Effect of glutathione depletion on the cytotoxicity of cisplatin and iproplatin in a human melanoma cell line

• Published in: Cancer chemotherapy and pharmacology Vol. 40; no. 1; pp. 38 - 44
• Main Authors: PENDYALA, L, PEREZ, R, WEINSTEIN, A, ZDANOWICZ, J, CREAVEN, P. J
• Format: Journal Article
• Language: English
• Published: Berlin Springer 1997
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Buthionine Sulfoximine - pharmacology; Cell Survival - drug effects; Cisplatin - pharmacology; General aspects; Glutathione - analysis; Glutathione - physiology; Humans; Medical sciences; Melanoma - pathology; Organoplatinum Compounds - pharmacology; Pharmacology. Drug treatments; Tumor Cells, Cultured; Antineoplastic agent; Human; Iproplatin; Melanoma; Cytotoxicity; In vitro; Biological activity; Cisplatin; Established cell line; Tumor; Mechanism of action; Tumor cell; Glutathione; Platinum II Complexes
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002800050622

Previous studies from our laboratory have indicated that glutathione (GSH) may affect the cytotoxicity of iproplatin to a greater extent than four other platinum agents tested including cisplatin. Therefore we studied the effect of GSH depletion by buthionine sulfoximine (BSO) on the cytotoxicity of iproplatin and cisplatin in a human melanoma cell line SK-MEL-2. Depletion of GSH was dependent on the concentration and time of incubation with BSO. BSO (100 microM) depleted GSH by 85% at 24 h and by 91% at 48 h. BSO (10 to 100 microM) by itself was not cytotoxic to SK-MEL-2 cells. At 85% depletion of GSH, cytotoxicity of iproplatin was increased by a factor of > 7 and that of cisplatin by < 2. These results confirm the previous finding that GSH interferes with the cytotoxicity of iproplatin to a significantly greater extent than that of cisplatin. Equitoxic IC65 and IC90 values of cisplatin (2 microM and 5 microM) or iproplatin (25 microM and 50 microM) had no effect on the intracellular GSH levels in SK-MEL-2 cells. Also, depletion of GSH by BSO had no effect on the accumulation of platinum from either cisplatin or iproplatin in this cell line. Our results suggest that the effect of GSH on the cytotoxicity of cisplatin and iproplatin in this cell line was not a consequence either of differences in GSH-Pt conjugate formation, or of differences in platinum accumulation induced by GSH depletion. GSH may have modulated the cytotoxicity of these platinum complexes by other means such as effects on DNA repair, apoptosis, free radical scavenging or through other yet unidentified mechanisms.