Chow Warren A, Guo Song, Valdes-Albini Frances
Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Anticancer Drugs. 2006 Sep;17(8):891-903. doi: 10.1097/01.cad.0000224448.08706.76.
"HIV protease-induced lipodystrophy syndrome" is associated with the use of HIV protease inhibitors for treatment of HIV infection. In-vitro studies suggest that alteration of sterol regulatory element binding protein-1 levels underlie its pathogenesis. We postulated that HIV protease inhibitors may represent a novel class of antiliposarcoma agents. SW872, FU-DDLS-1 and LiSa-2 liposarcoma, and HT1080 and 293 nonliposarcoma cell lines were treated with HIV protease inhibitors (nelfinavir, ritonavir, saquinavir, indinavir and amprenavir), and clonogenic assays were performed. Nelfinavir exhibited the most potent inhibition of clonogenicity, and further assays for proliferation, cell cycle and apoptosis were performed with nelfinavir. Immunoblots were performed for sterol regulatory element binding protein-1, proapoptotic and cell cycle-related protein expression after nelfinavir treatment. Finally, a sterol regulatory element binding protein-1-inducible SW872 cell line was developed to examine the phenotype resulting from upregulated sterol regulatory element binding protein-1. Nelfinavir selectively inhibited clonogenicity and proliferation, and induced G1 cell cycle block and induced apoptosis in a dose-dependent manner in SW872 and LiSa-2 cells, whereas it had minimal or no effect on these parameters in FU-DDLS-1 or nonliposarcoma cells. Nelfinavir induced significant sterol regulatory element binding protein-1 expression in a dose-dependent and time-dependent fashion in sensitive SW872 and LiSa-2 cells, modestly in HT1080 cells, but not in nelfinavir-insensitive FU-DDLS-1 and 293 cells without inducing adipocytic differentiation. Forced expression of sterol regulatory element binding protein-1 in inducible-SW872 cells led to the induction of proapoptotic and antiproliferative proteins, and consequent reduction of cellular proliferation. Our data indicate that nelfinavir represents a novel class of antiliposarcoma agent that acts by selectively upregulating sterol regulatory element binding protein-1 expression in liposarcomas.
“HIV蛋白酶诱导的脂肪代谢障碍综合征”与使用HIV蛋白酶抑制剂治疗HIV感染有关。体外研究表明，固醇调节元件结合蛋白-1水平的改变是其发病机制的基础。我们推测HIV蛋白酶抑制剂可能代表一类新型的抗脂肪肉瘤药物。用HIV蛋白酶抑制剂（奈非那韦、利托那韦、沙奎那韦、茚地那韦和安普那韦）处理SW872、FU-DDLS-1和LiSa-2脂肪肉瘤细胞系以及HT1080和293非脂肪肉瘤细胞系，并进行克隆形成试验。奈非那韦对克隆形成的抑制作用最强，随后用奈非那韦进行增殖、细胞周期和凋亡的进一步检测。在奈非那韦处理后，对固醇调节元件结合蛋白-1、促凋亡和细胞周期相关蛋白表达进行免疫印迹分析。最后，构建了一种固醇调节元件结合蛋白-1诱导型SW872细胞系，以研究固醇调节元件结合蛋白-1上调所导致的表型。奈非那韦在SW872和LiSa-2细胞中选择性地抑制克隆形成和增殖，并以剂量依赖性方式诱导G1期细胞周期阻滞和凋亡，而对FU-DDLS-1或非脂肪肉瘤细胞的这些参数影响极小或无影响。奈非那韦在敏感的SW872和LiSa-2细胞中以剂量和时间依赖性方式诱导固醇调节元件结合蛋白-1显著表达，在HT1080细胞中适度诱导，但在对奈非那韦不敏感的FU-DDLS-1和293细胞中不诱导，且不诱导脂肪细胞分化。在诱导型SW872细胞中强制表达固醇调节元件结合蛋白-1导致促凋亡和抗增殖蛋白的诱导，从而使细胞增殖减少。我们的数据表明，奈非那韦代表一类新型的抗脂肪肉瘤药物，其作用机制是在脂肪肉瘤中选择性地上调固醇调节元件结合蛋白-1的表达。
