• Cancer metabolism
• metastasis
• mitochondria
• reactive oxygen species

Metastatic progression is associated with poor prognosis for cancer patients. Tissue invasion and metastasis are among the most well-known hallmarks of cancer, and are characterized by the ability of tumor cells to migrate and invade surrounding tissues. Recently, these two features of aggressive cancers have been found to be promoted by mitochondrial reactive oxygen species (mtROS), justifying the study of mtROS scavengers, such as mitoTEMPO and mitoQ, to prevent tumor metastasis. These agents, however, are expected to be used in combination with chemotherapy, and several chemotherapeutic agents promote ROS production by tumor cells, which could participate in their therapeutic effects. Therefore, the aim of our study was to test the safety of combining mtROS scavengers with chemotherapy. We focused on triple negative breast cancer, a highly metastatic tumor type, and on cisplatin and paclitaxel, i.e., major chemotherapeutic treatment modalities for this type of cancer. Both drugs had been previously described to promote ROS production by tumor cells. Using murine 4T1 and human MDA-MB-231 cells as experimental models, we found that cisplatin, but no paclitaxel, increased ATP production, mitochondrial activity and mtROS generation at doses typically achieved in human tissues in the clinics. It also increased tumor cell migration in vitro. Importantly, we report that mitochondria-targeted superoxide scavengers mitoTEMPO and mitoQ repress cisplatin-induced tumor cell migration but do not interfere with the cytostatic and cytotoxic effects of cisplatin and paclitaxel. Our study thus indicates not only that it is possible to combine mitochondrial superoxide scavengers with cisplatin and paclitaxel chemotherapies, but also that these agents can prevent cisplatin-induced tumor cell migration.