Correction of altered plasma membrane potentials. A possible mechanism of cyclosporin A and verapamil reversal of pleiotropic drug resistance in neoplasia.

We have recently shown that cyclosporin A (CsA) reverses pleiotropic drug resistance in human acute lymphatic leukemia in vitro and daunorubicin resistance in Ehrlich ascites tumor in vivo. In the present study we examined the mechanisms by which CsA might reverse pleiotropic drug resistance relative to changes in cellular plasma membrane potentials and intracellular calcium ([Ca2+]i). Membrane potentials were measured with DIOC5 dye flow-cytometrically and [Ca2+]i levels with Quin 2 dye spectrofluorimetrically. All pleiotropic (PDR) drug-resistant tumor sublines had decreased membrane potentials (membrane depolarized) compared with their corresponding drug-sensitive parental tumors. In comparison, the membrane potentials of a control antimetabolite-resistant acute leukemia cell line were unchanged. The basal levels of [Ca2+]i in the PDR sublines were variable compared with those of parental drug-sensitive cell lines. Incubation of all PDR tumor sublines with CsA or verapamil resulted in the restoration of membrane potentials to that characteristic of the corresponding drug-sensitive parental tumor. Cyclosporin A produced variable changes in the levels of [Ca2+]i. These data suggest that alteration of membrane potentials is one of the mechanisms responsible for pleiotropic drug resistance in malignancy and show that this alteration is corrected by CsA and verapamil.