Sensitization to the Cytotoxicity of Adriamycin by Verapamil and Heat in Multidrug-Resistant Chinese Hamster Ovary Cells

Abstract

Development of multidrug resistance to anticancer agents is a major limitation for the success of cancer chemotherapy. The chemosensitizer verapamil increases intracellular accumulation of drugs such as adriamycin in certain multidrug-resistant cell lines. When combined with verapamil, hyperthermia should be able to alter membrane permeability to adriamycin and to enhance the cytotoxicity of the drug. Verapamil increased the cytotoxicity of adriamycin in multidrug-resistant Chinese hamster ovary cells (CH(R)C5) but not in drug-sensitive cells (AuxB1). Hyperthermia (42 degrees C) alone clearly increased the cytotoxicity of adriamycin in AuxB1 cells. There was also a small increase in CH(R)C5 cells at 42 and 43 degrees C. In drug-resistant cells, the cytotoxicity of adriamycin increased considerably when verapamil was combined with heat. This effect was dependent on temperature and increased with time of incubation. At 37 degrees C, verapamil increased the uptake of adriamycin in CH(R)C5 cells, while drug efflux decreased. When verapamil was combined with hyperthermia, drug efflux decreased even further. These results led to an overall increase in intracellular accumulation of the drug. In drug-sensitive cells, hyperthermia increased both the uptake and efflux of adriamycin, but verapamil had no effect. Verapamil plus heat increased the cytotoxicity of adriamycin in drug-resistant cells, and this was accompanied by altered permeability of the membrane to the drug. Hyperthermia combined with verapamil could be beneficial by increasing the effectiveness of adriamycin in the elimination of multidrug-resistant cells in a localized target region.