| Relationship between melanogenesis, glutathione levels and melphalan toxicity in human melanoma cells. | |
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MedLine Citation:
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PMID: 1337997 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Resistance to alkylating agents has been correlated with cellular levels of reduced glutathione (GSH) and glutathione-S-transferase (GST). GSH is also involved in regulation of melanin synthesis. Therefore, we examined sensitivity to melphalan as a function of differentiation and GSH/GST levels in three human melanoma cell lines. The Me8 cell line, classified as undifferentiated on the basis of cell shape, absence of pigment, insignificant dopa oxidase activity and presence of inhibitors of dopa-melanin formation, showed the lowest GST activity among the cell lines investigated. GLL19 cells exhibited normal differentiation as indicated by the presence of dendrites, typical eumelanosomes, melanin granules and dopa oxidase activity. These cells showed the highest GSH content and the highest GST activity. The JUSO cell line showed incomplete differentiation, and its dopa oxidase and GST activities were intermediate between the Me8 and GLL19 cell lines. The sensitivity of melanoma cell lines to melphalan increased with their degree of differentiation; it was lowest for Me8, intermediate for JUSO and highest for GLL19. Dibutyryl cyclic AMP (dbcAMP) enhanced melphalan toxicity against Me8 cells. Depletion of intracellular GSH with buthionine sulphoximine (BSO) resulted in a three-fold increase in melphalan sensitivity in all three cell lines. Our results indicate that melphalan toxicity is related to cell differentiation and GSH status of melanoma cells. Based on the observed relationship between dopa oxidase, GSH/GST levels and drug toxicity, it is proposed that competition for the GSH pool between quinonoid melanin intermediates and melphalan could diminish drug conjugation and increase cytotoxicity. |
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Authors:
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M Benathan; H Alvero-Jackson; A M Mooy; C Scaletta; E Frenk |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Melanoma research Volume: 2 ISSN: 0960-8931 ISO Abbreviation: Melanoma Res. Publication Date: 1992 Dec |
Date Detail:
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Created Date: 1993-04-02 Completed Date: 1993-04-02 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 9109623 Medline TA: Melanoma Res Country: ENGLAND |
Other Details:
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Languages: eng Pagination: 305-14 Citation Subset: IM |
Affiliation:
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Department of Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Bucladesine
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pharmacology Buthionine Sulfoximine Cell Differentiation / drug effects Cell Division / drug effects Cell Survival / drug effects Dose-Response Relationship, Drug Eye Neoplasms / metabolism*, pathology Glutathione / metabolism* Glutathione Transferase / metabolism* Humans Kinetics Melanins / biosynthesis* Melanoma / metabolism*, pathology, ultrastructure Melphalan / pharmacology* Methionine Sulfoximine / analogs & derivatives, pharmacology Microscopy, Electron Monophenol Monooxygenase / metabolism* Neoplasm Staging Skin Neoplasms / metabolism*, pathology Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Melanins; 148-82-3/Melphalan; 1982-67-8/Methionine Sulfoximine; 362-74-3/Bucladesine; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; EC 1.14.18.1/Monophenol Monooxygenase; EC 2.5.1.18/Glutathione Transferase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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