Targeting mitochondria with antibıotics as a means of overcoming chemoresistance in triple negative breast cancer

Cancer has remained a factor of mortality worldwide for more than half a century. Amongmany others, breast cancer is the most important cause of death in women. A particularsubtype known as triple negative breast cancer (TNBC) is the most aggressive and hasthe worst clinical prognosis. The absence of estrogen receptors (ER), progesteronereceptors (PR) and low expression of human epidermal growth factor receptors (HER2)allows TNBC to avoid hormonal therapy, forcing the search for other anti-cancer therapyapproaches. Since cancer patients do not die directly from primary malignant tumors, butfrom metastasis, which is often accompanied by cancer resistance, efforts need to be directed specifically at combating the emergence of metastatic disease. In part, thedevelopment of metastases is promoted by so-called cancer stem cells (CSCs) and - asubset of cells living in the tumor with a specific microenvironment, which eventuallyallows such cells to develop progenitors and colonize in distal organs giving metastases.CSCs are slow dividing and therefore resistant to chemotherapy cells, which often leadsto tumor recurrence. In addition, a regular course of chemo- or radiotherapy can select aspecific population of cancer resistant cells (CRC) that contribute as much tochemoresistance as CSCs. As shown by various studies, drug-resistant cancer cellsexhibit higher levels of mitochondrial respiration than sensitive cancer cells, which isoften fueled by ATP from mitochondria-driven oxidative phosphorylation (OXPHOS).Recently, it was suggested that OXPHOS inhibitors may resensitize chemoresistant cellsto anticancer therapy. Taking into account the endosymbiotic origin of mitochondria fromalphaproteobacteria, we attempted to select antibiotics as chemotherapeutic agents thatcould inhibit OXPHOS in chemoresistant cells. As a model, we used to cisplatin- resistantTNBC cells. Such cells were found to be OXPHOS-dependent an showed higher oxygenconsumption rate, higher doubling time, overexpression of stemness markers and highermetastatic potential compared to sensitive counterparts. After analyzing more than 50antibiotics, two promising drugs (Amoxicillin and Fosmidomycin soidum salt) withhigher toxic effects on chemoresistant cancer cells were selected. Those drugs showedsuppression of OXPHOS, decrease in metastatic potential and increase in the autophagyin resistant cells. Overall, our results suggest that some bactericidal antibiotics withproven activity against mitochondria may provide an alternative approach to treat patientswith chemoresista