Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models.
Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models.
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DOI：
10.1016/j.ajog.2014.10.026
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发表时间：
2015-04
影响因子：
9.8
通讯作者：
Romero, Iris L.
中科院分区：
文献类型：
--
作者：
Lengyel, Ernst;Litchfield, Lacey M.;Mitra, Anirban K.;Nieman, Kristin M.;Mukherjee, Abir;Zhang, Yilin;Johnson, Alyssa;Bradaric, Michael;Lee, WooSeok;Romero, Iris L.
越来越多的临床前证据表明，二甲双胍，一种通常用于治疗2型糖尿病的药物，可能会预防癌症。在这些新出现的证据的激励下，我们提出了两个问题：(A)二甲双胍能否通过改变新陈代谢来防止卵巢癌的生长，以及(B)二甲双胍是否会增加对化疗的敏感性。在体外和两种不同的小鼠模型上测试了二甲双胍对卵巢癌的作用。在体外，细胞株(n=6)用二甲双胍(10~40 mM)或PBS处理，比较两组细胞的增殖和代谢变化(AMP活化蛋白激酶活性、糖酵解、脂质合成)。在小鼠模型中，通过给小鼠腹腔注射二甲双胍(250 mg/kg/天)进行预防研究。或服用安慰剂2周，然后ip。比较SKOV3ip1人卵巢癌细胞系的接种情况和各治疗组的平均肿瘤种植数。在治疗研究中，采用LSL-K-RasG12D/+/PTENflxP/FloxP基因小鼠卵巢癌模型。给小鼠灌胃安慰剂紫杉醇(3 mg/kg/周ip)。X 7周)、二甲双胍(100 mg/kg/d加水×7周)或紫杉醇+二甲双胍治疗组之间的肿瘤体积和肿瘤体积进行比较。在体外，二甲双胍可抑制卵巢癌细胞株的增殖，并诱导细胞周期停滞，但不能诱导细胞凋亡。进一步的分析表明，二甲双胍改变了代谢的几个方面，包括AMP激活的蛋白激酶活性、糖酵解和脂肪合成。在预防性小鼠模型中，与对照组相比，用二甲双胍预处理的小鼠的肿瘤植入物减少了60%(p<；0.005)。在治疗研究中，与对照组相比，接受紫杉醇和二甲双胍治疗的小鼠的肿瘤重量减少了60%(p=0.02)；与单独使用紫杉醇或二甲双胍相比，肿瘤减少的程度更大。基于这些结果，我们得出结论，在体外和小鼠模型中，二甲双胍改变了卵巢癌细胞的新陈代谢，防止了肿瘤的生长，并增加了对化疗的敏感性。这些临床前的研究结果表明，二甲双胍作为卵巢癌的治疗药物值得进一步研究。
There is increasing pre-clinical evidence indicating that metformin, a medication commonly used for type 2 diabetes, may protect against cancer. Motivated by this emerging evidence we asked two questions: (a) can metformin prevent ovarian cancer growth by altering metabolism, and (b) will metformin increase sensitivity to chemotherapy. The effect of metformin in ovarian cancer was tested in vitro and by using two different mouse models. In vitro, cell lines (n=6) were treated with metformin (10 to 40 mM) or PBS and cellular proliferation and metabolic alterations (AMP-activated protein kinase activity, glycolysis, lipid synthesis) were compared between the two groups. In mouse models, a prevention study was performed by treating mice with metformin (250 mg/kg/day intraperitoneal (i.p.)) or placebo for 2 weeks followed by i.p. injection of the SKOV3ip1 human ovarian cancer cell line and the mean number of tumor implants in each treatment group was compared. In a treatment study, the LSL-K-rasG12D/+/PTENfloxP/floxP genetic mouse model of ovarian cancer was used. Mice were treated with placebo, paclitaxel (3 mg/kg/week i.p. x 7 weeks), metformin (100 mg/kg/day in water x 7 weeks), or paclitaxel plus metformin and tumor volume was compared between treatment groups. In vitro, metformin decreased proliferation of ovarian cancer cell lines and induced cell cycle arrest, but not apoptosis. Further analysis showed that metformin altered several aspects of metabolism including AMP-activated protein kinase activity, glycolysis, and lipid synthesis. In the prevention mouse model, mice pre-treated with metformin had 60 % fewer tumor implants compared to controls (p<0.005). In the treatment study, mice treated with paclitaxel plus metformin had a 60% reduction in tumor weight compared to controls (p=0.02); a level of tumor reduction greater than that resulting from either paclitaxel or metformin alone. Based on these results, we conclude that metformin alters metabolism in ovarian cancer cells, prevents tumor growth, and increases sensitivity to chemotherapy in vitro and in mouse models. These pre-clinical findings suggest that metformin warrants further investigation for use as an ovarian cancer therapeutic.
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影响因子：
2.9
作者：
Kisfalvi K;Moro A;Sinnett-Smith J;Eibl G;Rozengurt E
通讯作者：
Rozengurt E
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82.9
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Dinulescu, DM;Ince, TA;Jacks, T
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影响因子：
4.7
作者：
Gotlieb, Walter H.;Saumet, Julio;Bruchim, Ilan
通讯作者：
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影响因子：
9.7
作者：
Adams, CP;Brantner, VV
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Brantner, VV