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 PGC1α
mRNA expression, proliferation, cell cycle phase distribution, mitochondrial capacity and
superoxide generation, and sensitivity to the
chemotherapy drug doxorubicin.
Troglitazone increases expression of PGC1α, a key mediator of mitochondrial biogenesis, in normal mammary epithelial cells and in
breast cancer cell lines. The induction of PGC1α
mRNA is at least partially dependent on PPARγ 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 non-malignant mammary epithelial cells to
doxorubicin induced cytotoxicity, despite increasing PGC1α
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.