TIM16 a component of the translocase complex TIM23 of the mitochondrial inner membrane is encoded by the Magmas gene. Magmas was found to be over-expressed in human pituitary adenomas. Silencing Magmas in ACTH secreting rat pituitary adenoma cells enhances sensitivity to pro-apoptotic stimuli. Moreover, Magmas overexpression protects GH secreting rat pituitary adenoma cell lines towards apoptosis. Recently, we found that compound 5, a TIM16 inhibitor, is not cytotoxic but enhances the proapoptotic effects of staurosporine by reducing mitochondrial membrane potential (MMP) activation in a medullary thyroid carcinoma cell line, suggesting that compound 5 may be useful for cancer treatment in association with chemotherapeutic drugs. Since breast cancer (BC) displays high chemoresistance, the aim of our study was to investigate Magmas expression in human breast cancer cell lines and to verify whether compound 5 could increase the effects of a chemotherapeutic agent, such as Doxorubicin in these cells. As an in-vitro model we used three human breast cell lines: MCF7 and MDA-MB231 carcinoma cell lines and MCF12A normal breast cell line. We found that Magmas protein is highly expressed in the MCF7 cell line as compared to MDA-MB231 and MCF12A cells.
Our data show that treatment with compound 5 did not influences cell viability in the three cell lines, while Doxorubicin decreases this parameter by 2030%. Only in MCF7 cells co-treatment with compound 5 enhances by 1520% the antiproliferative effects of Doxorubicin, measured as cell viability and BrDU incorporation. MitoTox Glo assay shows that in MCF7 cells the enhancing effects of compound 5 on Doxorubicin action are due to mitochondrial toxicity. In summary, these data suggest a role for the use of compound 5 as a sensitising agent for chemoresistant breast cancer expressing high levels of TIM16.