Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland.
Department of Medicine II, University of Tübingen, Germany.
Leuk Res. 2014 Mar;38(3):383-92. doi: 10.1016/j.leukres.2013.12.017. Epub 2013 Dec 25.
Protein metabolism is an innovative potential therapeutic target for AML. Proteotoxic stress (PS) sensitizes malignant cells for proteasome inhibitor treatment. Some HIV protease inhibitors (HIV-PI) induce PS and may therefore be combined with proteasome inhibitors to achieve PS-targeted therapy of AML.
We investigated the effects of all nine approved HIV-PI alone and in combination with proteasome inhibitors on AML cell lines and primary cells in vitro.
Ritonavir induced cytotoxicity and PS at clinically achievable concentrations, and induced synergistic PS-triggered apoptosis with bortezomib. Saquinavir, nelfinavir and lopinavir were likewise cytotoxic against primary AML cells, triggered PS-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with bortezomib and carfilzomib at low micromolar concentrations. Exclusively nelfinavir inhibited intracellular proteasome activity, including the β2 proteasome activity that is not targeted by bortezomib/carfilzomib.
Of the nine currently approved HIV-PI, ritonavir, saquinavir, nelfinavir and lopinavir can sensitize AML primary cells for proteasome inhibitor treatment at low micromolar concentrations and may therefore be tested clinically toward a proteotoxic stress targeted therapy of AML.
蛋白质代谢是 AML 的一个创新潜在治疗靶点。蛋白毒性应激（PS）使恶性细胞对蛋白酶体抑制剂治疗敏感。一些 HIV 蛋白酶抑制剂（HIV-PI）诱导 PS，因此可能与蛋白酶体抑制剂联合使用，以实现 AML 的 PS 靶向治疗。
我们研究了所有九种已批准的 HIV-PI 单独使用和与蛋白酶体抑制剂联合使用对 AML 细胞系和原代细胞的体外影响。
利托那韦在临床可达到的浓度下诱导细胞毒性和 PS，并与硼替佐米诱导协同 PS 触发的细胞凋亡。沙奎那韦、奈非那韦和洛匹那韦同样对原代 AML 细胞具有细胞毒性，触发 PS 诱导的细胞凋亡，抑制 AKT 磷酸化，并在低微摩尔浓度下与硼替佐米和卡非佐米表现出协同细胞毒性。仅奈非那韦抑制细胞内蛋白酶体活性，包括硼替佐米/卡非佐米不靶向的β2 蛋白酶体活性。
在九种目前批准的 HIV-PI 中，利托那韦、沙奎那韦、奈非那韦和洛匹那韦可以在低微摩尔浓度下使 AML 原代细胞对蛋白酶体抑制剂治疗敏感，因此可能在临床上针对 AML 的蛋白毒性应激靶向治疗进行测试。
