邓琳;凌斌;

• 1:中日友好医院
• 2:中国医学科学院北京协和医学院研究生院

摘要(Abstract)：

子宫内膜癌是妇科常见三大恶性肿瘤之一,随着人们生活水平的提高,子宫内膜癌的发病率逐年提升。二甲双胍作为一种常用降糖药,其抗肿瘤作用得到越来越多的关注。二甲双胍可通过PI3K、IGF1、AMPK、p53、caspase、STAT3等多个通路抑制细胞增殖和转移,促进细胞凋亡,提高患者的生存期。二甲双胍和其他药物联用还能减少耐药,协同抗癌。本文现就二甲双胍在子宫内膜癌治疗中的应用及其作用机制的研究现状做一总结。

关键词(KeyWords)： 子宫内膜癌;二甲双胍;PI3K;IGF-1;AMPK

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 邓琳;凌斌;

DOI: 10.13283/j.cnki.xdfckjz.2019.12.015

参考文献(References)：

• [1] MacKintosh ML,Crosbie EJ,Wang XH,et al.Prevention strategies in endometrial carcinoma[Effects of metformin and adiponectin on endometrial cancer cells growth][J].Current Oncol Rep,2018,20(12):101
• [2] Gadducci A,Biglia N,Tana R,et al.Metformin use and gynecological cancers:A novel treatment option emerging from drug repositioning[J].Crit Rev Oncol Hematol,2016,105(1):73-83
• [3] Sivalingam VN,Myers J,Nicholas S,et al.Metformin in reproductive health,pregnancy and gynaecological cancer:established and emerging indications[J].Hum Reprod Update,2014,20(6):853-868
• [4] Kheirandish M,Mahboobi H,Yazdanparast M,et al.Anti-cancer effects of metformin:recent evidences for its role in prevention and treatment of cancer[J].Current Drug Metabol,2018,19(9):793-797
• [5] Zhao Y,Sun H,Feng M,et al.Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling[J].Gynecol Endocrinol,2018,34(5):428-432
• [6] Sivalingam VN,Kitson S,McVey R,et al.Measuring the biological effect of presurgical metformin treatment in endometrial cancer[J].Bri J Cancer,2016,114(3):281-289
• [7] Sivalingam V,McVey R,Gilmour K,et al.A presurgical window-of-opportunity study of metformin in obesity-driven endometrial cancer[J].Lancet (London,England),2015,385(Suppl 1):S90
• [8] Soliman PT,Zhang Q,Broaddus RR,et al.Prospective evaluation of the molecular effects of metformin on the endometrium in women with newly diagnosed endometrial cancer:A window of opportunity study[J].Gynecol Oncol,2016,143(3):466-471
• [9] Febbraro T,Lengyel E,Romero IL.Old drug,new trick:repurposing metformin for gynecologic cancers?[J].Gynecol Oncol,2014,135(3):614-621
• [10] Schuler KM,Rambally BS,DiFurio MJ,et al.Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer[J].Cancer Med,2015,4(2):161-173
• [11] Arima R,Marttila M,Hautakoski A,et al.Antidiabetic medication,statins and the risk and prognosis of non-endometrioid endometrial cancer in women with type 2 diabetes[J].Anticancer Res,2018,38(7):4169-4178
• [12] Clement NS,Oliver TR,Shiwani H,et al.Metformin for endometrial hyperplasia[J].Cochrane Database Systematic Rev,2017,10:Cd012214
• [13] Meireles CG,Pereira SA,Valadares LP,et al.Effects of metformin on endometrial cancer:Systematic review and meta-analysis[J].Gynecol Oncol,2017,147(1):167-180
• [14] Arima R,Hautakoski A,Marttila M,et al.Cause-specific mortality in endometrioid endometrial cancer patients with type 2 diabetes using metformin or other types of antidiabetic medication[J].Gynecol Oncol,2017,147(3):678-683
• [15] Xie W,Li T,Yang J,et al.Metformin use and survival outcomes in endometrial cancer:a systematic review and meta-analysis Metformin for endometrial hyperplasia[J].Oncotarget,2017,8(42):73079-73086
• [16] Guo J,Xu K,An M,et al.Metformin and endometrial cancer survival:a quantitative synthesis of observational studies[J].Oncotarget,2017,8(39):66169-66177
• [17] Chu D,Wu J,Wang K,et al.Effect of metformin use on the risk and prognosis of endometrial cancer:a systematic review and meta-analysis[J].BMC Cancer,2018,18(1):438
