Molecular targets of metformin antitumor action

Pharmacological Reports

Volumn 68, Issue 5, 2016, Pages 918-925

  Sośnicki, Stanisław ^a   Kapral, Małgorzata ^a   Wȩglarz, Ludmiła ^a  

^a MEDICAL UNIVERSITY OF SILESIA   (Poland)

Author keywords

Antitumor properties; Metformin; Molecular mechanisms

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; G PROTEIN COUPLED RECEPTOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; METFORMIN; MITOGENIC AGENT; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE LKB1; PROTEIN P53; SOMATOMEDIN; WNT PROTEIN; ANTIDIABETIC AGENT; ANTINEOPLASTIC AGENT;

ANTIDIABETIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CANCER PREVENTION; CELL METABOLISM; CLINICAL ASSESSMENT; CLINICAL EVALUATION; CLINICAL FEATURE; CLINICAL TRIAL (TOPIC); DRUG EFFECT; DRUG MECHANISM; ENZYME ACTIVATION; ENZYME ACTIVE SITE; ENZYME INHIBITION; GLUCONEOGENESIS; HUMAN; META ANALYSIS (TOPIC); MOLECULARLY TARGETED THERAPY; NONHUMAN; ONCOGENE; ONCOLOGY; PROTEIN FUNCTION; PROTEIN TARGETING; SIGNAL TRANSDUCTION; ANIMAL; DRUG DELIVERY SYSTEM; DRUG EFFECTS; NEOPLASMS; PROCEDURES;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; HUMANS; HYPOGLYCEMIC AGENTS; METFORMIN; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84976351314     PISSN: 22995684     EISSN: 22995684     Source Type: Journal    
DOI: 10.1016/j.pharep.2016.04.021     Document Type: Review

References (72)

