二甲双胍对消化系统肿瘤治疗作用研究进展
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摘要
二甲双胍作为最经典的治疗糖尿病的药物之一,近期因其潜在的抗肿瘤作用再次引起人们的广泛关注。研究发现二甲双胍不仅可以降低糖尿病人群多种肿瘤的发病率,同时还可以延长肿瘤患者的生存期,跟进的大量基础研究也证实了二甲双胍的抗肿瘤活性。在消化系统肿瘤方面,虽然多数回顾性流行病学研究发现二甲双胍对多种肿瘤患者有较好的保护作用,但仍有争议。目前的抗肿瘤依据主要源于回顾性病例对照研究,在前瞻性临床研究方面部分观察到积极的治疗作用,但具体二甲双胍的使用对哪种消化系统肿瘤的保护最为有力、多大剂量能发挥保护作用和患者的耐受性如何等仍处于临床探索阶段。文章将从抗肿瘤机制、回顾性流行病学证据和前瞻性临床研究方面,阐述二甲双胍对消化系统肿瘤的治疗作用。
Metformin is one of the most classic anti-diabetes medications. Recently, it's grabbing much attention as a potential anti-tumor treatment. Metformin has been shown to reduce the risk of various types of cancer and cancer mortality in patients with diabetes mellitus. Subsequently, preclinical studies have confirmed its anti-tumor activity. As for digestive system tumors, most retrospective epidemiological studies concluded that Metformin has good protective effect on different types of cancer, but there are still some controversial sounds. Anti-cancer activity of Metformin was based primarily on retrospective case control studies and some prospective studies certi?ed its promising effectiveness, but which type of digestive system tumors is best suited, how big a dose will be needed to be effective and will it be well tolerated still in clinical research. This article will elaborate anti-tumor properties of Metformin from anti-tumor mechanism, retrospective epidemiological evidence and prospective clinical studies.
Metformin is one of the most classic anti-diabetes medications. Recently, it's grabbing much attention as a potential anti-tumor treatment. Metformin has been shown to reduce the risk of various types of cancer and cancer mortality in patients with diabetes mellitus. Subsequently, preclinical studies have confirmed its anti-tumor activity. As for digestive system tumors, most retrospective epidemiological studies concluded that Metformin has good protective effect on different types of cancer, but there are still some controversial sounds. Anti-cancer activity of Metformin was based primarily on retrospective case control studies and some prospective studies certi?ed its promising effectiveness, but which type of digestive system tumors is best suited, how big a dose will be needed to be effective and will it be well tolerated still in clinical research. This article will elaborate anti-tumor properties of Metformin from anti-tumor mechanism, retrospective epidemiological evidence and prospective clinical studies.
引文
[1]陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤,2018(01):1-14.
[2]母义明,纪立农,宁光,等.二甲双胍临床应用专家共识[J].中国糖尿病杂志,2014(8):673-681.
[3]Cheung KS,Chan EW,Wong AYS,et al.Metformin use and gastric cancer risk in diabetic patients after helicobacter pylori eradication[J].J Natl Cancer Inst,2018.[Epub ahead of Print]
[4]Zhang ZJ,Li S.The prognostic value of metformin for cancer patients with concurrent diabetes:a systematic review and meta-analysis[J].Diabetes Obes Metab,2014,16(8):707-710.
[5]Evans JM,Donnelly LA,Emslie-Smith AM,et al.Metformin and reduced risk of cancer in diabetic patients[J].BMJ,2005,330(7503):1304-1305.
[6]Mohamed SN,Phyo WM,Yap HY,et al.Metformin inhibits cellular proliferation and bioenergetics in colorectal cancer patient-derived xenografts[J].Mol Cancer Ther,2017,16(9):2035-2044.
[7]Courtois S,Durán RV,Giraud J,et al.Metformin targets gastric cancer stem cells[J].Eur J Cancer,2017,84:193-201.
[8]Elgogary A,Xu Q,Poore B,et al.Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer[J].Proc Natl Acad Sci U S A,2016,113(36):E5328-E5336.
[9]Pusceddu S,Vernieri C,Di Maio M,et al.Metformin use is associated with longer progression-free survival of patients with diabetes and pancreatic neuroendocrine tumors receiving everolimus and/or somatostatin analogues[J].Gastroenterology,2018,155(2):479-489.
