Buranrat Benjaporn, Suwannaloet Wanwisa, Naowaboot Jarinyaporn
Faculty of Medicine, Mahasarakham University, Talad, Maha Sarakham 44000, Thailand.
College of Medicine and Public Health, Ubon Ratchathani University, Ubon Ratchathani, Warin chamrap, Ubon Ratchathani 34190, Thailand.
Oncol Lett. 2017 Nov;14(5):6243-6250. doi: 10.3892/ol.2017.6783. Epub 2017 Aug 21.
Simvastatin is a low density lipoprotein-lowering drug that is widely used to prevent and treat cardiovascular disease by inhibiting the mevalonate pathway. Simvastatin also exhibits inhibitory effects on a number of types of cancer. In the present study, the effects of simvastatin on the activity of doxorubicin in the breast cancer MCF-7 cell line, and the mechanisms by which this interaction occurs were investigated. The effect of simvastatin and doxorubicin treatment, alone and in combination, on the growth of MCF-7 cells was evaluated by a sulforhodamine B and colony formation assay. To delineate the mechanisms of cell death, the following parameters were measured: Reactive oxygen species (ROS) production using the fluorescence probe dihydroethidium; caspase 3 activity by the fluorometry method; gene expression by quantitative polymerase chain reaction; and apoptotic- and proliferative-related protein levels by western blotting. MCF-7 cell proliferation was significantly suppressed by 24-48 h treatment with simvastatin alone. Doses of 10-50 µM simvastatin also enhanced the cytotoxicity of doxorubicin against MCF-7 cells in a dose-dependent manner, and decreased the colony-forming ability of MCF-7 cells. Simvastatin alone or in combination with doxorubicin significantly increased ROS levels. Combination treatment significantly decreased expression of the cell cycle regulatory protein Ras-related C3 botulinum toxin substrate 1 and numerous downstream proteins including cyclin-dependent kinase (Cdk) 2, Cdk4 and Cdk6. Additionally, simvastatin in combination with doxorubicin significantly induced expression of the cyclin-dependent kinase inhibitor p21, increased cytochrome c and caspase 3 expression and reduced cyclin D1 expression. In conclusion, simvastatin acts synergistically with the anticancer drug doxorubicin against MCF-7 cells, possibly through a downregulation of the cell cycle or induction of apoptosis. Although additional studies are required, simvastatin and doxorubicin combination may be a reasonable regimen for the treatment of breast cancer.
辛伐他汀是一种降低低密度脂蛋白的药物，通过抑制甲羟戊酸途径广泛用于预防和治疗心血管疾病。辛伐他汀对多种类型的癌症也具有抑制作用。在本研究中，研究了辛伐他汀对乳腺癌MCF-7细胞系中阿霉素活性的影响以及这种相互作用发生的机制。通过磺基罗丹明B和集落形成试验评估了辛伐他汀和阿霉素单独及联合处理对MCF-7细胞生长的影响。为了阐明细胞死亡的机制，测量了以下参数：使用荧光探针二氢乙锭检测活性氧（ROS）的产生；通过荧光测定法检测半胱天冬酶3的活性；通过定量聚合酶链反应检测基因表达；通过蛋白质印迹法检测凋亡和增殖相关蛋白的水平。单独用辛伐他汀处理24 - 48小时可显著抑制MCF-7细胞增殖。10 - 50 μM剂量的辛伐他汀还以剂量依赖的方式增强了阿霉素对MCF-7细胞的细胞毒性，并降低了MCF-7细胞的集落形成能力。单独使用辛伐他汀或与阿霉素联合使用均显著提高了ROS水平。联合处理显著降低了细胞周期调节蛋白Ras相关的C3肉毒杆菌毒素底物1以及包括细胞周期蛋白依赖性激酶（Cdk）2、Cdk4和Cdk6在内的许多下游蛋白的表达。此外，辛伐他汀与阿霉素联合使用显著诱导细胞周期蛋白依赖性激酶抑制剂p21的表达，增加细胞色素c和半胱天冬酶3的表达并降低细胞周期蛋白D1的表达。总之，辛伐他汀与抗癌药物阿霉素对MCF-7细胞具有协同作用，可能是通过下调细胞周期或诱导凋亡实现的。尽管还需要进一步研究，但辛伐他汀和阿霉素联合使用可能是治疗乳腺癌的一种合理方案。
