Monensin Inhibits Triple Negative Breast Cancer in Mice by a Na+-Dependent Cytotoxic Action Unrelated to Cytostatic Effects

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and maintains a low rate of overall survival despite the recent advances in treatments. This study investigates Na+ homeostasis of TNBC cells as a novel therapeutic target to induce TNBC inhibition. To this purpose BALB/c mice were injected with breast cancer 4T1 cells and treated with the Na+ ionophore Monensin (8 mg/kg) or vehicle. Tumor development and Na+ increase were monitored by In Vivo Imaging techniques. Intracellular Na+ variations and cytotoxicity were followed by Live Cell Analysis. Monensin increased Na+ content of transformed tissue and significantly reduced TNBC growth. Monensin induced extended TNBC tumor necrosis without affecting the integrity of healthy organs and proliferating activity of both tumor and normal tissue. Monensin did not influence PCNA expression of 4T1 cells but exerted a cytotoxic effect preceded by an increase of intracellular Na+. Absent Na+ in the extracellular medium prevented Na+ load and 4T1 cell death. Monensin inhibits TNBC by a Na+-dependent and cancer specific cytotoxic action without exerting cytostatic effects in both normal and transformed tissues. These observations support the potential of Na+ ionophores as innovative agents for TNBC therapy.