P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells.
P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells.
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DOI：
10.1016/j.yexcr.2011.03.004
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发表时间：
2011-07-15
影响因子：
3.7
通讯作者：
Cabot, Myles C.
中科院分区：
文献类型：
--
作者：
Chapman, Jacqueline V.;Gouaze-Andersson, Valerie;Karimi, Ramin;Messner, Maria C.;Cabot, Myles C.
P-糖蛋白(P-gp)拮抗剂在糖基化的交界处抑制神经酰胺代谢。这项研究的目的是测试靶向P-gp是否是靶向葡萄糖神经酰胺合成酶(GCS)以增强神经酰胺细胞毒性的可行替代方案。使用A2780野生型、多药耐药的2780AD和NCI/ADR-RES人卵巢癌细胞系和细胞通透性神经酰胺类似物C6-神经酰胺(C6-Cer)。与缺乏P-gp的A2780细胞相比，富含P-gp的2780AD细胞将C6-Cer转化为无毒的C6-葡萄糖神经酰胺(C6-GC)的能力是A2780细胞的3.7倍，而无细胞的GCS活性相同。2780AD细胞对C6-Cer(10μM)表现出耐药性，P-gp拮抗剂他莫昔芬(5μM)可逆转这种耐药，但GCS抑制剂不能逆转这种耐药。C6-Cer和P-gp拮抗剂联合应用对NCI/ADR-RES细胞也有效。例如，C6-Cer、VX-710(Biricodar)和环孢菌素A(Cyc A)的暴露使对照的存活率达到约90%；然而，C6-Cer/VX-710和C6-Cer/Cyc A的添加是协同作用，分别导致22%和17%的存活率。此外，当C6-神经酰胺和Cyc A使caspase3/7活性增加1.5倍和零倍时，组合产生3.5倍的增加。尽管细胞死亡的上游因素尚未阐明，但新型C6-神经酰胺/P-gp拮抗剂组合值得进一步研究和评估临床翻译潜力。
P-glycoprotein (P-gp) antagonists inhibit ceramide metabolism at the juncture of glycosylation. The purpose of this study was to test whether targeting P-gp would be a viable alternative to targeting glucosylceramide synthase (GCS) for enhancing ceramide cytotoxicity. A2780 wild-type, and multidrug resistant 2780AD and NCI/ADR-RES human ovarian cancer cell lines and the cell-permeable ceramide analog, C6-ceramide (C6-cer), were employed. Compared to P-gp-poor A2780 cells, P-gp-rich 2780AD cells converted 3.7-fold more C6-cer to nontoxic C6-glucosylceramide (C6-GC), whereas cell-free GCS activities were equal. 2780AD cells displayed resistance to C6-cer (10 μM) that was reversed by inclusion of the P-gp antagonist tamoxifen (5 μM) but not by inclusion of a GCS inhibitor. Co-administration of C6-cer and P-gp antagonists was also effective in NCI/ADR-RES cells. For example, C6-cer, VX-710 (Biricodar), and cyclosporin A (cyc A) exposure resulted in viabilities of ~90% of control; however, C6-cer/VX-710 and C6-cer/cyc A additions were synergistic and resulted in viabilities of 22 and 17%, respectively. Further, whereas C6-ceramide and cyc A imparted 1.5- and zero-fold increases in caspase 3/7 activity, the combination produced a 3.5-fold increase. Although the upstream elements of cell death have not been elucidated, the novel C6-ceramide/P-gp antagonist combination merits further study and assessment of clinical translational potential.
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影响因子：
2.3
作者：
Germann, UA;Shlyakhter, D;Harding, MW
通讯作者：
Harding, MW
影响因子：
45.3
作者：
Fracasso, PM;Brady, MF;McGuire, WP
通讯作者：
McGuire, WP
影响因子：
4.1
作者：
Eckford, PDW;Sharom, FJ
通讯作者：
Sharom, FJ
影响因子：
3.5
作者：
Cabot, MC;Giuliano, AE;Han, TY
通讯作者：
Han, TY
影响因子：
4.7
作者：
Fracasso, P M
通讯作者：
Fracasso, P M