Resistance of human glioma to adriamycin in vitro: the role of membrane transport and its circumvention with verapamil

Abstract

We have investigated the mechanism of resistance to adriamycin (ADR) of 3 human glioma cell lines in culture. The cell lines had different inherent sensitivities to ADR. Verapamil increased the ADR sensitivities of the 2 most resistant cell lines (G-UVW and G-CCM) by up to 5-fold. This effect was not seen in a sensitive cell line (G-MCF). Although the accumulation of ADR in the 3 cell lines was not related to inherent sensitivity, energy deprivation or the addition of verapamil produced an increase (up to 46%) in net uptake for both G-UVW and G-CCM, but not for G-MCF. For G-UVW the ADR efflux data were consistent with an energy-dependent ADR efflux mechanism which could be inhibited by verapamil. A similar mechanism was not found for G-CCM. In this cell line verapamil may act by increasing intracellular ADR binding. These data indicate that, while inherent resistance to ADR may be multifactorial, one possible mechanism of resistance in human glioma may involve changes in drug accumulation and/or binding as has been seen in animals models. A potential clinical role for verapamil in overcoming drug resistance in human solid tumours is also indicated.