Department of Experimental Pathology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, USA.
Neoplasia. 2011 May;13(5):483-91. doi: 10.1593/neo.11148.
Ovarian cancer is the most lethal gynecologic cancer in women. Its high mortality rate (68%) reflects the fact that 75% of patients have extensive (>stage III) disease at diagnosis and also the limited efficacy of currently available therapies. Consequently, there is clearly a great need to develop improved upfront and salvage therapies for ovarian cancer. Here, we investigated the efficacy of metformin alone and in combination with cisplatin in vivo. A2780 ovarian cancer cells were injected intraperitoneally in nude mice; A2780-induced tumors in nude mice, when treated with metformin in drinking water, resulted in a significant reduction of tumor growth, accompanied by inhibition of tumor cell proliferation (as assessed by immunohistochemical staining of Ki-67, Cyclin D1) as well as decreased live tumor size and mitotic cell count. Metformin-induced activation of AMPK/mTOR pathway was accompanied by decreased microvessel density and vascular endothelial growth factor expression. More importantly, metformin treatment inhibited the growth of metastatic nodules in the lung and significantly potentiated cisplatin-induced cytotoxicity resulting in approximately 90% reduction in tumor growth compared with treatment by either of the drugs alone. Collectively, our data show for the first time that, in addition to inhibiting tumor cell proliferation, metformin treatment inhibits both angiogenesis and metastatic spread of ovarian cancer. Overall, our study provides a strong rationale for use of metformin in ovarian cancer treatment.
卵巢癌是女性中最致命的妇科癌症。其高死亡率（68%）反映了一个事实，即 75%的患者在诊断时已经患有广泛的（>III 期）疾病，以及当前可用疗法的疗效有限。因此，显然需要开发针对卵巢癌的改进的一线和挽救疗法。在这里，我们研究了二甲双胍单独使用和联合顺铂在体内的疗效。将 A2780 卵巢癌细胞注入裸鼠腹腔内；用饮用水中的二甲双胍处理 A2780 诱导的裸鼠肿瘤，导致肿瘤生长显著减少，伴随着肿瘤细胞增殖的抑制（通过 Ki-67、Cyclin D1 的免疫组织化学染色评估）以及活肿瘤大小和有丝分裂细胞计数的减少。二甲双胍诱导的 AMPK/mTOR 通路的激活伴随着微血管密度和血管内皮生长因子表达的降低。更重要的是，二甲双胍治疗抑制了肺转移结节的生长，并显著增强了顺铂诱导的细胞毒性，与单独使用任何一种药物相比，肿瘤生长减少了约 90%。总的来说，我们的数据首次表明，除了抑制肿瘤细胞增殖外，二甲双胍治疗还抑制了卵巢癌的血管生成和转移扩散。总体而言，我们的研究为在卵巢癌治疗中使用二甲双胍提供了强有力的依据。
