Mitochondrial amplification selectively increases doxorubicin sensitivity in breast cancer cells with acquired antiestrogen resistance

The metabolic phenotype of cancer, characterized by uncoupled mitochondrial respiration and increased mitochondrial oxidative stress, is an attractive pharmacological target for sensitizing cancer cells to therapies that rely on oxidative stress for their tumor specific cytotoxicity. The identification of specific cancer sub-types for which metabolic priming of tumors prior to chemotherapy is beneficial is critical, particularly in heterogeneous diseases such as breast cancer. The effects of the thiazolidinedione drug troglitazone were examined in normal mammary epithelial cells and cancer cell lines representing three clinically relevant breast cancer phenotypes. Endpoints measured were PGC1a mRNA expression, proliferation, cell cycle phase distribution, mitochondrial capacity and superoxide generation, and sensitivity to the chemotherapy drug doxorubicin. Troglitazone increases expression of PGC1a, a key mediator of mitochondrial biogenesis, in normal mammary epithelial cells and in breast cancer cell lines. The induction of PGC1a mRNA is at least partially dependent on PPARc activation. In estrogen receptor negative cells and cells with acquired antiestrogen resistance, troglitazone treatment increased mitochondrial superoxide production and mitochondrial capacity. At pharmacologically achievable doses, troglitazone pretreatment significantly enhanced the sensitivity of cancer cells to the chemotherapy agent doxorubicin. This effect was most dramatic in estrogen receptor positive cells with acquired antiestrogen resistance, in which troglitazone and doxorubicin combined had superadditive effects compared to treatment with either agent alone. In contrast, troglitazone treatment did not appreciably sensitize nonmalignant mammary epithelial cells to doxorubicin induced cytotoxicity, despite increasing PGC1a mRNA. These data suggest that troglitazone or a similarly acting compound could be used to selectively prime tumor cells to the cytotoxic effects of anticancer agents such as doxorubicin and ionizing radiation. This novel treatment strategy may be most effective in women with antiestrogen insensitive tumors, a patient population with historically poor response to traditional therapies.