二甲双胍抗肿瘤及调控HIF-1α的作用

摘要/Abstract

摘要： 研究发现二甲双胍对多种恶性肿瘤的增殖均有显著抑制作用，提示二甲双胍的抗肿瘤作用。二甲双胍可减少肿瘤细胞氧的消耗，经转录及转录后机制抑制缺氧诱导因子1α（HIF-1α）的聚集，通过激活腺苷酸活化蛋白激酶（AMPK）抑制HIF-1α的表达。

关键词: 二甲双胍, 肿瘤, 缺氧诱导因子1, α亚基

Abstract: Studies show that metformin inhibits the proliferation of several types of cancer cells. All evidences, therefore propose the antitumor effect of metformin. Metformin can repress the oxygen consumption of tumor cells, and suppress hypoxiainducible factor-1α (HIF-1α) accumulation through the translational and posttranslational mechanisms, and suppress the expression of HIF-1α by activating AMPactivated protein kinase (AMPK).

Key words: Metformin, Neoplasms, Hypoxiainducible factor 1, alpha subunit

高君蓉, 张倜, 曹曼卿, 张雪君, 朱晓琳. 二甲双胍抗肿瘤及调控HIF-1α的作用[J]. 国际肿瘤学杂志, 2016, 43(2): 113-.

GAO Jun-Rong, ZHANG Ti, CAO Man-Qing, ZHANG Xue-Jun, ZHU Xiao-Lin. Anticancer effect of metformin and regulation on HIF-1α[J]. Journal of International Oncology, 2016, 43(2): 113-.

参考文献

［1］ Harrison L, Blackwell K. Hypoxia and anemia: factors in decreased sensitivity to radiation therapy and chemotherapy?［J］. Oncologist, 2004, 9Suppl 5: 3140. DOI:10.1634/theoncologist.99000531. ［2］ Ben Sahra I, Le MarchandBrustel Y, Tanti JF. Metformin in cancer therapy: a new perspective for an old antidiabetic drug?［J］. Mol Cancer Ther, 2010, 9(5): 10921099. DOI: 10.1158/15357163.MCT091186. ［3］ Bonini MG, Gantner BN. The multifaceted activities of AMPK in tumor progressionwhy the "one size fits all" definition does not fit at all?［J］. IUBMB Life, 2013, 65(11): 889896. DOI:10.1002/iub.1213. ［4］ Shi WY, Xiao D, Wang L, et al. Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy［J］. Cell Death Dis, 2012, 3(3): e275. DOI:10.1038/cddis.2012.13. ［5］ Saito T, Chiba T, Yuki K, et al. Metformin, a diabetes drug, eliminates tumorinitiating hepatocellular carcinoma cells［J］. PLoS One, 2013, 8(7): e70010. DOI:10.1371/journal.pone.0070010. ［6］ Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells［J］. Sci Rep, 2012, 2: 362. DOI:10.1038/srep00362. ［7］ Queiroz EA, Puukila S, Eichler R, et al. Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF7 breast cancer cells［J］. PLoS One, 2014, 9(5): e98207. DOI:10.1371/journal.pone.0098207. ［8］ Liang J, Shao SH, Xu ZX, et al. The energy sensing LKB1AMPK pathway regulates p27(kip1)phosphorylation mediating the decision to enter autophagy or apoptosis［J］. Nat Cell Biol, 2007, 9(2): 218224. ［9］ Short JD, Houston KD, Dere R, et al. AMPactivated protein kinase signaling results in cytoplasmic sequestration of p27［J］. Cancer Res, 2008, 68(16): 64966506. DOI:10.1158/00085472.CAN075756. ［10］ Samani AA, Yakar S, Leroith D, et al. The role of the IGF system in cancer growth and metastasis: overview and recent insights［J］. Endocr Rev, 2007, 28(1): 2047. DOI:10.1210/er.20060001. ［11］ Scotlandi K, Picci P. Targeting insulinlike growth factor 1 receptor in sarcomas［J］. Curr Opin Oncol, 2008, 20(4): 419427. DOI:10.1097/CCO.0b013e328302edab. ［12］ Garofalo C, Capristo M, Manara MC, et al. Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug［J］. PLoS One, 2013, 8(12): e83832. DOI:10.1371/journal.pone.0083832. ［13］ Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning［J］. Cancer Discov, 2012, 2(9): 778790. DOI:10.1158/21598290.CD120263. ［14］ Rocha GZ, Dias MM, Ropelle ER, et al. Metformin amplifies chemotherapyinduced AMPK activation and antitumoral growth［J］. Clin Cancer Res, 2011, 17(12): 39934005. DOI:10.1158/10780432.CCR102243. ［15］ Zannella VE, Dal Pra A, Muaddi H, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response［J］. Clin Cancer Res, 2013, 19(24): 67416750. DOI:10.1158/10780432.CCR131787. ［16］ Hirsch HA, Iliopoulos D, Tsichlis PN, et al. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission［J］. Cancer Res, 2009, 69(19): 75077511. DOI:10.1158/00085472.CAN092994. ［17］ Blandino G, Valerio M, Cioce M, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and cMYC［J］. Nat Commun, 2012, 3: 865. DOI:10.1038/ncomms1859. ［18］ Takiyama Y, Harumi T, Watanabe J, et al. Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF1α expression and Oxygen metabolism［J］. Diabetes, 2011, 60(3): 981992. DOI:10.2337/db100655. ［19］ Ece H, Cigdem E, Yuksel K, et al. Use of oral antidiabetic drugs (metformin and pioglitazone) in diabetic patients with breast cancer: how does it effect serum Hif1 alpha and 8Ohdg levels?［J］. Asian Pac J Cancer Prev, 2012, 13(10): 51435148. ［20］ Krymskaya VP, Snow J, Cesarone G, et al. mTOR is required for pulmonary arterial vascular smooth muscle cell proliferation under chronic hypoxia［J］. FASEB J, 2011, 25(6): 19221933. DOI:10.1096/fj.10175018. ［21］ Ranasinghe WK, Sengupta S, Williams S, et al. The effects of nonspecific HIF1α inhibitors on development of castrate resistance and metastases in prostate cancer［J］. Cancer Med, 2014, 3(2): 245251. DOI:10.1002/cam4.189. ［22］ Ling S, Feng T, Ke Q, et al. Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines［J］. Oncol Rep, 2014, 31(6): 26112618. DOI:10.3892/or.2014.3151. ［23］ Sheng B, Liu J, Li GH. Metformin preconditioning protects Daphnia pulex from lethal hypoxic insult involving AMPK, HIF and mTOR signaling［J］. Comp Biochem Physiol B Biochem Mol Biol, 2012, 163(1): 5158. DOI:10.1016/j.cbpb.2012.04.009.

