Increase of vinblastine accumulation by inhibitors of calmodulin-dependent cell functions in rat ascites hepatoma AH66 cells.

ML-9, an inhibitor for myosin light chain kinase, and W-7, a calmodulin inhibitor, suppressed the efflux of vinblastine and increased the intracellular accumulation of vinblastine, but W-5, an inactive compound for calmodulin, did not so in rat ascites hepatoma AH66 cells, which have a multidrug-resistant phenotype. In sensitive counterpart AH66F cells, W-7 and ML-9 were less effective. W-7 and ML-9 did not interfere with [3H]azidopine photolabeling of P-glycoprotein in the plasma membrane from AH66 cells. While P-glycoprotein is reported to be superphosphorylated by protein kinases, W-7 did not influence the phosphorylation of the P-glycoprotein in AH66 cells. There may be an unknown Ca(2+)-calmodulin-dependent mechanism in the extrusion of vinblastine from AH66 cells.