Overexpression of
manganese superoxide dismutase (MnSOD) can sensitize a variety of
cancer cell lines to many anticancer drugs. Recent work has shown that
cancer cells can be sensitized to cell killing by raising
peroxide levels through increased
manganese superoxide dismutase (MnSOD) when combined with inhibition of
peroxide removal. Here we utilize the mechanistic property of one such anticancer
drug,
BCNU, which inhibits
glutathione reductase (GR), compromising the
glutathione peroxidase system thereby inhibiting
peroxide removal. The purpose of this study was to determine if anticancer modalities known to produce
superoxide radicals can increase the antitumor effect of MnSOD overexpression when combined with
BCNU. To enhance MnSOD, an adenoviral construct containing the
cDNA for MnSOD (AdMnSOD) was introduced into human
breast cancer cell line, ZR-75-1. AdMnSOD
infection alone did not alter cell killing, however when GR was inhibited with either
BCNU or
siRNA, cytotoxicity increased. Futhermore, when the AdMnSOD +
BCNU treatment was combined with agents that enhance steady-state levels of
superoxide (TNF-α,
antimycin,
adriamycin,
photosensitizers, and ionizing radiation), both cell cytotoxicity and intracellular
peroxide levels increased. These results suggest that the anticancer effect of AdMnSOD combined with
BCNU can be enhanced by agents that increase generation of
superoxide.