Enhancement by Verapamil of Neocarzinostatin Action on Multidrug‐resistant Chinese Hamster Ovary Cells: Possible Release of Nonprotein Chromophore in Cells

Multidrug‐resistant CH(R)C5 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 fiuorescein isothiocyanate‐labeled NCS by CH(R)C5 cells was similar to that of AUXB1 cells. On the other hand, 20 μM verapamil or 27 μM cepharanthine restored the susceptibility of CH(R)C5 cells to NCS and NPC to the level of AUXB1 cells. In addition, NPC was found to suppress the photolabeling of [(3)H]azidopine (a known P‐glycoprotein‐binding ligand) to plasma membranes of CH(H)C5 cells. All these findings favor the possibility that NPC was excreted via P‐glycoprotein, which may contribute to the resistance of CH(R)C5 cells to NCS.