Moxifloxacin and BH3 Mimetic-MIM1 Demonstrate a Potential Synergistic Anti-Melanoma Mode of Action by Cytotoxic and Proapoptotic Activity Enhancement in A375 and G361 Melanoma Cells

TL;DR

Moxifloxacin and MIM1, a BH3 mimetic, work together to kill melanoma cells by boosting cell death and reducing survival proteins.

Contribution

This study is the first to show a synergistic anti-melanoma effect of moxifloxacin and MIM1 through enhanced proapoptotic activity.

Findings

MXFL and MIM1 mixtures significantly increased cytotoxic and proapoptotic activity in A375 and G361 melanoma cells.

The combination modulated early and late apoptosis phases more effectively than either compound alone.

Mcl-1 protein is identified as a key target in this synergistic anti-melanoma mode of action.

Abstract

The MIM1-BH3 mimetic, which inhibits the Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MXFL) is able to modulate Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of the MXFL, MIM1, and MXFL/MIM1 mixtures on viability and apoptosis in amelanotic A375 and melanotic G361 melanoma cells. The obtained results showed that MXFL and MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of the MIM1 and MXFL mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity, shown as a modulatory effect on the early and late phases of apoptosis toward the analyzed melanoma cells when compared with MIM1 or MXFL alone. We report, for the first time, the high proapoptotic activity of MIM1 and MXFL applied in a two-component model toward melanoma cells, pointing to the Mcl-1 protein as an important molecular target. The observed potential synergistic mode of action—expressed as cytotoxic and proapoptotic activity enhancement, detected for MIM1 and MXFL—may represent a new direction for further in vitro and in vivo experiments concerning the role of the Mcl-1 protein in the treatment of melanoma. Moreover, the presented results certainly contribute to expanding the knowledge of the pharmacology of both fluoroquinolones and BH3 mimetics, and also enable a better understanding of melanoma cell biology.

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