Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells
Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells
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DOI：
10.1016/j.ygyno.2010.08.017
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发表时间：
2010-12-01
影响因子：
4.7
通讯作者：
Li, Andrew J.
中科院分区：
文献类型：
--
作者：
Taylor-Harding, Barbie;Orsulic, Sandra;Li, Andrew J.
客观的。他汀类药物治疗与卵巢癌患者的生存期延长有关。我们假设他汀类药物具有细胞毒性作用，并且氟伐他汀和顺铂的组合可抑制上皮性卵巢癌细胞的细胞增殖。方法。在 CAOV3 和 SKOV3 人卵巢癌细胞系中检查了氟伐他汀和顺铂。使用mu测定评估细胞增殖。膜联蛋白 V/碘化丙啶 (PI) 染色用于区分早期和晚期细胞凋亡，溴脱氧尿苷和 PI 染色用于细胞周期分析，蛋白质印迹用于蛋白质表达分析。使用等效线图分析确定协同作用。结果。与单独使用任一药物相比，多次剂量的氟伐他汀和顺铂联合治疗可显着增强对增殖的抑制作用。当检查氟伐他汀和顺铂的等效组合以确定潜在的协同作用时，确定 CAOV3 细胞的组合指数 (CI) 为 0.66，SKOV3 细胞的 CI 为 0.24，表明协同作用。与单独使用氟伐他汀或顺铂相比，氟伐他汀和顺铂的组合导致 G2/M 期阻滞，并且早期凋亡细胞显着增加。此外，补充法呢基焦磷酸（FPP）和香叶基香叶基焦磷酸（GGPP）表明，GGPP而不是FPP能够克服氟伐他汀诱导的细胞毒性。最后，两药联合损害了Ras通路蛋白的表达和修饰状态。结论。这些数据证明了氟伐他汀和顺铂通过过早凋亡和细胞周期停滞以及伴随的Ras途径蛋白失调而具有协同细胞毒性。我们的研究支持他汀类药物在卵巢癌辅助治疗中的合理治疗作用。 (C) 2010 Elsevier Inc. 保留所有权利。
Objective. Statin therapy has been associated with prolonged survival in patients with ovarian cancer. We hypothesized that statins have a cytotoxic effect and that the combination of fluvastatin and cisplatin inhibits cellular proliferation in epithelial ovarian cancer cells.Methods. Fluvastatin and cisplatin were examined in CAOV3 and SKOV3 human ovarian cancer cell lines. Cellular proliferation was assessed using mu assays. Annexin V/propidium iodide (PI) staining was used to discriminate between early and late apoptosis, bromodeoxyuridine and PI staining for cell cycle profiling, and Western blotting for protein expression analysis. Synergy was determined using isobologram analysis.Results. Treatment with combination fluvastatin and cisplatin at multiple doses resulted in significantly greater inhibition of proliferation compared to either drug alone. When examining equipotent combinations of fluvastatin and cisplatin to determine potential synergy, a combination index (Cl) of 0.66 was identified for CAOV3 cells and a Cl of 0.24 for SKOV3 cells indicating synergy. Combination fluvastatin and cisplatin resulted in G2/M arrest, and a significant increase in early apoptotic cells compared to fluvastatin or cisplatin alone. Moreover, supplementation of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) demonstrated that GGPP rather than FPP was able to overcome fluvastatin-induced cytotoxicity. Finally, the two-drug combination impaired the expression and modification status of proteins of the Ras pathway.Conclusions. These data demonstrate the synergistic cytotoxicity of fluvastatin and cisplatin, through premature apoptosis and cell cycle arrest, with concomitant dysregulation of Ras pathway proteins. Our studies support a plausible therapeutic role for statins in the adjuvant treatment of ovarian cancer. (C) 2010 Elsevier Inc. All rights reserved.