Enhancement by verapamil of neocarzinostatin action on multidrug-resistant Chinese hamster ovary cells: possible release of nonprotein chromophore in cells.

Multidrug-resistant CHRC5 cells were about 10-fold more resistant to the proteinaceous anticancer drug neocarzinostatin (NCS) and its nonprotein chromophore (NPC) than the parental AUXB1 cells. There was little difference in cell growth, glutathione content, or activities of several antioxidant enzymes between the two cell lines. The degree of intracellular incorporation and extracellular excretion of fluorescein isothiocyanate-labeled NCS by CHRC5 cells was similar to that of AUXB1 cells. On the other hand, 20 microM verapamil or 27 microM cepharanthine restored the susceptibility of CHRC5 cells to NCS and NPC to the level of AUXB1 cells. In addition, NPC was found to suppress the photolabeling of [3H]azidopine (a known P-glycoprotein-binding ligand) to plasma membranes of CHRC5 cells. All these findings favor the possibility that NPC was excreted via P-glycoprotein, which may contribute to the resistance of CHRC5 cells to NCS.