Thiol redox modulation of doxorubicin mediated cytotoxicity in cultured AIDS-related Kaposi's sarcoma cells

The chemotherapeutic, doxorubicin, is currently used empirically in the tre atment of AIDS- related Kaposi's sarcoma (AIDS-KS). Although often employed in a chemotherapeutic cocktail (doxorubicin, bleomycin, vincristine) singl e-agent therapy has recently been attempted with liposome encapsulated doxo rubicin. Although doxorubicin's mechanism of action against AIDS-KS is unkn own, we hypothesized that doxorubicin's ability to undergo redox cycling is associated with its clinical efficacy. The current study was conducted to investigate the effects of doxorubicin on selected xenobiotic-associated bi ochemical responses of three cellular populations: KS lesional cells, nonle sional cells from the KS donors, and fibroblasts obtained from HIV- aged ma tched men. Our results show that during doxorubicin challenge, there are st rong positive correlations between cellular glutathione (GSH) levels and vi ability (r = 0.94), NADPH levels and viability (r = 0.93), and GSH and NADP H levels (r = 0.93), and demonstrate that as a consequence of their abiliti es to maintain cellular thiol redox pools HIV- donor cells are significantl y less susceptible to doxorubicin's cytotoxic effects relative to AIDS-KS c ells. Additional studies further supported the contribution of reduced thio ls in mediating doxorubicin tolerance. While pretreatment with the GSH prec ursor, N-acetylcysteine was cytoprotective for all cell groups during doxor ubicin challenge, GSH depletion markedly enhanced doxorubicin's cytotoxic e ffects. Studies to investigate the effects of a hydroxyl scavenger and iron chelator during doxorubicin challenge showed moderate cytoprotection in th e AIDS-KS cells but deleterious effects in the HIV- control cells. Inactiva tion of the longer lived membrane generated ROI in the cytoprotective defic ient AIDS-KS cells, as well as an impairment of endogenous defenses in the HIV- donor control cells, may account for these scavenger and chelator asso ciated findings. In summary, our findings show that doxorubicin mediates, a t least in part, its AIDS-KS cellular cytotoxic effects by a redox related mechanism, and provides a biochemical rationale for doxorubicin's clinical efficacy in AIDS-KS treatment. (C) 1999 Wiley-Liss, Inc.