1. M. Grzybowska, J. Bober, and M. Olszewska Metformin - mechanisms of action and use for the treatment of type 2 diabetes mellitus Postepy Hig Med Dosw 65 2011 277 285
2. L.L. Brunton Goodman & Gilman's the pharmacological basis of therapeutics 11th ed. 2005 McGraw-Hill New York
3. E. Diamanti-Kandarakis, C.D. Christakou, E. Kandaraki, and F.N. Economou Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome Eur J Endocrinol 162 2010 193 212 10.1530/EJE-09-0733
4. J.M.M. Evans, L.A. Donelly, A.M. Emslie-Smith, D.R. Alessi, and A.D.M. Evans Metformin and reduced risk of cancer in diabetic patients Br Med J 330 2005 1304 1305 10.1136/bmj.38415.708634.F7
5. M. Bodmer, C. Meier, S. Krähenbühl, S.S. Jick, and C.R. Meier Long-term metformin use is associated with decreased risk of breast cancer Diabetes Care 33 2010 1304 1308 10.2337/dc09-1791
6. N.F. Col, L. Ochs, V. Springmann, A.K. Aragaki, and R.T. Chlebowski Metformin and breast cancer risk: a meta-analysis and critical literature review Breast Cancer Res Treat 135 2012 639 646 10.1007/s10549-012-2170-x
7. G. Libby, L.A. Donnelly, P.T. Donnan, D.R. Alessi, A.D. Morris, and J.M.M. Evans New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes Diabetes Care 32 2009 1620 1625 10.2337/dc08-2175
8. S.W. Lai, K.F. Liao, P.C. Chen, P.Y. Tsai, D.P.H. Hsieh, and C.C. Chens Antidiabetes drugs correlate with decreased risk of lung cancer: a population-based observation in Taiwan Clin Lung Cancer 13 2 2012 143 148 10.1016/j.cllc.2011.10.002
9. H. Noto, A. Goto, T. Tsujimoto, and M. Noda Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis PLoS ONE 7 3 2012 e33411 10.1371/journal.pone.0033411
10. C.J. Currie, C.D. Poole, and E.A.M. Gale The influence of glucose-lowering therapies on cancer risk in type 2 diabetes Diabetologia 52 2009 1766 1777 10.1007/s00125-009-1440-6
11. M.C. Hsieh, T.C. Lee, S.M. Cheng, S.T. Tu, M.H. Yen, and C.H. Tseng The influence of type 2 diabetes and glucose-lowering therapies on cancer risk in the Taiwanese Exp Diabetes Res 2012 10.1155/2012/413782
12. M.S. Lee, C.C. Hsu, M.L. Wahlqvist, H.N. Tsai, Y.H. Chang, and Y.C. Huang 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 BMC Cancer 11 2011 20 10.1186/1471-2407-11-20
13. D. Soranna, L. Scotti, A. Zambon, C. Bosetti, G. Grassi, A. Catapano, and et al. Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis Oncologist 17 2012 813 822 10.1634/theoncologist. 2011-0462
14. C.H. Tseng Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan Eur J Endocrinology 167 2012 409 416 10.1530/EJE-12-0369
15. H.C. Lin, B.H. Kachingwe, H.L. Lin, H.W. Cheng, Y.S. Uang, and L.H. Wang Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study Pharmacotherapy 34 1 2014 36 45 10.1002/phar.1334
16. S.A. Hawley, A.E. Gadalla, G.S. Olsen, and G. Hardie The antidiabetic drug metformin activates the amp-activated protein kinase cascade via an adenine nucleotide-independent mechanism Diabetes 51 2002 2420 2425
17. V. Brower Illuminating the diabetes-cancer link J Natl Cancer Inst 104 14 2012 1048 1050 10.1093/jnci/djs311
18. B. Jiang, X. Zhang, L.L. Du, Y. Wang, D.B. Liu, C.Z. Han, and et al. Possible roles of insulin, IGF-1 and IGFBPs in initiation and progression of colorectal cancer World J Gastroenterol 20 6 2014 1608 1613 10.3748/wjg.v20.i6.1608
19. K.M.J. De Bruijn, L.R. Arends, B.E. Hansen, S. Leeflang, R. Ruiter, and C.H.J. van Eijck Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer Br J Surg 100 2013 1421 1429 10.1002/bjs.9229
20. E. Rozengurt, J. Sinnett-Smith, and K. Kisfalvi Crosstalk between insulin/IGF-1 and GPCR signaling systems: a novel target for the anti-diabetic drug metformin in pancreatic cancer Clin Cancer Res 16 9 2010 2505 2511 10.1158/1078-0432.CCR-09-2229
21. M. Martini, E. Ciraolo, F. Gulluni, and E. Hirsch Targeting PI3K in cancer: any good news? Front Oncol 3 2013 10.3389/fonc.2013.00108
22. C.C. Dibble, and L.C. Cantley Regulation of mTORC1 by PI3K signaling Trends Cell Biol 25 9 2015 545 555 10.1016/j.tcb.2015.06.002
23. J.J. Howell, S.J.H. Ricoult, I. Ben-Sahra, and B.D. Manning A growing role for mTOR in promoting anabolic metabolism Biochem Soc Trans 41 2013 906 912 10.1042/BST20130041
24. M.C. Mendoza, E.E. Er, and J. Blenis The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation Trends Biochem Sci 36 6 2011 320 328 10.1016/j.tibs.2011.03.006
