Potentiation of sensitivity to bleomycin and the drug-induced DNA damage in EMT6 cells by the calmodulin inhibitor trifluoperazine.

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.