Enhancement of etoposide (VP-16) cytotoxicity by enzymatic and photodynamically induced oxidative stress.
The effects of glutathione (GSH) depletion by buthionine sulfoximane (BSO) or by photosensitization-induced oxidative stress using metallo-phthalocyanines (MePcS4) on etoposide (VP-16) cytotoxicity against K562 human leukemic cells were investigated. Both treatments enhanced VP-16 toxicity in a markedly synergistic way, as revealed by combination index analysis procedure. Synergistic drug interactions were accompanied by a supra-additive induction of DNA strand breaks. The proposed role of intracellular GSH in preventing metabolic transformations of VP-16 and thus decreasing its toxicity was confirmed by electron spin resonance (ESR) monitoring of the accumulation of the VP-16 phenoxyl radical in cell cytoplasm subjected to GSH depletion. Taken together the results emphasize the beneficial effect of GSH-related oxidative stress in enhancement of etoposide toxicity and possibly in its anticancer applications.
Gantchev
T G
TG
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Hunting
D J
DJ
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D005047:Etoposide / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D017319:Photosensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D005609:Free Radicals; D007211:Indoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; C048577:aluminum tetrasulfophthalocyanine; D019328:Buthionine Sulfoximine; C052735:zinc tetrasulfophthalocyanine; D005047:Etoposide; D005978:Glutathione