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Published in: Cancer Chemotherapy and Pharmacology 1/2016

01-07-2016 | Review Article

Combinational strategies of metformin and chemotherapy in cancers

Authors: Hui-Hui Zhang, Xiu-Li Guo

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2016

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Abstract

Chemotherapeutic regimens are the most common treatment to inhibit tumor growth, but there is great variability in clinical responses of cancer patients; cancer cells often develop resistance to chemotherapeutics which results in tumor recurrence and further progression. Metformin, an extensively prescribed and well-tolerated first-line therapeutic drug for type 2 diabetes mellitus, has recently been identified as a potential and attractive anticancer adjuvant drug combined with chemotherapeutic drugs to improve treatment efficacy and lower doses. In this review, we summarized the molecular mechanisms underlying anticancer effects of metformin, which included insulin- and AMPK-dependent effects, selectively targeting cancer stem cells, reversing multidrug resistance, inhibition of the tumor metastasis and described the antineoplastic effects of metformin combined with chemotherapeutic agents in digestive system cancers (colorectal, gastric, hepatic and pancreatic cancer), reproductive system cancers (ovarian and endometrial cancer), prostate cancer, breast cancer, lung cancer, etc. Moreover, the clinical trials regarding metformin in combination of chemotherapeutic drugs were presented and the clinical obstacle or limitation related to the potential role of metformin in cancer treatment was also discussed in this review.
Literature
2.
8.
go back to reference Kowall B, Stang A, Rathmann W, Kostev K (2015) No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol Drug Saf 24(8):865–874. doi:10.1002/pds.3823 CrossRefPubMed Kowall B, Stang A, Rathmann W, Kostev K (2015) No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol Drug Saf 24(8):865–874. doi:10.​1002/​pds.​3823 CrossRefPubMed
11.
go back to reference Simon D, Balkau B (2010) Comment on: Yang et al. (2010) Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes; 59:1254–1260. Diabetes 59(11):e25. doi:10.2337/db10-0937 CrossRefPubMed Simon D, Balkau B (2010) Comment on: Yang et al. (2010) Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes; 59:1254–1260. Diabetes 59(11):e25. doi:10.​2337/​db10-0937 CrossRefPubMed
13.
go back to reference Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D (2010) Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 70(2):741–751. doi:10.1158/0008-5472.can-09-2141 CrossRefPubMedPubMedCentral Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D (2010) Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res 70(2):741–751. doi:10.​1158/​0008-5472.​can-09-2141 CrossRefPubMedPubMedCentral
17.
go back to reference Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, Pasanisi P, Pilotti S (2013) Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 32(12):1475–1487. doi:10.1038/onc.2012.181 CrossRefPubMed Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T, Pasanisi P, Pilotti S (2013) Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 32(12):1475–1487. doi:10.​1038/​onc.​2012.​181 CrossRefPubMed
18.
go back to reference Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila) 5(4):536–543. doi:10.1158/1940-6207.capr-11-0536 CrossRef Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res (Phila) 5(4):536–543. doi:10.​1158/​1940-6207.​capr-11-0536 CrossRef
19.
go back to reference Lee SK, Lee JO, Kim JH, Kim SJ, You GY, Moon JW, Jung JH, Park SH, Uhm KO, Park JM, Suh PG, Kim HS (2011) Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J Cell Biochem 112(5):1259–1267. doi:10.1002/jcb.23000 CrossRefPubMed Lee SK, Lee JO, Kim JH, Kim SJ, You GY, Moon JW, Jung JH, Park SH, Uhm KO, Park JM, Suh PG, Kim HS (2011) Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J Cell Biochem 112(5):1259–1267. doi:10.​1002/​jcb.​23000 CrossRefPubMed
20.
go back to reference Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590CrossRefPubMed Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590CrossRefPubMed
21.
go back to reference Shaw RJ, Lamia KA, Vasquez D, Koo S-H, Bardeesy N, DePinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646CrossRefPubMedPubMedCentral Shaw RJ, Lamia KA, Vasquez D, Koo S-H, Bardeesy N, DePinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646CrossRefPubMedPubMedCentral
23.
24.
go back to reference Lonardo E, Cioffi M, Sancho P, Crusz S, Heeschen C (2015) Studying pancreatic cancer stem cell characteristics for developing new treatment strategies. J Vis Exp 100:e52801–e52801. doi:10.3791/52801 PubMed Lonardo E, Cioffi M, Sancho P, Crusz S, Heeschen C (2015) Studying pancreatic cancer stem cell characteristics for developing new treatment strategies. J Vis Exp 100:e52801–e52801. doi:10.​3791/​52801 PubMed
26.
