Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.
Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer.
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DOI：
10.1002/cam4.353
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发表时间：
2015-02
期刊：
影响因子：
4
通讯作者：
Bae-Jump, Victoria L.
中科院分区：
文献类型：
--
作者：
Schuler, Kevin M.;Rambally, Brooke S.;DiFurio, Megan J.;Sampey, Brante P.;Gehrig, Paola A.;Makowski, Liza;Bae-Jump, Victoria L.
我们在子宫内膜癌（EC）患者中进行了一项二甲双胍的术前窗口研究，并评估了其抗增殖、分子和代谢作用。20名患有类维生素C EC的肥胖女性在手术分期前每天接受二甲双胍（850 mg）治疗长达4周。通过免疫组织化学测定增殖标记物Ki-67、雌激素受体（ER）、孕激素受体（PR）、腺苷一磷酸活化蛋白激酶（AMPK）和哺乳动物雷帕霉素靶蛋白（mTOR）通路下游靶点的表达。对二甲双胍治疗前和治疗后的血清以及匹配的肿瘤进行了全局非靶向代谢组学分析。基于治疗前和治疗后子宫内膜肿瘤的比较，二甲双胍使增殖降低了11.75%（P = 0.008）。共有65%的患者对二甲双胍有反应，定义为治疗后子宫内膜肿瘤中Ki-67染色减少。二甲双胍降低磷酸化（p）-AMPK（P = 0.00001）、p-Akt（P = 0.0002）、p-S6（51.2%，P = 0.0002）、p-4 E-BP-1（P = 0.001）和ER（P = 0.0002）的表达，但不降低PR的表达。血清代谢组学分析表明，治疗应答者与治疗无应答者对二甲双胍诱导脂解的作用更敏感，这与匹配肿瘤中脂肪酸氧化和糖原代谢增加相关。总之，在肥胖EC患者的术前窗口研究中，二甲双胍降低了肿瘤增殖，对mTOR通路的抑制作用显著。二甲双胍诱导的脂质和糖原代谢的变化，这是更明显的血清和肿瘤的反应者与nonresponses to treatment.This研究提供了支持二甲双胍治疗肥胖患者EC的临床试验。
We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC.
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治疗子宫内膜癌的有前景的新疗法。
影响因子：
4.7
作者：
Gehrig PA;Bae-Jump VL
通讯作者：
Bae-Jump VL
影响因子：
16.2
作者：
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通讯作者：
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3.8
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影响因子：
4.7
作者：
Cantrell LA;Zhou C;Mendivil A;Malloy KM;Gehrig PA;Bae-Jump VL
通讯作者：
Bae-Jump VL
影响因子：
45.3
作者：
Bonanni, Bernardo;Puntoni, Matteo;DeCensi, Andrea
通讯作者：
DeCensi, Andrea