Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antimetabolites, Antineoplastic / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology*
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Buthionine Sulfoximine / pharmacology
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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DNA Damage / drug effects
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Drug Synergism
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Electron Spin Resonance Spectroscopy
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Etoposide / metabolism
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Etoposide / pharmacokinetics
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Etoposide / pharmacology*
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Free Radicals / metabolism
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Glutathione / metabolism
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Humans
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Indoles / pharmacology
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Leukemia / drug therapy
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Leukemia / pathology
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Organometallic Compounds / pharmacology
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Oxidative Stress / drug effects*
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Photosensitizing Agents / pharmacology*
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Tumor Cells, Cultured
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents, Phytogenic
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Free Radicals
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Indoles
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Organometallic Compounds
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Photosensitizing Agents
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aluminum tetrasulfophthalocyanine
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Buthionine Sulfoximine
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zinc tetrasulfophthalocyanine
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Etoposide
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Glutathione