Verticillin A increases the BIMEL/MCL-1 ratio to overcome ABT-737-resistance in human colon cancer cells by targeting the MEK/ERK pathway

ABT-737, a small molecule BH-3 mimetic, is less effective against human colon cancers due to its resistance. Verticillin A is a natural compound, which was previously purified from verticillium-infected mushrooms. Hence, we aimed at overcoming the ABT737 resistance observed in CRC tumors by combining Verticillin A with ABT-737 and figuring out the potential mechanism. In this study, we observed that Verticillin A could sensitize colon cancer to ABT-737-induced cell death through induction of mitochondrial-dependent apoptosis. Verticillin A could significantly increase the BIMEL/MCL-1 ratio to overcome ABT737 resistance through the suppression of the MEK/ERK pathway. In addition, up regulation of BIM protein levels to activate BAX translocation results in apoptosis induction. Altogether, our work suggested the potential application of Verticillin A as a MEK inhibitor in BH3-mimeticbased therapy. (c) 2021 Published by Elsevier Inc.

Automated summary

In this study, it was found that Verticillin A could sensitize colon cancer to ABT-737-induced cell death by increasing the BIMEL/MCL-1 ratio and suppressing the MEK/ERK pathway. Additionally, upregulation of BIM protein levels facilitated BAX translocation and apoptosis induction. The potential application of Verticillin A as a MEK inhibitor in BH3-mimetic-based therapy was suggested based on these findings.