27.
go back to reference Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cello ntogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9(18):3831–3838CrossRef Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cello ntogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9(18):3831–3838CrossRef
29.
go back to reference Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA (2010) Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle 9(22):4461–4468CrossRefPubMed Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA (2010) Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle 9(22):4461–4468CrossRefPubMed
30.
go back to reference Qu C, Zhang W, Zheng G, Zhang Z, Yin J, He Z (2014) Metformin reverses multidrug resistance and epithelial-mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells. Mol Cell Biochem 386(1–2):63–71. doi:10.1007/s11010-013-1845-x CrossRefPubMed Qu C, Zhang W, Zheng G, Zhang Z, Yin J, He Z (2014) Metformin reverses multidrug resistance and epithelial-mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells. Mol Cell Biochem 386(1–2):63–71. doi:10.​1007/​s11010-013-1845-x CrossRefPubMed
32.
go back to reference Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K (2015) Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget 6(14):12748–12762CrossRefPubMedPubMedCentral Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, Huang S, Wang J, Li Z, Xie K (2015) Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget 6(14):12748–12762CrossRefPubMedPubMedCentral
33.
go back to reference Jang SY, Kim A, Kim JK, Kim C, Cho YH, Kim JH, Kim CH, Lee JY (2014) Metformin inhibits tumor cell migration via down-regulation of MMP9 in tamoxifen-resistant breast cancer cells. Anticancer Res 34(8):4127–4134PubMed Jang SY, Kim A, Kim JK, Kim C, Cho YH, Kim JH, Kim CH, Lee JY (2014) Metformin inhibits tumor cell migration via down-regulation of MMP9 in tamoxifen-resistant breast cancer cells. Anticancer Res 34(8):4127–4134PubMed
34.
go back to reference Hsieh S-C, Tsai J-P, Yang S-F, Tang M-J, Hsieh Y-H (2014) Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 46(12):2809–2822CrossRefPubMed Hsieh S-C, Tsai J-P, Yang S-F, Tang M-J, Hsieh Y-H (2014) Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression. Amino Acids 46(12):2809–2822CrossRefPubMed
35.
go back to reference Zhang J, Shen C, Wang L, Ma Q, Xia P, Qi M, Yang M, Han B (2014) Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4. Biochem Biophys Res Commun 452(3):746–752. doi:10.1016/j.bbrc.2014.08.154 CrossRefPubMed Zhang J, Shen C, Wang L, Ma Q, Xia P, Qi M, Yang M, Han B (2014) Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: involvement of the tumor suppressor miR30a and its target gene SOX4. Biochem Biophys Res Commun 452(3):746–752. doi:10.​1016/​j.​bbrc.​2014.​08.​154 CrossRefPubMed
37.
go back to reference Deng YH, Pu XX, Huang MJ, Xiao J, Zhou JM, Lin TY, Lin EH (2010) 5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells. Chin J Cancer 29(9):810–815CrossRefPubMed Deng YH, Pu XX, Huang MJ, Xiao J, Zhou JM, Lin TY, Lin EH (2010) 5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells. Chin J Cancer 29(9):810–815CrossRefPubMed
38.
go back to reference Yamazaki K, Yasuda N, Inoue T, Nagakura T, Kira K, Saeki T, Tanaka I (2004) The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight. Eur J Pharmacol 488(1–3):213–218. doi:10.1016/j.ejphar.2004.02.019 CrossRefPubMed Yamazaki K, Yasuda N, Inoue T, Nagakura T, Kira K, Saeki T, Tanaka I (2004) The combination of metformin and a dipeptidyl peptidase IV inhibitor prevents 5-fluorouracil-induced reduction of small intestine weight. Eur J Pharmacol 488(1–3):213–218. doi:10.​1016/​j.​ejphar.​2004.​02.​019 CrossRefPubMed
39.