• [18] Mutombo AB,Simoens C,Tozin R,et al.Efficacy of commercially available biological agents for the topical treatment of cervical intraepithelial neoplasia:a systematic review Inhibins differentially antagonize activin and bone morphogenetic protein action in a mouse adrenocortical cell line[J].Syst Rev,2019,8(1):132
• [19] Gu CJ,Cheng J,Zhang B,et al.Protopanaxadiol and metformin synergistically inhibit estrogen-mediated proliferation and anti-autophagy effects in endometrial cancer cells[J].Am J Transl Res,2017,9(9):4071-4082
• [20] de Barros Machado A,Dos Reis V,Weber S,et al.Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment[J].Oncol Lett,2016,12(5):3626-3632
• [21] Mu N,Dong M,Li L,et al.Synergistic effect of metformin and medroxyprogesterone 17acetate on the development of endometrial cancer[J].Oncol Rep,2018,39(4):2015-2021
• [22] Mackay HJ,Eisenhauer EA,Kamel-Reid S,et al.Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer[J].Cancer,2014,120(4):603-610
• [23] Iglesias DA,Yates MS,van der Hoeven D,et al.Another surprise from Metformin:novel mechanism of action via K-Ras influences endometrial cancer response to therapy[J].Mol Cancer Ther,2013,12(12):2847-2856
• [24] Qiang P,Shao Y,Sun YP,et al.Metformin inhibits proliferation and migration of endometrial cancer cells through regulating PI3K/AKT/MDM2 pathway[J].Eur Rev Med Pharmacol Sci,2019,23(4):1778-1785
• [25] Laskov I,Drudi L,Beauchamp MC,et al.Anti-diabetic doses of metformin decrease proliferation markers in tumors of patients with endometrial cancer[J].Gynecol Oncol,2014,134(3):607-614
• [26] Sarfstein R,Friedman Y,Attias-Geva Z,et al.Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners[J].PloS One,2013,8(4):e61537
• [27] Cai D,Sun H,Qi Y,et al.Insulin-like growth factor 1/mammalian target of rapamycin and amp-activated protein kinase signaling involved in the effects of metformin in the human endometrial cancer[J].Int J Gynecol Cancer,2016,26(9):1667-1672
• [28] Xie Y,Wang JL,Ji M,et al.Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells Metformin down-regulates endometrial carcinoma cell secretion of IGF-1 and expression of IGF-1R[J].Oncol Lett,2014,8(5):1993-1999
• [29] Zhong T,Men Y,Lu L,et al.Metformin alters DNA methylation genome-wide via the H19/SAHH axis[J].Oncogene,2017,36(17):2345-2354
• [30] Zou J,Hong L,Luo C,et al.Metformin inhibits estrogen-dependent endometrial cancer cell growth by activating the AMPK-FOXO1 signal pathway[J].Cancer Sci,2016,107(12):1806-1817
• [31] Inoue Y,Iemura S,Natsume T,et al.Suppression of p53 activity through the cooperative action of Ski and histone deacetylase SIRT1[J].J Biol Chem,2011,286(8):6311-6320
• [32] TeSlaa T,Setoguchi K,Teitell MA.Mitochondria in human pluripotent stem cell apoptosis[J].Semin Cell Dev Biol,2016,52(1):76-83
• [33] Egan DF,Shackelford DB,Mihaylova MM,et al.Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy[J].Science (New York,NY),2011,331(6016):456-461
• [34] Taguchi A,Blood DC,del Toro G,et al.Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases[J].Nature,2000,405(6784):354-360
• [35] Xiao X,He Q,Lu C,et al.Metformin impairs the growth of liver kinase B1-intact cervical cancer cells[J].Gynecol Oncol,2012,127(1):249-255
• [36] Takahashi A,Kimura F,Yamanaka A,et al.Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis[J].Cancer Cell Int,2014,14:53
• [37] Wallbillich JJ,Josyula S,Saini U,et al.High glucose-mediated stat3 activation in endometrial cancer is inhibited by metformin:therapeutic implications for endometrial cancer[J].PloS One,2017,12(1):e0170318