2012
DOI: 10.1002/ijc.27832
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Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild‐type ovarian cancer cells

Abstract: 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 compromise… Show more

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Cited by 33 publications
(34 citation statements)
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“…A single limited previous study examined the combination of Nutlin-3a with cisplatin in A2780p, A2780cis and the OV90 cell lines. The results showed a synergistic effect in A2780p and A2780cis, consistent with our study [10]. …”
Section: Discussionsupporting
confidence: 93%
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“…A single limited previous study examined the combination of Nutlin-3a with cisplatin in A2780p, A2780cis and the OV90 cell lines. The results showed a synergistic effect in A2780p and A2780cis, consistent with our study [10]. …”
Section: Discussionsupporting
confidence: 93%
“…This suggests some mutant forms of p53 still show evidence of degradation by MDM2 which is prevented by the MDM2 inhibitors. These results are consistent with limited previous studies [10, 21] demonstrating that wild-type TP53 ovarian cancer cell lines are responsive to Nutlin-3 and extends observations to the second generation MDM2 inhibitor RG7388 currently in early phase clinical trials.…”
Section: Discussionsupporting
confidence: 92%
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“…Enhanced effects of recovering a proapoptotic p53 function and induction of genotoxic stress are probable, and a sensitizing effect of a combined treatment has been demonstrated for several cancer entities [26][27][28]. Furthermore, nutlin-3a has been shown to inhibit FOXM1 activity and expression, which is usually activated after cisplatin treatment and contributes to platin-based che- motherapy resistance [29][30][31].…”
Section: Combined Treatment Of Krj-i Cells With Nutlin-3a Sensitizes mentioning
confidence: 99%
“…Despite these agents needing to overcome intrinsic mechanisms that confer protection against apoptosis to cancer cells, these trials are yielding promising results. Synergistic effects have been noted when Nutlin-3, an MDM2 inhibitor that is known to arrest the cell cycle in a p53-dependent manner, was combined with established anticancer agents such as doxorubicin, vincristine or cisplatin, among others [5][6][7]. The most intriguing results in the development of such therapies have recently been described in an extensive review by Hoe et al [4].…”
Section: Targeting P53 In Anticancer Therapymentioning
confidence: 97%