go back to reference Sui X, Xu Y, Yang J, Fang Y, Lou H, Han W, Zhang M, Chen W, Wang K, Li D, Jin W, Lou F, Zheng Y, Hu H, Gong L, Zhou X, Pan Q, Pan H, Wang X, He C (2014) Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. Plos One 9(5):e97781. doi:10.1371/journal.pone.0097781 CrossRefPubMedPubMedCentral Sui X, Xu Y, Yang J, Fang Y, Lou H, Han W, Zhang M, Chen W, Wang K, Li D, Jin W, Lou F, Zheng Y, Hu H, Gong L, Zhou X, Pan Q, Pan H, Wang X, He C (2014) Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation. Plos One 9(5):e97781. doi:10.​1371/​journal.​pone.​0097781 CrossRefPubMedPubMedCentral
40.
go back to reference Li W, Wang Q-L, Liu X, Dong S-H, Li H-X, Li C-Y, Guo L-S, Gao J-M, Berger NA, Li L, Ma L, Wu Y-J (2015) Combined use of Vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. Cancer Prev Res 8(2):139–148. doi:10.1158/1940-6207.capr-14-0128 CrossRef Li W, Wang Q-L, Liu X, Dong S-H, Li H-X, Li C-Y, Guo L-S, Gao J-M, Berger NA, Li L, Ma L, Wu Y-J (2015) Combined use of Vitamin D3 and metformin exhibits synergistic chemopreventive effects on colorectal neoplasia in rats and mice. Cancer Prev Res 8(2):139–148. doi:10.​1158/​1940-6207.​capr-14-0128 CrossRef
41.
go back to reference Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, Ghavamzadeh A (2014) Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells. Int J Hematol-Oncol Stem Cell Res 8(3):12–19PubMedPubMedCentral Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, Ghavamzadeh A (2014) Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells. Int J Hematol-Oncol Stem Cell Res 8(3):12–19PubMedPubMedCentral
42.
go back to reference Cui XD, Lee MJ, Kim JH, Hao PP, Liu L, Yu GR, Kim DG (2013) Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis. Hepatology 57(6):2248–2260. doi:10.1002/hep.26253 CrossRefPubMed Cui XD, Lee MJ, Kim JH, Hao PP, Liu L, Yu GR, Kim DG (2013) Activation of mammalian target of rapamycin complex 1 (mTORC1) and Raf/Pyk2 by growth factor-mediated Eph receptor 2 (EphA2) is required for cholangiocarcinoma growth and metastasis. Hepatology 57(6):2248–2260. doi:10.​1002/​hep.​26253 CrossRefPubMed
44.
go back to reference Petrushev B, Tomuleasa C, Soritau O, Aldea M, Pop T, Susman S, Kacso G, Berindan I, Irimie A, Cristea V (2012) Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma. Exp Oncol 34(1):17–24PubMed Petrushev B, Tomuleasa C, Soritau O, Aldea M, Pop T, Susman S, Kacso G, Berindan I, Irimie A, Cristea V (2012) Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma. Exp Oncol 34(1):17–24PubMed
45.
46.
go back to reference Bhardwaj V, Bhushan A, Lai JC, Tadinada SM (2012) Pancreatic cancer - molecular mechanism and targets. In: Sanjay K. Srivastava (ed) Failure of pancreatic cancer chemotherapy: consequences of drug resistance mechanisms. INTECH Open Access Publisher, Rijeka, pp 143–160 Bhardwaj V, Bhushan A, Lai JC, Tadinada SM (2012) Pancreatic cancer - molecular mechanism and targets. In: Sanjay K. Srivastava (ed) Failure of pancreatic cancer chemotherapy: consequences of drug resistance mechanisms. INTECH Open Access Publisher, Rijeka, pp 143–160
47.
go back to reference Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, Huang H, DiPaola RS, Tan XL (2015) Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget 6(25):21208–21224CrossRefPubMedPubMedCentral Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, Huang H, DiPaola RS, Tan XL (2015) Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget 6(25):21208–21224CrossRefPubMedPubMedCentral
48.
go back to reference Baron B, Wang Y, Maehara S-I, Maehara Y, Kuramitsu Y, Nakamura K (2015) Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action. Anticancer Res 35(4):1941–1949PubMed Baron B, Wang Y, Maehara S-I, Maehara Y, Kuramitsu Y, Nakamura K (2015) Resistance to gemcitabine in the pancreatic cancer cell line KLM1-R reversed by metformin action. Anticancer Res 35(4):1941–1949PubMed
49.
