Women's Cancer Research Institute and Division of Gynecologic Oncology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Gynecol Oncol. 2010 Dec;119(3):549-56. doi: 10.1016/j.ygyno.2010.08.017. Epub 2010 Sep 15.
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.
Fluvastatin and cisplatin were examined in CAOV3 and SKOV3 human ovarian cancer cell lines. Cellular proliferation was assessed using MTT 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.
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 (CI) of 0.66 was identified for CAOV3 cells and a CI 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.
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.
他汀类药物治疗与卵巢癌患者的生存延长有关。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联合抑制上皮性卵巢癌细胞的细胞增殖。
在 CAOV3 和 SKOV3 人卵巢癌细胞系中检查氟伐他汀和顺铂。使用 MTT 测定法评估细胞增殖。使用 Annexin V/碘化丙啶（PI）染色来区分早期和晚期凋亡，使用溴脱氧尿苷和 PI 染色进行细胞周期分析，以及使用 Western blot 进行蛋白质表达分析。使用等对数图分析确定协同作用。
与单独使用任何一种药物相比，联合使用氟伐他汀和顺铂的多种剂量导致增殖的抑制显著增加。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，CAOV3 细胞的组合指数（CI）为 0.66，SKOV3 细胞的 CI 为 0.24，表明存在协同作用。联合氟伐他汀和顺铂导致 G2/M 期阻滞，并与单独使用氟伐他汀或顺铂相比，早期凋亡细胞明显增加。此外，法尼基焦磷酸（FPP）和香叶基焦磷酸（GGPP）的补充表明，GGPP 而不是 FPP 能够克服氟伐他汀诱导的细胞毒性。最后，两药联合抑制了 Ras 通路蛋白的表达和修饰状态。
这些数据表明氟伐他汀和顺铂的协同细胞毒性作用，通过早期凋亡和细胞周期阻滞，同时伴随着 Ras 通路蛋白的失调。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。