25. A.Y. Choo, P.P. Roux, and J. Blenis Mind the GAP: Wnt steps onto the mTORC1 Train Cell 126 2006 834 836 10.1016/j.cell.2006.08.025
26. K. Inoki, T. Zhu, and K.L. Guan TSC2 mediates cellular energy response to control cell growth and survival Cell 115 2003 577 590
27. R.M. Memmott, J.R. Mercado, C.R. Maier, S. Kawabata, S.D. Fox, and P.A. Dennis Metformin prevents tobacco carcinogen-induced lung tumorigenesis Cancer Prev Res 3 9 2010 1066 1076 10.1158/1940-6207.CAPR-10-0055
28. C. Algire, M. Zakikhani, M.J. Blouin, J.H. Shuai, and M. Pollak Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth Endocr Relat Cancer 15 2008 833 839 10.1677/ERC-08-0038
29. C. Algire, L. Amrein, M. Zakikhani, L. Panasci, and M. Pollak Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase Endocr Relat Cancer 17 2010 351 360 10.1677/ERC-09-0252
30. B. Salani, S. Maffioli, M. Hamoudane, A. Parodi, S. Ravera, M. Passalacqua, and et al. Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells FASEB J 26 2011 788 798 10.1096/fj.11-192088
31. R. Sarfstein, Y. Friedman, Z. Attias-Geva, A. Fishman, I. Bruchim, and H. Werner 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 PLOS ONE 8 4 2013 e61537 10.1371/journal.pone.0061537
32. M. Zakikhani, M.J. Blouin, E. Piura, and M.N. Pollak Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells Breast Cancer Res Trans 123 1 2010 271 279 10.1007/s10549-010-0763-9
33. E. Karnevi, K. Said, R. Andersson, and A.H. Rosendahl Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells BMC Cancer 13 2013 235 10.1186/1471-2407-13-235
34. K. Hosono, H. Endo, H. Takahashi, M. Sugiyama, E. Sakai, T. Uchiyama, and et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial Cancer Prev Res 3 2010 1077 1083 10.1158/1940-6207.CAPR-10-0186
35. K. Hosono, H. Endo, H. Takahashi, M. Sugiyama, T. Uchiyama, K. Suzuki, and et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase Mol Carcinog 49 2010 662 671 10.1002/mc.20637
36. X. Huang, S. Wullschleger, N. Shpiro, V.A. McGuire, K. Sakamoto, Y.L. Woods, and et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice Biochem J 412 2008 211 221 10.1042/BJ20080557
37. Z. Qu, Y. Zhang, M. Liao, Y. Chen, J. Zhao, and Y. Pan In vitro and in vivo antitumoral action of metformin on hepatocellular carcinoma Hepatol Res 42 2012 922 933 10.1111/j.1872-034X.2012.01007.x
38. S. Cufí, B. Corominas-Faja, L. Lopez-Bonet, R. Bonavia, S. Pernas, I. Lopez, and et al. Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin Oncotarget 4 2013 1484 1495
39. A. Vazquez-Martin, C. Oliveras-Ferraros, S. Del Barco, B. Martin-Castillo, and J.A. Menendez The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells Breast Cancer Res Trans 126 2011 355 364 10.1007/s10549-010-0924-x
40. G.Z. Rocha, M.M. Dias, E.R. Ropelle, F.O. Costa, F.A. Rosatto, A.E. Vercesi, and et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth Clin Cancer Res 17 2011 3993 4005 10.1158/1078-0432.CCR-10-2243
41. A.J. Colquhoun, N.A. Venier, A.D. Vandersluis, R. Besla, L.M. Sugar, A. Kiss, and et al. Metformin enhances the antiproliferative and apoptotic effect of bicalutamide in prostate cancer Prostate Cancer Prostate Dis 15 2012 346 352 10.1038/pcan.2012.16
42. K. Kisfalvi, A. Moro, J. Sinnet-Smith, G. Eibl, and E. Rozengurt Metformin inhibits the growth of human pancreatic cancer xenografts Pancreas 42 2013 781 785
43. R.J.O. Dowling, M. Zakikhani, I.G. Fantus, M. Pollak, and N. Sonenberg Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells Cancer Res 67 22 2007 10804 10812 10.1158/0008-5472.CAN-07-2310
44. L.A. Cantrell, C. Zhou, A. Mendivil, K.M. Malloy, P.A. Gehrig, and V.L. Bae-Jump Metformin is a potent inhibitor of endometrial cancer cell proliferation - implications for a novel treatment strategy Gynecol Oncol 116 2010 92 98 10.1016/j.ygyno.2009.09.024
45. R.K. Hanna, C. Zhou, K.M. Malloy, L. Sun, Y. Zhong, P.A. Gehrig, and et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway Gynecol Oncol 125 2012 458 469 10.1016/j.ygyno.2012.01.009
46. R. Rattan, R.P. Graham, J.L. Maguire, S. Giri, and V. Shridhar Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo Neoplasia 13 2011 483 491 10.1593/neo.11148
47. A. Sikka, M. Kaur, C. Agarwal, G. Deep, and R. Agarwal Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation Cell Cycle 11 7 2012 1374 1382 10.4161/cc.19798
48. R. Rattan, S. Giri, L.C. Hartmann, and V. Shridhar Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner J Cell Mol Med 15 1 2009 166 178 10.1111/j.1582-4934.2009.00954.x