go back to reference Chai X, Chu H, Yang X, Meng Y, Shi P, Gou S (2015) Metformin increases sensitivity of pancreatic cancer cells to gemcitabine by reducing CD133 + cell populations and suppressing ERK/P70S6 K signaling. Sci Reports 5:14404. doi:10.1038/srep14404 CrossRef Chai X, Chu H, Yang X, Meng Y, Shi P, Gou S (2015) Metformin increases sensitivity of pancreatic cancer cells to gemcitabine by reducing CD133 + cell populations and suppressing ERK/P70S6 K signaling. Sci Reports 5:14404. doi:10.​1038/​srep14404 CrossRef
50.
go back to reference Reni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, Liberati D, Pasquale V, Scavini M, Maggiora P, Sordi V, Lampasona V, Ceraulo D, Di Terlizzi G, Doglioni C, Falconi M, Piemonti L (2015) (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase 2 trial. Clin Cancer Res. doi:10.1158/1078-0432.ccr-15-1722 PubMed Reni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, Liberati D, Pasquale V, Scavini M, Maggiora P, Sordi V, Lampasona V, Ceraulo D, Di Terlizzi G, Doglioni C, Falconi M, Piemonti L (2015) (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase 2 trial. Clin Cancer Res. doi:10.​1158/​1078-0432.​ccr-15-1722 PubMed
52.
go back to reference Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V (2011) Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia (New York, NY) 13(5):483–491CrossRef Rattan R, Graham RP, Maguire JL, Giri S, Shridhar V (2011) Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia (New York, NY) 13(5):483–491CrossRef
53.
go back to reference Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, Johnson A, Bradaric M, Lee W, Romero IL (2015) Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol. doi:10.1016/j.ajog.2014.10.026 PubMed Lengyel E, Litchfield LM, Mitra AK, Nieman KM, Mukherjee A, Zhang Y, Johnson A, Bradaric M, Lee W, Romero IL (2015) Metformin inhibits ovarian cancer growth and increases sensitivity to paclitaxel in mouse models. Am J Obstet Gynecol. doi:10.​1016/​j.​ajog.​2014.​10.​026 PubMed
54.
go back to reference Kim NY, Lee HY, Lee C (2015) Metformin targets Axl and Tyro3 receptor tyrosine kinases to inhibit cell proliferation and overcome chemoresistance in ovarian cancer cells. Int J Oncol 47(1):353–360. doi:10.3892/ijo.2015.3004 PubMed Kim NY, Lee HY, Lee C (2015) Metformin targets Axl and Tyro3 receptor tyrosine kinases to inhibit cell proliferation and overcome chemoresistance in ovarian cancer cells. Int J Oncol 47(1):353–360. doi:10.​3892/​ijo.​2015.​3004 PubMed
55.
go back to reference Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, Liao QP (2011) Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol 126(3–5):113–120. doi:10.1016/j.jsbmb.2010.12.006 CrossRefPubMed Xie Y, Wang YL, Yu L, Hu Q, Ji L, Zhang Y, Liao QP (2011) Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol 126(3–5):113–120. doi:10.​1016/​j.​jsbmb.​2010.​12.​006 CrossRefPubMed
57.
go back to reference Uehara T, Mitsuhashi A, Tsuruoka N, Shozu M (2015) Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro. Oncol Rep 33(2):744–750. doi:10.3892/or.2014.3611 PubMed Uehara T, Mitsuhashi A, Tsuruoka N, Shozu M (2015) Metformin potentiates the anticancer effects of cisplatin under normoxic conditions in vitro. Oncol Rep 33(2):744–750. doi:10.​3892/​or.​2014.​3611 PubMed
58.
go back to reference Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, Pollak M, Lui L, Endt K, Schiess R, Ruschoff JH, Cathomas R, Gillessen S (2014) Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol 66(3):468–474. doi:10.1016/j.eururo.2013.12.057 CrossRefPubMed Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bartschi D, Pollak M, Lui L, Endt K, Schiess R, Ruschoff JH, Cathomas R, Gillessen S (2014) Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol 66(3):468–474. doi:10.​1016/​j.​eururo.​2013.​12.​057 CrossRefPubMed
59.
go back to reference Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, DeBerardinis RJ, Siegel PM, Jones RG (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124. doi:10.1016/j.cmet.2012.12.001 CrossRefPubMed Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, DeBerardinis RJ, Siegel PM, Jones RG (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124. doi:10.​1016/​j.​cmet.​2012.​12.​001 CrossRefPubMed
60.
