Mitochondrial reactive oxygen species (mtROS) possess both tumor-promoting and tumor-suppressive activities according to their net concentration resulting for production levels and antioxidant detoxification. mtROS promote cancer cell fitness at low doses (mitohormesis), are cytotoxic at high doses and promote cancer migration, invasion and metastasis at intermediate doses. These intracellular doses vary from a model to another. Yet, we recently identified that mitochondria-targeted ROS scavengers mitoTEMPO and mitoQ prevent cancer metastasis in several in vivo models (Porporato et al. Cell Reports 2014;8:754-66). Interestingly, several anticancer drugs, among which doxorubicin, are well known to trigger mtROS production in cancer cells, but whether this response participates in cell killing or in resistance is still debated. We therefore tested whether combining mitochondria-targeted antioxidants with doxorubicin could help controlling cancer cell proliferation in vitro and tumor growth in mice. Using breast cancer cells lines MCF7 and 4T1 as models, we first found that subcytotoxic doses of doxorubicin increased cell respiration and, thereby, mitochondrial superoxide production. Downstream, mtROS activated the TGFβ pathway and induced cancer cell migration, invasion, epithelial-mesenchymal transition (EMT) and metastatic take in lungs. MitoTEMPO and mitoQ almost totally blocked these phenotypical changes. Together, our data provide a strong rationale for combining doxorubicin chemotherapy with drugs lowering mtROS production in breast cancer.

Citation Format: Paolo E. Porporato, Pierre Sonveaux. The prometastatic effects of subcytotoxic doses of doxorubicin are countered by agents inactivating mitochondrial reactive oxygen species [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 793.