Mcl-1 Inhibitor Induces Cells Death in BRAF-Mutant Amelanotic Melanoma Trough GSH Depletion, DNA Damage and Cell Cycle Changes

Abstract

Mcl-1 is a potent antiapoptotic protein and amplifies frequently in many human cancer. Currently, it is considered that the extensively expressed of Mcl-1 protein in melanoma cells is associated with rapid tumor progression, poor prognosis and low chemosensitivity. Therefore, the antiapoptotic protein Mcl-1 could be considered as a potential target for malignant melanoma treatment. The aim of this study was to assess the effect of MIM1 a specific low molecular Mcl-1 protein inhibitor and mixture of MIM1 and dacarbazine on the viability, cell cycle progression and apoptosis induction in amelanotic C32 melanoma cells. The cytotoxic activity of MIM1 towards C32 melanoma cells was examined by the WST-1 test. The Mcl-1 protein level as a drug target in amelanotic melanoma cells was defined by Western blot analysis. Cell cycle progression, DNA fragmentation as well as GSH depletion were determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrate that the specific Mcl-1 protein inhibitor - MIM1 decreases cell viability and induce apoptosis (S-phase arrest, DNA fragmentation and redox imbalance) in amelanotic melanoma cells and intensify the proapoptotic properties of DTIC, as a result of interactions with Mcl-1 protein. Taken together, the presented data suggest that Mcl-1 protein is a an important target in malignant melanoma treatment and provide for the first time convincing evidence that MIM1, which inhibits Mcl-1 antiapoptotic protein is able to induce apoptosis and sensitize melanoma cells to alkylating agent.