Stimulation of C32 and G361 melanoma cells using oleoyl acetyl glycerol and its effect on sulphur mustard cytotoxicity.
Epidermal melanocytes have a higher sensitivity to sulphur mustard (HD) compared with other skin cell types. This may be due to the enzymatic production of melanin precursors exerting an additional cytotoxic effect following HD depletion of the cellular protectant, GSH. Stimulation of the protein kinase C pathway in melanocytes is known to increase melanin production in melanocytes and melanoma cell lines. In order to investigate the role of pigment synthesis in HD toxicology, cultures of an unpigmented melanoma cell line (C32) and of a pigmented melanoma line (G361) were treated with the potent diacyl glycerol analogue, oleoyl acetyl glycerol (OAG), in order to determine if protein kinase C-mediated increases in pigment production could increase sensitivity to subsequent HD exposure. Stimulation of C32 cells with OAG exerted a significant protective effect against the cytotoxic effects of HD. However, this was not due to increased melanin synthesis because this cell line cannot synthesize melanin pigments. The protective action observed is postulated to be due to modulation of protein kinase C activity. In contrast, stimulation of G361 melanoma cells with OAG resulted in an increased level of cytotoxicity upon subsequent exposure to HD. Protein kinase C controls several cellular pathways including checkpoints in the cell cycle, stalling the cell in G and promoting transition through the G2/M boundary. Given the genotoxic properties of HD, these two points in the cell cycle are important in determining the overall cytotoxic effect of HD. Control of the cell cycle by protein kinase C modulation and manipulation of melanin synthetic pathways may have therapeutic benefits.
Smith
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Biomedical Sciences Department, Dstl Chemical and Biological Sciences, Salisbury, Wiltshire, UK.
Lindsay
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D002455:Cell Division; D003879:Dermatologic Agents / Q000494:pharmacology*; D004075:Diglycerides / Q000494:pharmacology*; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009151:Mustard Gas / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003879:Dermatologic Agents; D004075:Diglycerides; D008543:Melanins; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D009151:Mustard Gas