Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo
Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo
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DOI：
10.1158/1078-0432.ccr-07-0161
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发表时间：
2007-09-01
影响因子：
11.5
通讯作者：
Dennis, Phillip A.
中科院分区：
文献类型：
--
作者：
Gills, JoellJ.;Lo Piccolo, Jaclyn;Dennis, Phillip A.
目的：新的癌症药物的开发是缓慢和昂贵的。HIV蛋白酶抑制剂是食品和药物管理局批准用于HIV患者的。由于这些药物引起的毒性，可以与抑制Akt，一个新兴的目标在癌症中，我们评估了潜在的HIV蛋白酶抑制剂作为anticanceragents.Experimental Design：HIV蛋白酶抑制剂进行了筛选，在体外使用测定细胞增殖，凋亡和非凋亡细胞死亡，内质网（ER）的压力，自噬和激活Akt。奈非那韦在非小细胞肺癌（NSCLC）异种移植物中进行了生物标志物assessment.Results：三个六个HIV蛋白酶抑制剂，奈非那韦，利托那韦，和sacluinavir，抑制NSCLC细胞的增殖，以及在NCI 60细胞系面板中的每一个细胞系。奈非那韦是最有效的，平均50%的生长抑制5.2 μ mol/L，在HIV患者中可达到的浓度。奈非那韦引起两种类型的细胞死亡，半胱天冬酶依赖性凋亡和半胱天冬酶非依赖性死亡，其特征在于诱导ER应激和自噬。自噬是保护性的，因为自噬抑制剂增加奈非那韦诱导的死亡。HIV蛋白酶抑制剂可抑制Akt，但奈非那韦对内源性和生长因子诱导的Akt活化的抑制作用最大。奈非那韦降低了一组耐药乳腺癌细胞系的生存能力，并抑制了NSCLC异种移植物的生长，这与诱导ER应激，自噬和apoptosis.Conclusions：奈非那韦是一种领先的HIV蛋白酶抑制剂，在癌细胞中具有多效作用。鉴于其广泛的活性，口服可用性和熟悉的管理，奈非那韦是食品和药物管理局批准的药物，可以重新定位为癌症治疗。
Purpose: The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents.Experimental Design: HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non-small cell lung carcinoma (NSCLC) xenografts with biomarker assessment.Results: Three of six HIV protease inhibitors, nelfinavir, ritonavir, and sacluinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 mu mol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis.Conclusions: Nelfinavir is a lead HIV protease inhibitor with pleioitropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration-approved drug that could be repositioned as a cancer therapeutic.