The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo
The human immunodeficiency virus-1 protease inhibitor nelfinavir impairs proteasome activity and inhibits the proliferation of multiple myeloma cells in vitro and in vivo
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DOI：
10.3324/haematol.2011.049981
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发表时间：
2012-07-01
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影响因子：
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通讯作者：
Arnulf, Bertrand
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文献类型：
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作者：
Bono, Camille;Karlin, Lionel;Arnulf, Bertrand
背景多发性骨髓瘤（MM）是以肿瘤浆细胞在骨髓中的积聚为特征的疾病.尽管蛋白酶体抑制剂如硼替佐米带来了治疗上的改进，但骨髓瘤仍然是一种不治之症。在多种人类癌症中，人类免疫缺陷病毒蛋白酶抑制剂（例如奈非那韦）可有效抑制肿瘤进展，但其对骨髓瘤的影响尚不清楚。我们评估了nelfinavir在体外和体内对多发性myeloma.Design和MethodsThe影响nelfinavir（1-10 μ M）对蛋白酶体活性，增殖和生存能力的骨髓瘤细胞系和浆细胞从患者进行了评估，通过测量PERK，AKT，STAT 3和ERK 1/2磷酸化和CHOP表达与免疫印迹或流式细胞术。在NOD/SCID小鼠中评估体内效应，所述小鼠注射表达荧光素酶的人骨髓瘤细胞系并以75 mg/kg/天的剂量用奈非那韦处理。肿瘤的进展进行了评估，使用生物发光system.ResultsNelfinavir抑制26 S糜蛋白酶样蛋白酶体活性，受损的增殖，并引发骨髓瘤细胞系和新鲜浆细胞的凋亡。它通过诱导PERK磷酸化和CHOP表达激活促凋亡未折叠蛋白反应途径。奈非那韦治疗引发的细胞死亡与AKT、STAT 3和ERK 1/2磷酸化水平降低相关。奈非那韦增强了硼替佐米，地塞米松和组蛋白去乙酰化酶抑制剂的抗增殖活性，并延迟了骨髓瘤小鼠model.ConclusionsThese结果表明，奈非那韦，在药理学剂量，单独或联合使用，可能是有用的骨髓瘤的治疗。我们的数据为奈非那韦在骨髓瘤患者中的临床试验提供了临床前基础。
BackgroundMultiple myeloma is characterized by the accumulation of tumor plasma cells in the bone marrow. Despite therapeutic improvements brought by proteasome inhibitors such as bortezomib, myeloma remains an incurable disease. In a variety of human cancers, human immunodeficiency virus protease inhibitors (e.g. nelfinavir) effectively inhibit tumor progression, but their impact on myeloma is unknown. We assessed the in vitro and in vivo effects of nelfinavir on multiple myeloma.Design and MethodsThe effects of nelfinavir (1-10 mu M) on proteasome activity, proliferation and viability of myeloma cell lines and plasma cells from patients were assessed by measuring PERK, AKT, STAT3 and ERK1/2 phosphorylation and CHOP expression with immunoblotting or flow cytometry. The in vivo effect was assessed in NOD/SCID mice injected with luciferase expressing human myeloma cell lines and treated with nelfinavir at a dose of 75 mg/kg/day. Tumor progression was evaluated using a bioluminescent system.ResultsNelfinavir inhibited 26S chymotrypsin-like proteasome activity, impaired proliferation and triggered apoptosis of the myeloma cell lines and fresh plasma cells. It activated the pro-apoptotic unfolded protein response pathway by inducing PERK phosphorylation and CHOP expression. Cell death triggered by nelfinavir treatment correlated with decreased phosphorylation of AKT, STAT3 and ERK1/2. Nelfinavir enhanced the anti-proliferative activity of bortezomib, dexamethasone and histone deacetylase inhibitors and delayed tumor growth in a myeloma mouse model.ConclusionsThese results suggest that nelfinavir, used at a pharmacological dosage, alone or in combination, may be useful in the treatment of myeloma. Our data provide a preclinical basis for clinical trials using nelfinavir in patients with myeloma.