go back to reference Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F (2010) Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 70(6):2465–2475. doi:10.1158/0008-5472.can-09-2782 CrossRefPubMed Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F (2010) Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res 70(6):2465–2475. doi:10.​1158/​0008-5472.​can-09-2782 CrossRefPubMed
61.
go back to reference Babcook MA, Shukla S, Fu P, Vazquez EJ, Puchowicz MA, Molter JP, Oak CZ, MacLennan GT, Flask CA, Lindner DJ, Parker Y, Daneshgari F, Gupta S (2014) Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol Cancer Ther 13(10):2288–2302. doi:10.1158/1535-7163.mct-14-0451 CrossRefPubMedPubMedCentral Babcook MA, Shukla S, Fu P, Vazquez EJ, Puchowicz MA, Molter JP, Oak CZ, MacLennan GT, Flask CA, Lindner DJ, Parker Y, Daneshgari F, Gupta S (2014) Synergistic simvastatin and metformin combination chemotherapy for osseous metastatic castration-resistant prostate cancer. Mol Cancer Ther 13(10):2288–2302. doi:10.​1158/​1535-7163.​mct-14-0451 CrossRefPubMedPubMedCentral
62.
go back to reference Babcook M, Sramkoski R, Fujioka H, Daneshgari F, Almasan A, Shukla S, Nanavaty R, Gupta S (2014) Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1-and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells. Cell Death Dis 5(11):e1536CrossRefPubMedPubMedCentral Babcook M, Sramkoski R, Fujioka H, Daneshgari F, Almasan A, Shukla S, Nanavaty R, Gupta S (2014) Combination simvastatin and metformin induces G1-phase cell cycle arrest and Ripk1-and Ripk3-dependent necrosis in C4-2B osseous metastatic castration-resistant prostate cancer cells. Cell Death Dis 5(11):e1536CrossRefPubMedPubMedCentral
63.
64.
go back to reference Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302. doi:10.1200/jco.2009.19.6410 CrossRefPubMedPubMedCentral Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302. doi:10.​1200/​jco.​2009.​19.​6410 CrossRefPubMedPubMedCentral
65.
go back to reference Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC, Schulz CO, Possinger K, Eucker J (2012) Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res 32(5):1627–1637PubMed Liu H, Scholz C, Zang C, Schefe JH, Habbel P, Regierer AC, Schulz CO, Possinger K, Eucker J (2012) Metformin and the mTOR inhibitor everolimus (RAD001) sensitize breast cancer cells to the cytotoxic effect of chemotherapeutic drugs in vitro. Anticancer Res 32(5):1627–1637PubMed
66.
go back to reference Soo JS-S, Ng C-H, Tan SH, Malik RA, Teh Y-C, Tan B-S, Ho G-F, See M-H, Taib NAM, Yip C-H, Chung FF-L, Hii L-W, Teo S-H, Leong C-O (2015) Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis Int J Program Cell Death 20(10):1373–1387. doi:10.1007/s10495-015-1158-5 CrossRef Soo JS-S, Ng C-H, Tan SH, Malik RA, Teh Y-C, Tan B-S, Ho G-F, See M-H, Taib NAM, Yip C-H, Chung FF-L, Hii L-W, Teo S-H, Leong C-O (2015) Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells. Apoptosis Int J Program Cell Death 20(10):1373–1387. doi:10.​1007/​s10495-015-1158-5 CrossRef
67.
69.
go back to reference Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA (2011) The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 126(2):355–364. doi:10.1007/s10549-010-0924-x CrossRefPubMed Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA (2011) The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 126(2):355–364. doi:10.​1007/​s10549-010-0924-x CrossRefPubMed
70.
go back to reference Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, Martin-Castillo B, Menendez JA (2012) Metformin-induced preferential killing of breast cancer initiating CD44 + CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2 + human breast cancer xenografts. Oncotarget 3(4):395–398CrossRefPubMedPubMedCentral Cufi S, Corominas-Faja B, Vazquez-Martin A, Oliveras-Ferraros C, Dorca J, Bosch-Barrera J, Martin-Castillo B, Menendez JA (2012) Metformin-induced preferential killing of breast cancer initiating CD44 + CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2 + human breast cancer xenografts. Oncotarget 3(4):395–398CrossRefPubMedPubMedCentral
71.
go back to reference Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD (2011) Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle 10(17):2959–2966CrossRefPubMed Liu B, Fan Z, Edgerton SM, Yang X, Lind SE, Thor AD (2011) Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle 10(17):2959–2966CrossRefPubMed
72.