49. S. Gou, P. Cui, X. Li, P. Shi, T. Liu, and C. Wang Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action PLOS ONE 8 5 2013 e63969 10.1371/journal.pone.0063969
50. I. Ben Sahra, C. Regazzetti, G. Robert, K. Laurent, Y. Le Marchand-Brustel, P. Auberger, and et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1 Cancer Res 71 13 2011 4366 4372 10.1158/0008-5472.CAN-10-1769
51. A. Kalender, A. Selvaraj, S.Y. Kim, P. Gulati, S. Brǔle, B. Viollet, and et al. Metformin, independent of AMPK, inhibits mTORC1 in a Rag GTPase-dependent manner Cell Metab 11 2010 390 401 10.1016/j.cmet.2010.03.014
52. X. Zhou, M. Tan, V.S. Hwathorne, K.S. Klos, K.H. Lan, Y. Yang, and et al. Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers Clin Cancer Res 10 2004 6779 6788
53. I.N. Alimova, B. Liu, Z. Fan, S.M. Edgerton, T. Dillon, S.E. Lind, and et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro Cell Cycle 8 6 2009 909 915
54. T. Akinyeke, S. Matsumura, X. Wang, Y. Wu, E.D. Schalfer, A. Saxena, and et al. Metformin targets c-MYC oncogene to prevent prostate cancer Carcinogenesis 34 12 2013 2823 2832 10.1093/carcin/bgt307
55. D.A. Fruman, and A.L. Edinger Cancer therapy: staying current with AMPK Biochem J 412 2008 e3 e5 10.1042/BJ20080823
56. D.M. Gwinn, D.B. Shackelford, D.F. Egan, M.M. Mihaylova, A. Mery, D.S. Vasquez, and et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint Mol Cell 30 2 2008 214 226 10.1016/j.molcel.2008.03.003
57. J. Menendez, C. Oliveras-Ferraros, S. Cufí, B. Corominas-Faja, J. Joven, B. Martin-Castillo, and et al. Metformin is synthetically lethal with glucose withdrawal in cancer cells Cell Cycle 11 15 2012 2782 2792 10.4161/cc.20948
58. M. Buzzai, R. Jones, R. Amaravadi, J. Lum, R. DeBerardinis, F. Zhao, and et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth Cancer Res 67 2007 6745 6752 10.1158/0008-5472.CAN-06-4447
59. I. Ben Sahra, K. Laurent, S. Giuliano, F. Larbret, G. Ponzio, P. Gounon, and et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells Cancer Res 70 2010 2465 2475 10.1158/0008-5472.CAN-09-2782
60. H.T. Kwan, D.W. Chan, P.C.H. Cai, C.S.L. Mak, M.M.H. Yung, T.H.Y. Leung, and et al. AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/β-catenin signaling activity PLOS ONE 8 1 2013 e53597 10.1371/journal.pone.0053597
61. M.R. Owen, E. Doran, and A.P. Halestrap Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain Biochem J 348 2000 607 614
62. M.Y. El-Mir, V. Nogueira, E. Fontaine, N. Avéret, M. Rigoulet, and X. Leverve Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I J Biol Chem 275 2000 223 228
63. J.P. Fulgencio, C. Kohl, J. Girard, and J.P. Pègorier Effect of metformin on fatty acid and glucose metabolism in freshly isolated hepatocytes and on specific gene expression in cultured hepatocytes Biochem Pharmacol 62 2001 439 446
64. D.K. Chan, and W.K. Miskimins Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures J Ovarian Res 5 2012 19 10.1186/1757-2215-5-19
65. M. Zakikhani, R.J.O. Dowling, N. Sonenberg, and M.N. Pollak The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase Cancer Prev Res 1 5 2008 369 375 10.1158/1940-6207.CAPR-08-0081
66. R.M. Memmott, and P.A. Dennis LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin J Clin Oncol 27 34 2009 10.1200/JCO.2009.25.3963
67. 2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases J Biol Chem 280 32 2005 29060 29066 10.1074/jbc.M503824200
68. G.D. Dakubo Mitochondrial genetics and cancer 2010 Springer-Verlag Heidelberg
69. S. Javeshghani, M. Zakikhani, S. Austin, M. Bazile, M. Blouin, I. Topisirovic, and et al. Carbon source and myc expression influence the antiproliferative actions of metformin Cancer Res 72 2012 6257 6267 10.1158/0008-5472.CAN-12-2907
70. H.A. Hirsch, D. Iliopoulos, P.N. Tsichlis, and K. Struhl Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission Cancer Res 69 19 2009 7507 7511 10.1158/0008-5472.CAN-09-2994
71. A. Isakovic, L. Harhaji, D. Stevanovic, Z. Markovic, M. Sumarac-Dumanovic, V. Starcevic, and et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis Cell Mol Life Sci 64 2007 1290 1302 10.1007/s00018-007-7080-4
72. H. Lee, H.J. Park, C.S. Park, E.T. Oh, B.H. Choi, B. Williams, and et al. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined PLOS ONE 9 2 2014 e87979 10.1371/journal.pone.0087979