[1]	刘娜, 寇介丽, 杨枫, 刘桃桃, 李丹萍, 韩君蕊, 杨立洲. 血清miR-106b-5p、miR-760联合低剂量螺旋CT诊断早期肺癌的临床价值[J]. 国际肿瘤学杂志, 2024, 51(6): 321-325.
[2]	杨蜜, 别俊, 张加勇, 邓佳秀, 唐组阁, 卢俊. 局部晚期可切除食管癌新辅助治疗疗效及预后分析[J]. 国际肿瘤学杂志, 2024, 51(6): 332-337.
[3]	袁健, 黄燕华. Hp-IgG抗体联合血清DKK1、sB7-H3对早期胃癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(6): 338-343.
[4]	陈红健, 张素青. 血清miR-24-3p、H2AFX与肝癌患者临床病理特征及术后复发的关系研究[J]. 国际肿瘤学杂志, 2024, 51(6): 344-349.
[5]	郭泽浩, 张俊旺. PFDN及其亚基在肿瘤发生发展中的作用[J]. 国际肿瘤学杂志, 2024, 51(6): 350-353.
[6]	张百红, 岳红云. 新作用机制的抗肿瘤药物进展[J]. 国际肿瘤学杂志, 2024, 51(6): 354-358.
[7]	许凤琳, 吴刚. EBV在鼻咽癌肿瘤免疫微环境和免疫治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 359-363.
[8]	王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.
[9]	张蕊, 褚衍六. 基于FIT与肠道菌群的结直肠癌风险评估模型的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 370-375.
[10]	高凡, 王萍, 杜超, 褚衍六. 肠道菌群与结直肠癌非手术治疗的相关研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 376-381.
[11]	王丽, 刘志华, 杨伟洪, 蒋凤莲, 李全泳, 宋浩杰, 鞠文东. ROS1突变肺腺鳞癌合并脑梗死为主要表现的Trousseau综合征1例[J]. 国际肿瘤学杂志, 2024, 51(6): 382-384.
[12]	刘静, 刘芹, 黄梅. 基于SMOTE算法的食管癌放化疗患者肺部感染的预后模型构建[J]. 国际肿瘤学杂志, 2024, 51(5): 267-273.
[13]	杨琳, 路宁, 温华, 张明鑫, 朱琳. 炎症负荷指数与胃癌临床关系研究[J]. 国际肿瘤学杂志, 2024, 51(5): 274-279.
[14]	王俊毅, 洪楷彬, 纪荣佳, 陈大朝. 癌结节对结直肠癌根治性切除术后肝转移的影响[J]. 国际肿瘤学杂志, 2024, 51(5): 280-285.
[15]	张宁宁, 杨哲, 檀丽梅, 李振宁, 王迪, 魏永志. 宫颈细胞DNA倍体分析联合B7-H4和PKCδ对宫颈癌的诊断价值[J]. 国际肿瘤学杂志, 2024, 51(5): 286-291.