go back to reference Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA (2010) Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle 9(1):188–197CrossRefPubMed Anisimov VN, Egormin PA, Piskunova TS, Popovich IG, Tyndyk ML, Yurova MN, Zabezhinski MA, Anikin IV, Karkach AS, Romanyukha AA (2010) Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle 9(1):188–197CrossRefPubMed
73.
go back to reference Zhu P, Davis M, Blackwelder AJ, Bachman N, Liu B, Edgerton S, Williams LL, Thor AD, Yang X (2014) Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev Res (Phila) 7(2):199–210. doi:10.1158/1940-6207.capr-13-0181 CrossRef Zhu P, Davis M, Blackwelder AJ, Bachman N, Liu B, Edgerton S, Williams LL, Thor AD, Yang X (2014) Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prev Res (Phila) 7(2):199–210. doi:10.​1158/​1940-6207.​capr-13-0181 CrossRef
74.
go back to reference Lau YK, Du X, Rayannavar V, Hopkins B, Shaw J, Bessler E, Thomas T, Pires MM, Keniry M, Parsons RE, Cremers S, Szabolcs M, Maurer MA (2014) Metformin and erlotinib synergize to inhibit basal breast cancer. Oncotarget 5(21):10503–10517CrossRefPubMedPubMedCentral Lau YK, Du X, Rayannavar V, Hopkins B, Shaw J, Bessler E, Thomas T, Pires MM, Keniry M, Parsons RE, Cremers S, Szabolcs M, Maurer MA (2014) Metformin and erlotinib synergize to inhibit basal breast cancer. Oncotarget 5(21):10503–10517CrossRefPubMedPubMedCentral
75.
78.
go back to reference Chen H, Yao W, Chu Q, Han R, Wang Y, Sun J, Wang D, Wang Y, Cao M, He Y (2015) Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Letters 369(1):97–102. doi:10.1016/j.canlet.2015.08.024 CrossRefPubMed Chen H, Yao W, Chu Q, Han R, Wang Y, Sun J, Wang D, Wang Y, Cao M, He Y (2015) Synergistic effects of metformin in combination with EGFR-TKI in the treatment of patients with advanced non-small cell lung cancer and type 2 diabetes. Cancer Letters 369(1):97–102. doi:10.​1016/​j.​canlet.​2015.​08.​024 CrossRefPubMed
79.
go back to reference Kitazono S, Takiguchi Y, Ashinuma H, Saito-Kitazono M, Kitamura A, Chiba T, Sakaida E, Sekine I, Tada Y, Kurosu K, Sakao S, Tanabe N, Iwama A, Yokosuka O, Tatsumi K (2013) Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line. Int J Oncol 43(6):1846–1854. doi:10.3892/ijo.2013.2120 PubMedPubMedCentral Kitazono S, Takiguchi Y, Ashinuma H, Saito-Kitazono M, Kitamura A, Chiba T, Sakaida E, Sekine I, Tada Y, Kurosu K, Sakao S, Tanabe N, Iwama A, Yokosuka O, Tatsumi K (2013) Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line. Int J Oncol 43(6):1846–1854. doi:10.​3892/​ijo.​2013.​2120 PubMedPubMedCentral
80.
go back to reference Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, Li K, Chen H, Sun F, Yang Z, Jiang J, He Y (2014) Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res 20(10):2714–2726. doi:10.1158/1078-0432.ccr-13-2613 CrossRefPubMed Li L, Han R, Xiao H, Lin C, Wang Y, Liu H, Li K, Chen H, Sun F, Yang Z, Jiang J, He Y (2014) Metformin sensitizes EGFR-TKI-resistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal. Clin Cancer Res 20(10):2714–2726. doi:10.​1158/​1078-0432.​ccr-13-2613 CrossRefPubMed
82.