[10]Pierotti MA,Berrino F,Gariboldi M,et al.Targeting metabolism for cancer treatment and prevention:metformin,an old drug with multi-faceted effects[J].Oncogene,2013,32(12):1475-1487.
[11]Pernicova I,Korbonits M.Metformin--mode of action and clinical implications for diabetes and cancer[J].Nat Rev Endocrinol,2014,10(3):143-156.
[12]Safe S,Nair V,Karki K.Metformin-induced anticancer activities:recent insights[J].Biol Chem,2018,399(4):321-335.
[13]Shackelford DB,Shaw RJ.The LKB1-AMPK pathway:metabolism and growth control in tumour suppression[J].Nat Rev Cancer,2009,9(8):563-575.
[14]Cha JH,Yang WH,Xia W,et al.Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1[J].Mol Cell,2018,71(4):606-620.
[15]Deng J,Peng M,Wang Z,et al.Novel application of metformin combined with targeted drugs on anticancer treatment[J].Cancer Sci,2019,110(1):23-30.
[16]Kim SH,Kim SC,Ku JL.Metformin increases chemosensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells[J].Oncotarget,2017,8(34):56546-56557.
[17]Ling S,Song L,Fan N,et al.Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway[J].Int J Oncol,2017,50(1):297-309.
[18]Casadei GA,Faloppi L,De Matteis S,et al.Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib:validation study and biological rationale[J].Eur J Cancer,2017,86:106-114.
[19]Coker OO,Dai Z,Nie Y,et al.Mucosal microbiome dysbiosis in gastric carcinogenesis[J].Gut,2018,67(6):1024-1032.
[20]Geller LT,Barzily-Rokni M,Danino T,et al.Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine[J].Science,2017,357(6356):1156-1160.
[21]Kostic AD,Chun E,Robertson L,et al.Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment[J].Cell Host Microbe,2013,14(2):207-215.
[22]Sun L,Xie C,Wang G,et al.Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[J].Nat Med,2018,24(12):1919-1929.
[23]Shin NR,Lee JC,Lee HY,et al.An increase in the Akkermansia spp.population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice[J].Gut,2014,63(5):727-735.
[24]Paleari L,Burhenne J,Weiss J,et al.High accumulation of metformin in colonic tissue of subjects with diabetes or the metab olic syndrome[J].Gastroenterology,2018,154(5):1543-1545.
[25]Zhang P,Li H,Tan X,et al.Association of metformin use with cancer incidence and mortality:a meta-analysis[J].Cancer Epidemiol,2013,37(3):207-218.
[26]Coyle C,Cafferty FH,Vale C,et al.Metformin as an adjuvant treatment for cancer:a systematic review and meta-analysis[J].Ann Oncol,2016,27(12):2184-2195.
[27]Singh PP,Shi Q,Foster NR,et al.Relationship between metformin use and recurrence and survival in patients with resected stageⅢcolon cancer receiving adjuvant chemotherapy:results from North Central Cancer Treatment Group N0147(Alliance)[J].Oncologist,2016,21(12):1509-1521.
[28]Mei ZB,Zhang ZJ,Liu CY,et al.Survival benefits of metformin for colorectal cancer patients with diabetes:a systematic review and meta-analysis[J].PLoS One,2014,9(3):e91818.
[29]Tseng CH.Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus[J].Aging(Albany NY),2016,8(8):1636-1649.
[30]Kim YI,Kim SY,Cho SJ,et al.Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment:a nationwide cohort study[J].Aliment Pharmacol Ther,2014,39(8):854-863.
[31]Lee MS,Hsu CC,Wahlqvist ML,et al.Type 2 diabetes increases and metformin reduces total,colorectal,liver and pancreatic cancer incidences in Taiwanese:a representative population prospective cohort study of 800,000 individuals[J].BMC Cancer,2011,11:20.
[32]Zhou XL,Xue WH,Ding XF,et al.Association between metformin and the risk of gastric cancer in patients with type2 diabetes mellitus:a meta-analysis of cohort studies[J].Oncotarget,2017,8(33):55622-55631.
[33]Chaiteerakij R,Petersen GM,Bamlet WR,et al.Metformin use and survival of patients with pancreatic cancer:a cautionary lesson[J].J Clin Oncol,2016,34(16):1898-1904.
[34]Amin S,Mhango G,Lin J,et al.Metformin improves survival in patients with pancreatic ductal adenocarcinoma and predxisting diabetes:a propensity score analysis[J].Am JGastroenterol,2016,111(9):1350-1357.
[35]Bodmer M,Becker C,Meier C,et al.Use of antidiabetic agents and the risk of pancreatic cancer:a case-control analysis[J].Am J Gastroenterol,2012,107(4):620-626.
[36]Chan KM,Kuo CF,Hsu JT,et al.Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection[J].Liver Int,2017,37(3):434-441.
[37]Ma SJ,Zheng YX,Zhou PC,et al.Metformin use improves survival of diabetic liver cancer patients:systematic review and meta-analysis[J].Oncotarget,2016,7(40):66202-66211.
[38]Van De Voorde L,Janssen L,Larue R,et al.Can metformin improve'the tomorrow'of patients treated for oesophageal cancer?[J].Eur J Surg Oncol,2015,41(10):1333-1339.
[39]Skinner HD,McCurdy MR,Echeverria AE,et al.Metformin use and improved response to therapy in esophageal adenocarcinoma[J].Acta Oncol,2013,52(5):1002-1009.
[40]Khawaja MR,Nick AM,Madhusudanannair V,et al.PhaseⅠdose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers[J].Cancer Chemother Pharmacol,2016,77(5):973-977.
[41]MacKenzie MJ,Ernst S,Johnson C,et al.A phaseⅠstudy of temsirolimus and metformin in advanced solid tumours[J].Invest New Drugs,2012,30(2):647-652.
[42]Kordes S,Pollak MN,Zwinderman AH,et al.Metformin in patients with advanced pancreatic cancer:a double-blind,randomised,placebo-controlled phase 2 trial[J].Lancet Oncol,2015,16(7):839-847.
[43]Reni M,Dugnani E,Cereda S,et al.(Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer:an openlabel,randomized phaseⅡtrial[J].Clin Cancer Res,2016,22(5):1076-1085.
[44]Miranda VC,Braghiroli MI,Faria LD,et al.Phase 2 trial of metformin combined with 5-Fluorouracil in patients with refractory metastatic colorectal cancer[J].Clin Colorectal Cancer,2016,15(4):321-328.
[45]Mayer RJ,Van Cutsem E,Falcone A,et al.Randomized trial of TAS-102 for refractory metastatic colorectal cancer[J].N Engl J Med,2015,372(20):1909-1919.
[46]Higurashi T,Hosono K,Takahashi H,et al.Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes:a multicentre double-blind,placebo-controlled,randomised phase3 trial[J].Lancet Oncol,2016,17(4):475-483.
[47]Mitsuhashi A,Sato Y,Kiyokawa T,et al.PhaseⅡstudy of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer[J].Ann Oncol,2016,27(2):262-266.
[48]Rothermundt C,Hayoz S,Templeton AJ,et al.Metformin in chemotherapy-naive castration-resistant prostate cancer:a multicenter phase 2 trial(SAKK 08/09)[J].Eur Urol,2014,66(3):468-474.
[2]母义明,纪立农,宁光,等.二甲双胍临床应用专家共识[J].中国糖尿病杂志,2014(8):673-681.
[3]Cheung KS,Chan EW,Wong AYS,et al.Metformin use and gastric cancer risk in diabetic patients after helicobacter pylori eradication[J].J Natl Cancer Inst,2018.[Epub ahead of Print]
[4]Zhang ZJ,Li S.The prognostic value of metformin for cancer patients with concurrent diabetes:a systematic review and meta-analysis[J].Diabetes Obes Metab,2014,16(8):707-710.
[5]Evans JM,Donnelly LA,Emslie-Smith AM,et al.Metformin and reduced risk of cancer in diabetic patients[J].BMJ,2005,330(7503):1304-1305.
[6]Mohamed SN,Phyo WM,Yap HY,et al.Metformin inhibits cellular proliferation and bioenergetics in colorectal cancer patient-derived xenografts[J].Mol Cancer Ther,2017,16(9):2035-2044.
[7]Courtois S,Durán RV,Giraud J,et al.Metformin targets gastric cancer stem cells[J].Eur J Cancer,2017,84:193-201.
[8]Elgogary A,Xu Q,Poore B,et al.Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer[J].Proc Natl Acad Sci U S A,2016,113(36):E5328-E5336.
[9]Pusceddu S,Vernieri C,Di Maio M,et al.Metformin use is associated with longer progression-free survival of patients with diabetes and pancreatic neuroendocrine tumors receiving everolimus and/or somatostatin analogues[J].Gastroenterology,2018,155(2):479-489.
[10]Pierotti MA,Berrino F,Gariboldi M,et al.Targeting metabolism for cancer treatment and prevention:metformin,an old drug with multi-faceted effects[J].Oncogene,2013,32(12):1475-1487.
[11]Pernicova I,Korbonits M.Metformin--mode of action and clinical implications for diabetes and cancer[J].Nat Rev Endocrinol,2014,10(3):143-156.
[12]Safe S,Nair V,Karki K.Metformin-induced anticancer activities:recent insights[J].Biol Chem,2018,399(4):321-335.
[13]Shackelford DB,Shaw RJ.The LKB1-AMPK pathway:metabolism and growth control in tumour suppression[J].Nat Rev Cancer,2009,9(8):563-575.
[14]Cha JH,Yang WH,Xia W,et al.Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1[J].Mol Cell,2018,71(4):606-620.
[15]Deng J,Peng M,Wang Z,et al.Novel application of metformin combined with targeted drugs on anticancer treatment[J].Cancer Sci,2019,110(1):23-30.
[16]Kim SH,Kim SC,Ku JL.Metformin increases chemosensitivity via gene downregulation encoding DNA replication proteins in 5-Fu resistant colorectal cancer cells[J].Oncotarget,2017,8(34):56546-56557.
[17]Ling S,Song L,Fan N,et al.Combination of metformin and sorafenib suppresses proliferation and induces autophagy of hepatocellular carcinoma via targeting the mTOR pathway[J].Int J Oncol,2017,50(1):297-309.
[18]Casadei GA,Faloppi L,De Matteis S,et al.Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib:validation study and biological rationale[J].Eur J Cancer,2017,86:106-114.
[19]Coker OO,Dai Z,Nie Y,et al.Mucosal microbiome dysbiosis in gastric carcinogenesis[J].Gut,2018,67(6):1024-1032.
[20]Geller LT,Barzily-Rokni M,Danino T,et al.Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine[J].Science,2017,357(6356):1156-1160.
[21]Kostic AD,Chun E,Robertson L,et al.Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment[J].Cell Host Microbe,2013,14(2):207-215.
[22]Sun L,Xie C,Wang G,et al.Gut microbiota and intestinal FXR mediate the clinical benefits of metformin[J].Nat Med,2018,24(12):1919-1929.
[23]Shin NR,Lee JC,Lee HY,et al.An increase in the Akkermansia spp.population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice[J].Gut,2014,63(5):727-735.
[24]Paleari L,Burhenne J,Weiss J,et al.High accumulation of metformin in colonic tissue of subjects with diabetes or the metab olic syndrome[J].Gastroenterology,2018,154(5):1543-1545.
[25]Zhang P,Li H,Tan X,et al.Association of metformin use with cancer incidence and mortality:a meta-analysis[J].Cancer Epidemiol,2013,37(3):207-218.
[26]Coyle C,Cafferty FH,Vale C,et al.Metformin as an adjuvant treatment for cancer:a systematic review and meta-analysis[J].Ann Oncol,2016,27(12):2184-2195.
[27]Singh PP,Shi Q,Foster NR,et al.Relationship between metformin use and recurrence and survival in patients with resected stageⅢcolon cancer receiving adjuvant chemotherapy:results from North Central Cancer Treatment Group N0147(Alliance)[J].Oncologist,2016,21(12):1509-1521.
[28]Mei ZB,Zhang ZJ,Liu CY,et al.Survival benefits of metformin for colorectal cancer patients with diabetes:a systematic review and meta-analysis[J].PLoS One,2014,9(3):e91818.
[29]Tseng CH.Metformin reduces gastric cancer risk in patients with type 2 diabetes mellitus[J].Aging(Albany NY),2016,8(8):1636-1649.
