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

Abstract

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.

• Authors: S R Mallery, Y M Clark, G M Ness, O M Minshawi, P Pei, C M Hohl
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 73 Issue 2 Pg. 259-77 (May 01 1999) ISSN: 0730-2312 [Print] United States
• PMID: 10227389 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Sulfhydryl Compounds
• Doxorubicin
• 1,3-dimethylthiourea
• Glutathione
• Thiourea
• Deferoxamine

Topics

• AIDS-Related Opportunistic Infections (metabolism, pathology)
• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• DNA Replication (drug effects)
• Deferoxamine (pharmacology)
• Doxorubicin (pharmacology)
• Glutathione (metabolism)
• HIV Seronegativity
• Humans
• Male
• Oxidation-Reduction
• Sarcoma, Kaposi (metabolism, pathology)
• Sulfhydryl Compounds (metabolism)
• Thiourea (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured