Effect of L-dopa methylester and glutathione depletion on murine B16BL6 melanoma growth in vitro.
The cytotoxic and growth-inhibitory effect of levodopa methylester (LDME) in murine B16BL6 (BL6) melanoma cells after glutathione (GSH) depletion was studied in vitro. Pretreatment of BL6 cells with 50 microM buthionine sulfoximine (BSO) depleted GSH content by nearly 90% and enhanced the growth-inhibitory effect of even a minimally cytotoxic concentration of LDME. Radiothymidine incorporation into BL6 cells significantly increased compared to untreated controls during the first 4 h of exposure to 0.2 mM LDME. However, pretreatment with BSO prevented this LDME-induced increase in radiothymidine incorporation. Because the percentage of cells in S-phase of the cell cycle was not altered, these results suggest that BSO exposure may be inhibiting unscheduled DNA synthesis, which could contribute to the cytotoxic effects of LDME. In addition, spectrophotometric studies indicated that in a cell-free system, GSH scavenged dopaquinone produced by the tyrosinase-mediated oxidation of LDME, presumably by formation of glutathionyldopa. Thus, enhancement of LDME cytotoxicity by BSO may also involve depleting the amount of GSH available for the nucleophilic addition to the quinone.
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Pharmaceutical Sciences, College of Pharmacy, Washington State University 99164-6510.
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D000818:Animals; D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000032:analysis* / Q000172:deficiency; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000473:pathology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice
D008717:Methionine Sulfoximine; D007980:Levodopa; D019328:Buthionine Sulfoximine; D005978:Glutathione; C035420:levodopa methyl ester