated insulin-like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR), respectively. Conclusion: Metformin-induced down-regulation of Sp proteins affects multiple pro-oncogenic pathways. Significance: These results identify important metformin-induced anticancer activities.

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“…Studies of various solid tumors and adult leukemia showed that different tumor cell lines show different Bcl-2 expression. Cells with high Bcl-2 expression display apoptotic suppression as well as resistance to chemotherapeutic drugs (Yasmeen et al, 2011;Mendilcioglu et al, 2011). SODD binds specifically to Bcl-2 through the DD after its abscission from TNFR-I.…”

Section: Discussionmentioning

confidence: 99%

Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy

Tao¹,

Liu²,

Fang³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. This study explored the clinical significance of silencer of death domain (SODD) expression in childhood acute lymphoblastic leukemia (ALL) and its influence on chemotherapy as well as the effect of SODD expression on apoptosis of leukemic cells. The expression of SODD proteins in different ALL groups was determined by immunocytochemistry. The SODD RNAi-interfering plasmid was constructed and transferred to Jurkat cells, and the effects of SODD expression on cell proliferation and apoptosis were analyzed using the MTT and FCM methods. The expressions of SODD, Phospho-NF-κB-P65, Bcl-2, and Caspase 3 were detected by Western blot analysis. The expression of SODD proteins was significantly higher in the ALL groups than in the control group (P < 0.05). The positive expression rate of SODD was significantly higher in refractory/relapsed and clinical high-risk groups than in standard-risk, initial treatment, and complete remission groups (P < 0.05). Microtubule-targeting drugs such as vincristine and taxol can notably down-regulate SODD expression during apoptosis, whereas DNR, and Ara-c cannot. The sensitivity of Jurkat cells to chemotherapeutic drugs increased with down-regulated SODD expression induced by SODD-interfering plasmid transfection. The sensitivity of the cells transfected with SODD-cloning genes decreased. SODD expression was high in the ALL children. These findings indicated that SODD over-expression might be correlated with the clinical classification, curative effect, and prognosis of ALL cells. Microtubule-targeting drugs can specifically down-regulate SODD expression in leukemic cells, thereby increasing the sensitivity of leukemic cells to SODD-targeting chemotherapeutics. In contrast, increased SODD expression tends to reduce sensitivity.

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Induction of apoptosis by metformin in epithelial ovarian cancer: Involvement of the Bcl-2 family proteins

Cited by 116 publications

References 38 publications

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

Mechanism of Metformin-dependent Inhibition of Mammalian Target of Rapamycin (mTOR) and Ras Activity in Pancreatic Cancer

Significance of SODD expression in childhood acute lymphoblastic leukemia and its influence on chemotherapy

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