McLean Karen, VanDeVen Natalie A, Sorenson Dorothy R, Daudi Sayeema, Liu J Rebecca
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
Gynecol Oncol. 2009 Mar;112(3):623-30. doi: 10.1016/j.ygyno.2008.11.028. Epub 2009 Jan 15.
HIV patients taking antiretroviral protease inhibitors have a lower incidence of infection-associated malignancies, leading to the hypothesis that these drugs have antineoplastic activity. Given the need for novel treatment approaches in ovarian cancer, we sought to determine whether the protease inhibitor saquinavir has antineoplastic activity in ovarian cancer cell lines, and to elucidate the mechanism through which this occurs.
A panel of ovarian cancer cell lines was treated with saquinavir. The effect of saquinavir on cell growth, viability, apoptotic and non-apoptotic cell death was determined. Stimulation of endoplasmic reticulum stress (ERS) response was assessed by immunoblotting for ERS regulators GRP78 and ATF6. Induction of autophagy was assessed using transmission electron microscopy (TEM), and confocal microscopy was performed to demonstrate changes in green fluorescent protein-labeled LC3 expression patterns.
Saquinavir induced cell death in chemosensitive and chemoresistant ovarian cancer cells in a time- and dose-dependent manner. Saquinavir treatment resulted in caspase-dependent apoptosis and caspase-independent cell death characterized by induction of ERS and autophagy. Cellular morphology assessed by TEM revealed apoptotic, autophagic, and necrotic cell death.
Saquinavir is an FDA-approved agent for the treatment of HIV, and our data suggest that it may also have clinical application in the treatment of ovarian cancer. Saquinavir induces endoplasmic reticulum stress, autophagy, and apoptosis in ovarian cancer cells. Given the challenges of chemoresistance in ovarian cancer, saquinavir may have particular benefit in the treatment of chemoresistant tumors that may respond to the induction of caspase-independent cell death by mechanisms such as autophagy.
服用抗逆转录病毒蛋白酶抑制剂的HIV患者感染相关恶性肿瘤的发病率较低，由此产生了这些药物具有抗肿瘤活性的假说。鉴于卵巢癌需要新的治疗方法，我们试图确定蛋白酶抑制剂沙奎那韦在卵巢癌细胞系中是否具有抗肿瘤活性，并阐明其发生的机制。
用沙奎那韦处理一组卵巢癌细胞系。测定沙奎那韦对细胞生长、活力、凋亡和非凋亡性细胞死亡的影响。通过对内质网应激（ERS）调节因子GRP78和ATF6进行免疫印迹来评估ERS反应的激活情况。使用透射电子显微镜（TEM）评估自噬的诱导情况，并进行共聚焦显微镜检查以显示绿色荧光蛋白标记的LC3表达模式的变化。
沙奎那韦以时间和剂量依赖性方式诱导化疗敏感和化疗耐药的卵巢癌细胞死亡。沙奎那韦治疗导致依赖半胱天冬酶的凋亡和以ERS及自噬诱导为特征的非半胱天冬酶依赖性细胞死亡。通过TEM评估的细胞形态显示有凋亡、自噬和坏死性细胞死亡。
沙奎那韦是一种经美国食品药品监督管理局（FDA）批准用于治疗HIV的药物，我们的数据表明它在卵巢癌治疗中也可能有临床应用。沙奎那韦在卵巢癌细胞中诱导内质网应激、自噬和凋亡。鉴于卵巢癌化疗耐药的挑战，沙奎那韦在治疗可能通过自噬等机制对非半胱天冬酶依赖性细胞死亡诱导产生反应的化疗耐药肿瘤方面可能具有特殊益处。
