The human multidrug resistance P-glycoprotein is inactive when its maturation is inhibited: potential for a role in cancer chemotherapy

The human multidrug resistance P-glycoprotein (P-gp) contributes to the phe nomenon of multidrug resistance during cancer and AIDS chemotherapy. A pote ntial novel strategy to circumvent the effects of P-gp during chemotherapy is to prevent maturation of P-gp during biosynthesis so that the transporte r does not reach the cell surface. Here we report that immature, core-glyco sylated P-gp that is prevented from reaching the cell surface by processing mutations or by proteasome inhibitors such as lactacystin or MG-132 exhibi ted no detectable drug-stimulated ATPase activity. Disulfide cross-linking analysis also showed that the immature P-gp did not exhibit ATP-induced con formational changes as found in the mature enzyme. In addition, the immatur e P-gp was more sensitive to trypsin than the mature enzyme. These results suggest that P-gp is unlikely to be functional immediately after synthesis. These differences in the structural and enzymatic properties of the mature and core-glycosylated, immature P-g-p could potentially be used during che motherapy, and should result in the search for compounds that can specifica lly inhibit the maturation of P-gp.-Loo, T. W., Clarke, D. M. The human mul tidrug resistance P-glycoprotein is inactive when its maturation is inhibit ed: potential for a role in cancer chemotherapy.