P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug resistant cancer cells

摘要: Abstract P-glycoprotein (P-gp) antagonists inhibit ceramide metabolism at the juncture of glycosylation. The purpose this study was to test whether targeting P-gp would be a viable alternative glucosylceramide synthase (GCS) for enhancing cytotoxicity. A2780 wild-type, and multidrug-resistant 2780AD NCI/ADR-RES human ovarian cancer cell lines cell-permeable analog, C6-ceramide (C6-cer), were employed. Compared P-gp-poor cells, P-gp-rich cells converted 3.7-fold more C6-cer nontoxic C6-glucosylceramide (C6-GC), whereas cell-free GCS activities equal. displayed resistance (10 μM) that reversed by inclusion antagonist tamoxifen (5 μM) but not inhibitor. Co-administration also effective in cells. For example, C6-cer, VX-710 (Biricodar), cyclosporin A (cyc A) exposure resulted viabilities ~ 90% control; however, C6-cer/VX-710 C6-cer/cyc additions synergistic 22% 17%, respectively. Further, cyc imparted 1.5- 0-fold increases caspase 3/7 activity, combination produced 3.5-fold increase. Although upstream elements death have been elucidated, novel C6-ceramide/P-gp merits further assessment clinical translational potential.