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Thiol redox modulation of doxorubicin mediated cytotoxicity in cultured AIDS‐related Kaposi's sarcoma cells
Author(s) -
Mallery Susan R.,
Clark Ying Mei,
Ness Gregory M.,
Minshawi Omar M.,
Pei Ping,
Hohl Charlene M.
Publication year - 1999
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(19990501)73:2<259::aid-jcb12>3.0.co;2-3
Subject(s) - doxorubicin , glutathione , pharmacology , cytotoxic t cell , viability assay , bleomycin , cytotoxicity , chemistry , intracellular , cancer research , cell , medicine , biochemistry , chemotherapy , in vitro , enzyme
The chemotherapeutic, doxorubicin, is currently used empirically in the treatment of AIDS‐ related Kaposi's sarcoma (AIDS‐KS). Although often employed in a chemotherapeutic cocktail (doxorubicin, bleomycin, vincristine) single‐agent therapy has recently been attempted with liposome encapsulated doxorubicin. Although doxorubicin's mechanism of action against AIDS‐KS is unknown, 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 biochemical responses of three cellular populations: KS lesional cells, nonlesional cells from the KS donors, and fibroblasts obtained from HIV − aged matched men. Our results show that during doxorubicin challenge, there are strong positive correlations between cellular glutathione (GSH) levels and viability (r = 0.94), NADPH levels and viability (r = 0.93), and GSH and NADPH levels (r = 0.93), and demonstrate that as a consequence of their abilities to maintain cellular thiol redox pools HIV − donor cells are significantly less susceptible to doxorubicin's cytotoxic effects relative to AIDS‐KS cells. Additional studies further supported the contribution of reduced thiols in mediating doxorubicin tolerance. While pretreatment with the GSH precursor, N‐acetylcysteine was cytoprotective for all cell groups during doxorubicin challenge, GSH depletion markedly enhanced doxorubicin's cytotoxic effects. Studies to investigate the effects of a hydroxyl scavenger and iron chelator during doxorubicin challenge showed moderate cytoprotection in the AIDS‐KS cells but deleterious effects in the HIV − control cells. Inactivation of the longer lived membrane generated ROI in the cytoprotective deficient AIDS‐KS cells, as well as an impairment of endogenous defenses in the HIV − donor control cells, may account for these scavenger and chelator associated findings. In summary, our findings show that doxorubicin mediates, at 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. J. Cell. Biochem. 73:259–277, 1999. © 1999 Wiley‐Liss, Inc.