Growth inhibition, cytokinesis failure and apoptosis of multidrug-resistant leukemia cells after treatment with P-glycoprotein inhibitory agents

The multidrug transporter P-glycoprotein (Pgp), which is frequently overexp ressed in multidrug resistant leukemia, has many proposed physiological fun ctions including involvement in transmembraneous transport of certain growt h-regulating cytokines. Therefore, we studied cell growth of three pairs of drug resistant and sensitive leukemia cell lines (KG1a, K562 and HL60) exp osed to three different inhibitors of Pgp. The resistant KG1a and K562 subl ines, which expressed high levels of Pgp, responded to low doses of the cyc losporin SDZ PSC 833, the cyclopeptolide SDZ 280-446, and the cyclopropyldi benzosuberane LY335979 with a dose-dependent growth inhibition. In the resi stant variants of KG1a and K562 cells the mean half-maximal growth inhibito ry doses (GI(50)) of SDZ PSC 833 were 312 (SE 41) and 414 (SE 50) nM, those of SDZ 280-446 were 685 (SE 51) and 578 (SE 54) nM, and those of LY335979 were 66 (SE 1) and 48 (SE 8) nM, respectively. Exposure to 1 mu M SDZ PSC 8 33 resulted in tetraploidization, cytokinesis failure and apoptosis of the KG1a and K562 MDR variants. Conversely, parental cells with no or low level s of Pgp and the non-Pgp resistant variant of HL60 cells were not receptive to these cytotoxic effects. We conclude that inhibition of Pgp may exercis e selective cytotoxicity in Pgp-rich leukemia cells indicating a possible t herapeutic target in multiresistant leukemia.