Melanoma is the most aggressive form of skin cancer. Despite the development of the therapies it remains one of the most invasive and highly drug resistance cancers. The dysregulation of apoptosis are thought to be one barrier to effective systemic treatment of melanoma. The overexpression of anti-apoptotic Bcl-2 family proteins has been associated with inferior survival, poor prognosis and chemoresistance of several cancers including malignant melanoma. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xL and Bcl-w, has demonstrated efficacy in several forms of hematological and non-hematological cancers. However, the efficacy of ABT-737 is diminished in cancer cells with high levels of Mcl-1, another anti-apoptotic member of the Bcl-2 family. The overexpression of Mcl-1 is frequently observed in melanoma and therefore, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. The treatments of Maritoclax reduce the cell viabilities of melanoma cells with an IC50 of between 2.2-5.0μM. Further, treatment of melanoma cells with 2.5 μM Maritoclax for 24 h showed significant decrease in Mcl-1 expression. We found that Maritoclax is able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induces Mcl-1 degradation via the proteasome system, which is associated with its pro-apoptotic activity. Importantly, Maritoclax markedly enhances the efficacy of ABT-737 against melanoma cells. As a single agent, ABT-737 was not efficient in killing UACC 903 cells with IC50 values of >30 μm. However, in combination with a sub-optimal dose of Maritoclax (2.5μM), the efficacy of ABT-737 was enhanced (IC50 1.3 μm). Similarly, Maritoclax potentiated apoptotic effects of ABT-737 from 20%-71% and 18%-62% when measured by Live and Dead and annexin-V assay, respectively. Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy to sensitize melanoma cells to ABT-737-induced apoptosis.

Citation Format: Manoj K. Pandey, Krishne Gowda, Kenichiro Doi, Arun Sharma, Hong-Gang Wang, Shantu Amin. Maritoclax, a selective Mcl-1 inhibitor, sensitizes melanoma cells to the Bad BH3-mimetic ABT-737. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1720. doi:10.1158/1538-7445.AM2013-1720

©2013 American Association for Cancer Research
2013