[30]Kim YI,Kim SY,Cho SJ,et al.Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment:a nationwide cohort study[J].Aliment Pharmacol Ther,2014,39(8):854-863.
[31]Lee MS,Hsu CC,Wahlqvist ML,et al.Type 2 diabetes increases and metformin reduces total,colorectal,liver and pancreatic cancer incidences in Taiwanese:a representative population prospective cohort study of 800,000 individuals[J].BMC Cancer,2011,11:20.
[32]Zhou XL,Xue WH,Ding XF,et al.Association between metformin and the risk of gastric cancer in patients with type2 diabetes mellitus:a meta-analysis of cohort studies[J].Oncotarget,2017,8(33):55622-55631.
[33]Chaiteerakij R,Petersen GM,Bamlet WR,et al.Metformin use and survival of patients with pancreatic cancer:a cautionary lesson[J].J Clin Oncol,2016,34(16):1898-1904.
[34]Amin S,Mhango G,Lin J,et al.Metformin improves survival in patients with pancreatic ductal adenocarcinoma and predxisting diabetes:a propensity score analysis[J].Am JGastroenterol,2016,111(9):1350-1357.
[35]Bodmer M,Becker C,Meier C,et al.Use of antidiabetic agents and the risk of pancreatic cancer:a case-control analysis[J].Am J Gastroenterol,2012,107(4):620-626.
[36]Chan KM,Kuo CF,Hsu JT,et al.Metformin confers risk reduction for developing hepatocellular carcinoma recurrence after liver resection[J].Liver Int,2017,37(3):434-441.
[37]Ma SJ,Zheng YX,Zhou PC,et al.Metformin use improves survival of diabetic liver cancer patients:systematic review and meta-analysis[J].Oncotarget,2016,7(40):66202-66211.
[38]Van De Voorde L,Janssen L,Larue R,et al.Can metformin improve'the tomorrow'of patients treated for oesophageal cancer?[J].Eur J Surg Oncol,2015,41(10):1333-1339.
[39]Skinner HD,McCurdy MR,Echeverria AE,et al.Metformin use and improved response to therapy in esophageal adenocarcinoma[J].Acta Oncol,2013,52(5):1002-1009.
[40]Khawaja MR,Nick AM,Madhusudanannair V,et al.PhaseⅠdose escalation study of temsirolimus in combination with metformin in patients with advanced/refractory cancers[J].Cancer Chemother Pharmacol,2016,77(5):973-977.
[41]MacKenzie MJ,Ernst S,Johnson C,et al.A phaseⅠstudy of temsirolimus and metformin in advanced solid tumours[J].Invest New Drugs,2012,30(2):647-652.
[42]Kordes S,Pollak MN,Zwinderman AH,et al.Metformin in patients with advanced pancreatic cancer:a double-blind,randomised,placebo-controlled phase 2 trial[J].Lancet Oncol,2015,16(7):839-847.
[43]Reni M,Dugnani E,Cereda S,et al.(Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer:an openlabel,randomized phaseⅡtrial[J].Clin Cancer Res,2016,22(5):1076-1085.
[44]Miranda VC,Braghiroli MI,Faria LD,et al.Phase 2 trial of metformin combined with 5-Fluorouracil in patients with refractory metastatic colorectal cancer[J].Clin Colorectal Cancer,2016,15(4):321-328.
[45]Mayer RJ,Van Cutsem E,Falcone A,et al.Randomized trial of TAS-102 for refractory metastatic colorectal cancer[J].N Engl J Med,2015,372(20):1909-1919.
[46]Higurashi T,Hosono K,Takahashi H,et al.Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes:a multicentre double-blind,placebo-controlled,randomised phase3 trial[J].Lancet Oncol,2016,17(4):475-483.
[47]Mitsuhashi A,Sato Y,Kiyokawa T,et al.PhaseⅡstudy of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer[J].Ann Oncol,2016,27(2):262-266.
[48]Rothermundt C,Hayoz S,Templeton AJ,et al.Metformin in chemotherapy-naive castration-resistant prostate cancer:a multicenter phase 2 trial(SAKK 08/09)[J].Eur Urol,2014,66(3):468-474.