Sensitization to DNA damage by okadaic acid or bromodeoxyuridine involves unequal effects on melanoma cell adhesion and differentiation.
Because melanoma tumors originate partly from excessive UV exposure but become relatively resistant to radiation, we have now compared the effects of okadaic acid, a phosphatase inhibitor, with that of the thymidine analog bromodeoxyuridine as sensitizers of DNA damage in B16 melanoma. We now show that 25 nM okadaic acid promotes DNA fragmentation in B16 melanoma, increasing cell detachment as well as pigmentation, a characteristic of melanocytic cell differentiation. At lower levels, okadaic acid synergizes with UV exposure to increase DNA fragmentation. Although bromodeoxyuridine also caused DNA damage, it did not increase pigmentation and it suppressed cell detachment. Okadaic acid was also more effective in promoting DNA laddering in growing versus quiescent melanocytes. Because DNA damaging effects of okadaic acid are mediated by different pathways from those used by nucleoside analogs, like bromodeoxyuridine, we propose their concurrent effect with radiation as sensitizers to DNA damage.
Rieber
M S
MS
Instituto Venezolano de Investigaciones Cientificas (IVIC), Centre for Microbiology and Cell Biology, Caracas, Venezuela. mrieber@pasteur.ivic.ve
Rieber
M
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001152:Arsenicals / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004249:DNA Damage; D053938:DNA Fragmentation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010858:Pigmentation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D000964:Antimetabolites, Antineoplastic; D001152:Arsenicals; D004791:Enzyme Inhibitors; D011500:Protein Synthesis Inhibitors; D011838:Radiation-Sensitizing Agents; C029341:oxophenylarsine; D019319:Okadaic Acid; D003513:Cycloheximide; D010749:Phosphoprotein Phosphatases; D001973:Bromodeoxyuridine