go back to reference Ko JC, Chiu HC, Wo TY, Huang YJ, Tseng SC, Huang YC, Chen HJ, Syu JJ, Chen CY, Jian YT, Jian YJ, Lin YW (2013) Inhibition of p38 MAPK-dependent MutS homologue-2 (MSH2) expression by metformin enhances gefitinib-induced cytotoxicity in human squamous lung cancer cells. Lung Cancer (Amsterdam, Netherlands) 82(3):397–406. doi:10.1016/j.lungcan.2013.09.011 CrossRef Ko JC, Chiu HC, Wo TY, Huang YJ, Tseng SC, Huang YC, Chen HJ, Syu JJ, Chen CY, Jian YT, Jian YJ, Lin YW (2013) Inhibition of p38 MAPK-dependent MutS homologue-2 (MSH2) expression by metformin enhances gefitinib-induced cytotoxicity in human squamous lung cancer cells. Lung Cancer (Amsterdam, Netherlands) 82(3):397–406. doi:10.​1016/​j.​lungcan.​2013.​09.​011 CrossRef
83.
go back to reference Morgillo F, Sasso FC, Della Corte CM, Vitagliano D, D’Aiuto E, Troiani T, Martinelli E, De Vita F, Orditura M, De Palma R, Ciardiello F (2013) Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res 19(13):3508–3519. doi:10.1158/1078-0432.ccr-12-2777 CrossRefPubMed Morgillo F, Sasso FC, Della Corte CM, Vitagliano D, D’Aiuto E, Troiani T, Martinelli E, De Vita F, Orditura M, De Palma R, Ciardiello F (2013) Synergistic effects of metformin treatment in combination with gefitinib, a selective EGFR tyrosine kinase inhibitor, in LKB1 wild-type NSCLC cell lines. Clin Cancer Res 19(13):3508–3519. doi:10.​1158/​1078-0432.​ccr-12-2777 CrossRefPubMed
84.
go back to reference Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, Chen HH, Su WC (2013) Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol 49(2):241–250. doi:10.1165/rcmb.2012-0244OC CrossRefPubMed Lin CC, Yeh HH, Huang WL, Yan JJ, Lai WW, Su WP, Chen HH, Su WC (2013) Metformin enhances cisplatin cytotoxicity by suppressing signal transducer and activator of transcription-3 activity independently of the liver kinase B1-AMP-activated protein kinase pathway. Am J Respir Cell Mol Biol 49(2):241–250. doi:10.​1165/​rcmb.​2012-0244OC CrossRefPubMed
86.
go back to reference Teixeira SF, Guimaraes IdS, Madeira KP, Daltoe RD, Silva IV, Rangel LBA (2013) Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells. J Bras Pneumol 39(6):644–649CrossRefPubMedPubMedCentral Teixeira SF, Guimaraes IdS, Madeira KP, Daltoe RD, Silva IV, Rangel LBA (2013) Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells. J Bras Pneumol 39(6):644–649CrossRefPubMedPubMedCentral
87.
go back to reference Tseng SC, Huang YC, Chen HJ, Chiu HC, Huang YJ, Wo TY, Weng SH, Lin YW (2013) Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem Pharmacol 85(4):583–594. doi:10.1016/j.bcp.2012.12.001 CrossRefPubMed Tseng SC, Huang YC, Chen HJ, Chiu HC, Huang YJ, Wo TY, Weng SH, Lin YW (2013) Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem Pharmacol 85(4):583–594. doi:10.​1016/​j.​bcp.​2012.​12.​001 CrossRefPubMed
88.
go back to reference Xiao Z, Sperl B, Ullrich A, Knyazev P (2014) Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. Oncotarget 5(24):12877CrossRefPubMedPubMedCentral Xiao Z, Sperl B, Ullrich A, Knyazev P (2014) Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. Oncotarget 5(24):12877CrossRefPubMedPubMedCentral
89.
go back to reference Groenendijk FH, Mellema WW, van der Burg E, Schut E, Hauptmann M, Horlings HM, Willems SM, van den Heuvel MM, Jonkers J, Smit EF, Bernards R (2015) Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation. Int J Cancer 136(6):1434–1444. doi:10.1002/ijc.29113 CrossRefPubMed Groenendijk FH, Mellema WW, van der Burg E, Schut E, Hauptmann M, Horlings HM, Willems SM, van den Heuvel MM, Jonkers J, Smit EF, Bernards R (2015) Sorafenib synergizes with metformin in NSCLC through AMPK pathway activation. Int J Cancer 136(6):1434–1444. doi:10.​1002/​ijc.​29113 CrossRefPubMed
90.
go back to reference Lin Y-C, Wu M-H, Wei T-T, Lin Y-C, Huang W-C, Huang L-Y, Lin Y-T, Chen C-C (2014) Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress. Oncotarget 5(1):298–308PubMedPubMedCentral Lin Y-C, Wu M-H, Wei T-T, Lin Y-C, Huang W-C, Huang L-Y, Lin Y-T, Chen C-C (2014) Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress. Oncotarget 5(1):298–308PubMedPubMedCentral
91.
