title: Potentiation of sensitivity to bleomycin and the drug-induced DNA damage in EMT6 cells by the calmodulin inhibitor trifluoperazine.
abstract: It has been shown that inhibitors of calmodulin can increase the sensitivity of rodent cells to Bleomycin by interfering with DNA repair functions. As a result of this study we have found that treatment of plateau-phase EMT6 cells with Bleomycin causes a decrease in cell survival due to DNA damage. This toxic effect can be potentiated by the addition of a nonlethal dose of the calmodulin inhibitor Trifluoperazine. Furthermore, it was found that Trifluoperazine greatly potentiated Bleomycin-induced DNA breakage. Considering the results obtained by alkaline-denaturation assay (detects single-strand breaks, including these arising from alkali-labile lesions) and nucleoid sedimentation (in neutral sucrose gradients) assay (detects only frank breaks), a difference, presumably due to the Trifluoperazine-produced discrete block in the repair of Bleomycin-induced DNA alkali-labile lesions was found. These data suggest a role for calmodulin in the DNA repair pathway and provide a rational basis for the use of calmodulin inhibitors in cancer chemotherapy.
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004247:DNA / Q000187:drug effects*; D004260:DNA Repair; D004357:Drug Synergism; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D002147:Calmodulin; D001761:Bleomycin; D014268:Trifluoperazine; D004247:DNA