Selective drug efflux in multidrug-resistant immunoblastic B lymphoma cells with overexpressed P-glycoprotein

Abstract

Multidrug-resistant (MDR) sublines of the immunoblastic B lymphoma cell line were established by sequentially selecting in increasing concentrations of vincristine or adriamycin. The vincristine- and adriamycin-resistant cell lines, HOB1/VCR and HOB1/ADR, respectively, demonstrated resistance to a wide spectrum of chemotherapeutic agents including MDR drugs (Vinca alkaloids and anthracycline), antimicrotubule drugs (colchicine), and DNA-damaging agents (cisplatin and mitomycin C). The expression of human mdrl gene, as analyzed by Western blotting and reverse transcription-polymerase chain reaction (RT-PCR), revealed a 10–15-fold overexpression in both drug-resistant cell lines. Drug accumulation analysis demonstrated reduced accumulation of vincristine but not adriamycin in HOB1/VCR and HOB1/ADR cell lines. Inhibition of vincristine resistance was observed in both cell lines by verapamil, associated with restoration of drug accumulation, suggesting that acquired resistance in these cells is mainly due to P-glycoprotein. The drug accumulation was also examined in two series of previously characterized adriamycin-selected MDR colon adenocarcinoma cells and vincristin-selected non-MDR lung cancer cells. These studies demonstrated that immunoblastic B lymphoma cells selected for vincristine or adriamycin resistance preferentially develop P-glycoprotein-mediated vincristine efflux which plays a pivotal role in vincristine resistance. In contrast, these cells did not elevate adriamycin efflux, suggesting an additional mechanism responsible for adriamycin resistance.