Mitochondrial ROS inhibition prevents doxorubicin-induced breast cancer cell migration and invasion.

For cancer patients, metastasis is a life-threatening event limiting therapeutic options. Molecularly, the metastatic phenotype can be conferred by mitochondrial reactive oxygen species (mtROS) generated upon metabolic stress. Mitochondrial damage can also trigger mtROS production, which is particularly well illustrated for anthracyclines. Here, we tested in mouse models of murine and human breast cancer whether this type of chemotherapy can trigger metastasis. We report that subcytotoxic doses of doxorubicin mimicking the clinical situation in poorly perfused tumor areas sequential trigger mtROS production, activate TGFβ pathway effector Pyk2, and increase cancer cell migration and invasion. Fortunately, the metastatic switch was incompletely induced, and doxorubicin did not promote breast cancer metastasis in immunocompetent mice. Yet, MitoTEMPO fully prevented metastatic dissemination and did not interfere with doxorubicin cytotoxicity, making it attractive to combine anthracyclines with mitochondria-targeted antioxidants.