Cellular Levels of Thioredoxin Associated with Drug Sensitivity to Cisplatin, Mitomycin C, Doxorubicin, and Etoposide1

Thioredoxin, a cellular thiol, functions as a self-defense mechanism in response to environmental stimuli, including oxidative stress. We first determined cellular levels of thioredoxin in several human bladder and prostatic cancer cell lines resistant to cis-diamminedichloroplatinum(II) (cisplatin). AH cisplatin-resistant cell lines had much higher levels of thioredoxin than those in their drug-sensitive parental counterpart. We then, by introducing thioredoxin antisense expression plasmids into hu man bladder cancer T24 cells, established two bladder cancer cell lines that had decreased levels of thioredoxin. These thioredoxin antisense transfectants showed increased sensitivity to cisplatin and also to other superoxide-generating agents, i.e., doxorubicin, mitomycin C, etoposide, and hydrogen peroxide, as well as to UV irradiation, but not to the tubulin-targeting agents, vincristine, and colchicine. Cellular levels of thioredoxin thus appear to limit sensitivity to various superoxide-gener ating anticancer drugs in cancer cells.