文章：

奈非那韦增强骨髓瘤细胞中硼替佐米对蛋白酶体的抑制，克服硼替佐米和卡非佐米的耐药性

Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance

原文发布日期：2013-03-01

DOI: 10.1038/bcj.2013.2

类型: Original Article

开放获取: 是

英文摘要：

HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μM. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro.

摘要翻译： 

HIV蛋白酶抑制剂是用于HIV治疗的口服药物。该类药物通过诱导内质网应激、抑制磷酸化AKT及蛋白酶体发挥抗肿瘤活性，提示其具有抗骨髓瘤作用。本研究系统评估了所有已获批的HIV蛋白酶抑制剂对骨髓瘤细胞的影响。我们通过体外骨髓瘤细胞实验，比较了各药物在细胞毒性、蛋白酶体活性抑制、内质网应激诱导及AKT磷酸化抑制等方面的作用。奈非那韦对原代骨髓瘤细胞展现出最强的细胞毒性活性，其IC50值接近治疗血药浓度（8–14μM），且与硼替佐米敏感性无关。在低于40μM浓度下，仅奈非那韦能在原位抑制细胞内蛋白酶体活性。利托那韦、沙奎那韦和洛匹那韦对p-AKT的抑制能力与奈非那韦相当，并与硼替佐米协同作用于硼替佐米敏感细胞。奈非那韦与硼替佐米/卡非佐米联用时，尤其对硼替佐米/卡非佐米耐药细胞表现出更卓越的协同活性。该药物不仅能像硼替佐米/卡非佐米那样抑制蛋白酶体β1/β5活性位点，还可额外抑制硼替佐米/卡非佐米不作用的β2蛋白酶体活性。已知对β2蛋白酶体活性的附加抑制可增强细胞对硼替佐米和卡非佐米的敏感性。奈非那韦具有独特的蛋白酶体抑制特性，尤其能针对完整骨髓瘤细胞中硼替佐米/卡非佐米不敏感的胰蛋白酶样（β2）蛋白酶体活性，并在体外实验中有效抑制硼替佐米/卡非佐米耐药骨髓瘤细胞。

原文链接：

Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance