Possible involvement of thioredoxin reductase as well as thioredoxin in cellular sensitivity to cis-diamminedichloroplatinum (II)

The thioredoxin (TRX) system, composed of nicotinamide adenine dinucleotide phosphate (reduced form), TRX, and TRX reductase (TRXR), has multiple biol ogic functions via thiol-mediated redox control. In this study, we investig ated the relationship between intracellular TRXR levels and cellular sensit ivity to cis-diamminedichloroplatinum (II) (CDDP). HeLa, a human cervical c arcinoma cell line, cultured with CDDP showed a time- and dose-dependent re duction of intracellular TRXR activity, which was well correlated with the decrease in cell viability after exposure to CDDP. In a cell-free system, C DDP was found to directly inactivate the reduced form of purified human TRX R. The CDDP-resistant variants of HeLa cells, established by continuous exp osure to CDDP, exhibited an increased expression and activity of TRXR as we ll as TRX compared with the parental cells. In addition, sodium selenate, a n inhibitor of TRXR, was found to increase the susceptibility to CDDP in th e CDDP-resistant cells. Moreover, the HeLa cells transfected with an antise nse TRXR RNA expression vector to reduce the intracellular enzyme activity displayed an enhanced sensitivity to CDDP. Taken together with previous rep orts on TRX, these results indicate the possible involvement of TRXR as wel l as TRX in the cellular sensitivity and resistance to CDDP. (C) 1999 Elsev ier Science Inc.