Metformin induced lactic acidosis impaired response of cancer cells towards paclitaxel and doxorubicin: Role of monocarboxylate transporter

Abstract

Abnormal glucose metabolism in cancer cells causes generation and secretion of excess lactate, which results in acidification of the extracellular microenvironment. This altered metabolism aids not only in survival and proliferation but also in suppressing immune-mediated destruction of cancer cells. However, how it influences the response of cancer cells to chemotherapeutic drugs is not clearly understood. We employed appropriate in vitro approaches to explore the role of mono-carboxylate transporter 4 (MCT4) mediated altered intra and extracellular pH on the outcome of the therapeutic efficacy of chemotherapeutic drugs in breast and lung cancer models. We demonstrate by in vitro experiments that inhibition of complex I enhances glycolysis and increases expression as well as membrane translocation of MCT4. It causes a decrease in extracellular pH (pHe) and impairs doxorubicin and paclitaxel's therapeutic efficacy. Acidic pHe inhibits doxorubicin's uptake, while acidic intracellular pH (pH i) impairs the efficacy of paclitaxel. Under in vivo experimental settings, the modulation of pHe with phloretin or alkalizer (NaHCO3) enhances cytotoxicity of drugs and inhibits the growth of MCF-7 xenografts in mice. In a nutshell, this study indicates that MCT4 mediated extracellular acidosis is involved in impairing chemotherapeutic drugs' efficacy on cancer cells. Therefore, the use of pH neutralizing agents or MCT inhibitors may be beneficial towards circumventing impairment in the efficacy of certain drugs that are sensitive to pH changes.