MIM1 induces COLO829 melanoma cell death through mitochondrial membrane breakdown, GSH depletion, and DNA damage

Abstract

Malignant melanoma is a high aggressive malignancy in humans and causes 60-80% of deaths from skin cancer. Defect in an intrinsic pathway of apoptosis via overexpression of Mcl-1 is responsible for malignant melanoma development and progression, and also for resistance to chemotherapeutic agents. MIM1 is a specific low molecular Mcl-1 protein inhibitor that is able to induce Mcl-1-dependent cancer cells death. Here, we examined the effect of MIM1 as well as MIM1 and dacarbazine (DTIC) mixture on cell viability, apoptosis, and cell cycle progression in COLO829 melanoma cells. Cell viability was performed by the WST-1 assay. Analysis of apoptosis as well as cell cycle progression was determined by fluorescence image cytometer NucleoCounter NC-3000. The obtained results demonstrated that the MIM1 exhibited high cytotoxicity against melanotic melanoma cells and induced mitochondrial membrane breakdown, GSH depletion, and DNA fragmentation. Additionally, MIM1 enhanced the proapoptotic effect of DTIC toward melanoma cells; furthermore, a mixture of these drugs caused cell cycle arrest at G2/M phase in COLO829 cells. Taken together, these data provide, for the first time, evidence that a low molecular weight Mcl-1 inhibitor-MIM1 may be a promising agent with antitumor and proapoptotic properties toward melanoma cells.