Gentamicin Induces Selective Toxicity in Metabolically Altered Vemurafenib-Resistant A375 Cells

Year 2024, Volume: 52 Issue: 3, 189 - 197, 01.07.2024

Fulya Dal Yöntem , Gökhan Ağtürk , Sinem Ayaz , Şeyma Ateşoğlu , Hülya Irmak Aksan , Huri Bulut , Handan Akçakaya , Müfide Aydoğan Ahbab , Ebru Hacıosmanoğlu Aldoğan

https://doi.org/10.15671/hjbc.1404345

Abstract

This study investigates the potential repurposing of gentamicin for treating drug-resistant melanoma by targeting metabolic alterations. Rising global cancer incidence and mortality, coupled with the challenge of drug resistance, necessitate novel therapeutic strategies. Initially, we addressed the influence of antibiotics on mitochondrial function, a crucial player in oxidative phosphorylation (OXPHOS). To assess this impact, we first cultured two different cancer cells, A375 and PC3, in antibiotic-free medium and showed that mitochondrial membrane potential of cells was increased in the absence of antibiotics compared to cells cultured in antibiotic containing medium. Next, we developed vemurafenib resistance in A375 cells, which were continuously cultured in antibiotic-free medium. The resistant cells exhibited a marked increase in oxygen consumption rate, indicating a shift towards OXPHOS. Finally, we treated these vemurafenib-resistant cells and noncancerous human fibroblast cells (CCD-1072Sk) with varying concentrations of gentamicin (1-1000 µM). Remarkably, gentamicin showed selective cytotoxicity towards the resistant cells while sparing non-resistant counterparts and noncancerous cells. Our findings highlight gentamicin's potential as a therapeutic agent in targeting the metabolic vulnerabilities of drug-resistant melanoma, presenting a viable new pathway in cancer treatment.

Keywords

Gentamicin, vemurafenib, melanoma, drug repurposing

Supporting Institution

Haliç University Scientific Research Projects Unit

Project Number

HBAP604-I-4

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