Dysfunctional mitochondrial bioenergetics sustains drug resistance in cancer cells.

Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin (CL) reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by l-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.NEW & NOTEWORTHY Cancer drug resistance (CDR) is increasingly becoming a concerning clinical problem. The mechanisms behind the onset of CDR are still not well defined. In this study, we demonstrated that a treatment mimicking long-term clinical protocols with commonly used chemotherapeutic agents promotes mitochondrial bioenergetic dysfunction, leading to the acquisition of CDR. In a future perspective, interventions aimed at inhibiting fermentation and restoring OXPHOS efficiency may offer tangible opportunities to reduce the clinical burden of CDR.