go back to reference Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ, Kwong A, Tsumura A, Murphy R, Rappersberger K, Ortiz-Urda S (2015) Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 6(2):969CrossRefPubMed Vujic I, Sanlorenzo M, Posch C, Esteve-Puig R, Yen AJ, Kwong A, Tsumura A, Murphy R, Rappersberger K, Ortiz-Urda S (2015) Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget 6(2):969CrossRefPubMed
92.
go back to reference Cerezo M, Tomic T, Ballotti R, Rocchi S (2015) Is it time to test biguanide metformin in the treatment of melanoma? Pigment Cell Melanoma Res 28(1):8–20CrossRefPubMed Cerezo M, Tomic T, Ballotti R, Rocchi S (2015) Is it time to test biguanide metformin in the treatment of melanoma? Pigment Cell Melanoma Res 28(1):8–20CrossRefPubMed
93.
go back to reference Niehr F, von Euw E, Attar N, Guo D, Matsunaga D, Sazegar H, Ng C, Glaspy JA, Recio JA, Lo RS, Mischel PS, Comin-Anduix B, Ribas A (2011) Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med 9:76. doi:10.1186/1479-5876-9-76 CrossRefPubMedPubMedCentral Niehr F, von Euw E, Attar N, Guo D, Matsunaga D, Sazegar H, Ng C, Glaspy JA, Recio JA, Lo RS, Mischel PS, Comin-Anduix B, Ribas A (2011) Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations. J Transl Med 9:76. doi:10.​1186/​1479-5876-9-76 CrossRefPubMedPubMedCentral
94.
go back to reference Honjo S, Ajani JA, Scott AW, Chen Q, Skinner HD, Stroehlein J, Johnson RL, Song S (2014) Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol 45(2):567–574. doi:10.3892/ijo.2014.2450 PubMedPubMedCentral Honjo S, Ajani JA, Scott AW, Chen Q, Skinner HD, Stroehlein J, Johnson RL, Song S (2014) Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int J Oncol 45(2):567–574. doi:10.​3892/​ijo.​2014.​2450 PubMedPubMedCentral
95.
go back to reference Janjetovic K, Vucicevic L, Misirkic M, Vilimanovich U, Tovilovic G, Zogovic N, Nikolic Z, Jovanovic S, Bumbasirevic V, Trajkovic V, Harhaji-Trajkovic L (2011) Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol 651(1–3):41–50. doi:10.1016/j.ejphar.2010.11.005 CrossRefPubMed Janjetovic K, Vucicevic L, Misirkic M, Vilimanovich U, Tovilovic G, Zogovic N, Nikolic Z, Jovanovic S, Bumbasirevic V, Trajkovic V, Harhaji-Trajkovic L (2011) Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt. Eur J Pharmacol 651(1–3):41–50. doi:10.​1016/​j.​ejphar.​2010.​11.​005 CrossRefPubMed
97.
go back to reference Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2010) Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle (Georgetown, Tex) 9(6):1057–1064CrossRef Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2010) Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle (Georgetown, Tex) 9(6):1057–1064CrossRef
98.
go back to reference Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong J, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50(2):81–98CrossRefPubMed Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong J, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50(2):81–98CrossRefPubMed
99.
go back to reference Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, Guerrieri-Gonzaga A, Gentilini OD, Pagani G, Dell’Orto P, Lazzeroni M, Serrano D, Viale G, Bonanni B (2013) The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer 109(11):2792–2797. doi:10.1038/bjc.2013.657 CrossRefPubMedPubMedCentral Cazzaniga M, DeCensi A, Pruneri G, Puntoni M, Bottiglieri L, Varricchio C, Guerrieri-Gonzaga A, Gentilini OD, Pagani G, Dell’Orto P, Lazzeroni M, Serrano D, Viale G, Bonanni B (2013) The effect of metformin on apoptosis in a breast cancer presurgical trial. Br J Cancer 109(11):2792–2797. doi:10.​1038/​bjc.​2013.​657 CrossRefPubMedPubMedCentral
Metadata
Title
Combinational strategies of metformin and chemotherapy in cancers
Authors
Hui-Hui Zhang
Xiu-Li Guo
Publication date
01-07-2016
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-016-3037-3

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