Circumvention of P‐glycoprotein‐mediated drug resistance in human leukaemic cells by non‐immunosuppressive cyclosporin D analogue, SDZ PSC 833

Abstract

Cyclosporin A (CSA) exhibits greater multidrug resistance (MDR) modulating activity in vitro than other MDR modulators such as verapamil and quinidine. However, the immunosuppressive and nephrotoxic effects of CSA may limit its clinical use. PSC 833, a new cyclosporin D derivative, exerts a higher MDR reversal activity but lacks toxic or immunosuppressive effects. The drug-resistant sublines K/DAU100, K/DAU200, K/DAU300, K/DAU400, K/DAU500 and K/DAU600 have been derived from the drug-sensitive parental cell line, K562 cl.6 and CEM/VLB100 is a drug-resistant derivative of CCRF-CEM. We report a comparison of the effects of PSC 833 and CSA on daunorubicin (DAU) transport kinetics and chemosensitivity in these cell lines. Both CEM/VBL100 and K562 cl.6 DAU-resistant cells displayed high levels of P-glycoprotein (PGP), decreased DAU accumulation and increased DAU efflux when compared to their parental cells. PSC 833 was 1.6-, 3.4-, 4.9- and 4.6-fold more effective than CSA in reversing DAU resistance in higher resistance CEM/VLB100, K/DAU400, K/DAU500 and K/DAU600 cells respectively. DAU transport kinetics showed that PSC 833 was more effective than CSA in increasing cellular DAU accumulation and decreasing DAU efflux in higher resistant leukaemia subclones. PSC 833 could restore DAU retention at lower doses and was more active than CSA in all the resistant cells. A 89-100% restoration of intracellular DAU retention were gained by PSC 833 at 1.0 microM in K562 cl.6 DAU-resistant sublines, whereas a 73-100% restoration of DAU retention was obtained by CSA only at 30.0 microM in the same resistant sublines. PSC 833 at 3.0 microM is sufficient to restore full DAU retention in all resistant cells. CSA, however, even at 30.0 microM, cannot confer full restoration of DAU retention in higher resistance K562 cl.6/DAU sublines. By measuring MDR modulator-mediated short-term inhibition of PGP function, PSC 833 was found to be at least 10-30 times more active than CSA. As no effect on DAU retention and sensitivity has been found in sensitive parental cells with PSC 833, it is suggested that PSC 833 may act by blocking the effluxing function of PGP in the resistant leukaemia cells.