Thiol redox modulation of doxorubicin mediated cytotoxicity in cultured AIDS-related Kaposi's sarcoma cells.
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.
Mallery
S R
SR
College of Dentistry, Department of Oral and Maxillofacial Surgery and Pathology, Ohio State University, Columbus 43210-1241, USA.
Clark
Y M
YM
Ness
G M
GM
Minshawi
O M
OM
Pei
P
P
Hohl
C M
CM
D017088:AIDS-Related Opportunistic Infections / Q000378:metabolism / Q000473:pathology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D018023:HIV Seronegativity; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D013438:Sulfhydryl Compounds; D004317:Doxorubicin; C038983:1,3-dimethylthiourea; D005978:Glutathione; D013890:Thiourea; D003676:Deferoxamine