Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells.

Abstract

BACKGROUND AND PURPOSE:

Metastatic melanoma remains one of the most invasive and highly drug resistant cancers. The over expression of anti-apoptotic protein Mcl-1 has been associated with inferior survival, poor prognosis and chemoresistance of malignant melanoma. A BH3 mimetic, ABT-737, has demonstrated efficacy in several forms of cancers. However, the efficacy of ABT-737 depends on Mcl-1. Because the over expression of Mcl-1 is frequently observed in melanoma, 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.

EXPERIMENTAL APPROACH:

For cell viability assessment we performed MTT assay. Apoptosis was determined using western blot and flow cytometric analysis.

KEY RESULTS:

The treatment of Maritoclax reduced the cell viability of melanoma cells with an IC50 of between 2.2-5.0 µM. Further, treatment of melanoma cells with Maritoclax showed significant decrease in Mcl-1 expression. We found that Maritoclax was able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induced Mcl-1 degradation via the proteasome system, which was associated with its pro-apoptotic activity. We also found that Maritoclax treatment increased mitochondrial translocation of Bim and Bmf. Importantly, Maritoclax markedly enhanced the efficacy of ABT-737 against melanoma cells in both two- and three-dimensional spheroids.

CONCLUSIONS AND IMPLICATIONS:

Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy for melanoma treatment that warrants further investigation as a single therapy or in combination with other agents such as Bcl-2 inhibitors.

• Authors: Manoj K Pandey, Krishne Gowda, Kenichiro Doi, Arun K Sharma, Hong-Gang Wang, Shantu Amin
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e78570 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24223823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• BMF protein, human
• Bcl-2-Like Protein 11
• Biphenyl Compounds
• Growth Inhibitors
• MCL1 protein, human
• Membrane Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins
• Pyrroles
• Sulfonamides
• marinopyrrole A
• Caspases
• Proteasome Endopeptidase Complex

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Biphenyl Compounds (pharmacology)
• Caspases (genetics, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Drug Therapy, Combination
• Epithelial Cells (drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Growth Inhibitors (pharmacology)
• Humans
• Inhibitory Concentration 50
• Membrane Proteins (genetics, metabolism)
• Mitochondria (drug effects, metabolism)
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Proteolysis
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyrroles (pharmacology)
• Signal Transduction
• Skin (drug effects, metabolism, pathology)
• Sulfonamides (pharmacology)