Journal of Cancer Research and Clinical Oncology

, Volume 142, Issue 10, pp 2159–2171 | Cite as

Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification

Review – Clinical Oncology

Abstract

Purpose

Three major chemotherapy strategies have emerged in the treatment of PDAC in the recent past: multiple drug combination, stroma depletion, and use of nanodrug therapy. Anti-diabetic metformin was shown to improve the outcome of a number of cancer types the first seminal report on an observational study published in 2005 and the first hospital-based case–control study on pancreatic cancer in 2009.

Methods

In this review paper, we confront the findings of a selected number of epidemiological studies and clinical trials on the use of metformin in pancreatic cancer treatment with basic knowledge and research. We particularly emphasize on the point that contradictory clinical results likely originate from heterogeneous study design due to a trial and error approach rather than an evidence-based and scientific approach. A non-rigorous selection of patients suffering from PDAC and often a poor understanding of the biological mechanism of metformin coupled with lack of scientific data has led to general statements on metformin positive or negative action, another aspect which we highlight in the review.

Results

We here present a few pathways which in our opinion are predominant for pancreatic cancer specifically: mitochondrial activity, AMPK activation, mTOR inhibition, and decreased IGF-1R and HIF-1α expression.

Conclusion

We stress on the need for a better stratification of patients and a more rigorous planning of clinical trials not only focusing on classical parameters but also on potential predictive biomarkers (AMPK, mTOR, HIF-1α, IGF-1R) and metformin dosage for positive outcome.

Keywords

Metformin Pancreatic cancer Cancer biology Clinical trials Biomarkers 

Abbreviations

AKT

Protein kinase B

AMPK

5′ Adenosine monophosphate-activated protein kinase

APC

Advanced pancreatic cancer

EGF

Epidermal growth factor

ERK

Extracellular signal-regulated kinase

HIF-1α

Hypoxia-inducible factor-1α

HR

Hormone receptor

IGF

Insulin-like growth factor

IGF-1R

Insulin-like growth factor 1 receptor

INSR

Insulin receptor

mTOR

Mammalian target of rapamycin

MEK

Mitogen-activated protein kinase

MPC

Metastatic pancreatic cancer

NFκB

Nuclear factor kappa B

PI3K

Phosphoinositide 3-kinase

PTEN

Phosphatase and tensin homologue

SIAH

Seven in abstensia homologue

STAT3

Signal transducer and activator of transcription 3

T2DM

Type 2 diabetes mellitus

References

  1. Ahlin G, Chen L, Lazorova L et al (2011) Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions. Pharmacogenomics J 11(6):400–411. doi:10.1038/tpj.2010.54 PubMedCrossRefGoogle Scholar
  2. Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M (2011) Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo. Oncogene 30:1174–1182PubMedCrossRefGoogle Scholar
  3. Alvarez R, Musteanu M, Garcia-Garcia E et al (2013) Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer 109:926–933PubMedPubMedCentralCrossRefGoogle Scholar
  4. Ambe CM, Mahipal A, Fulp J, Chen L, Malafa MP (2016) Effect of metformin use on survival in resectable pancreatic cancer: a single-institution experience and review of the literature. PLoS ONE 11(3):e0151632. doi:10.1371/journal.pone.0151632 PubMedPubMedCentralCrossRefGoogle Scholar
  5. Amgen (2012) Amgen announces termination of ganitumab phase 3 study for futility. In: Metastatic pancreatic cancer. http://www.prnewswire.com/news-releases/amgen-announces-termination-of-ganitumab-phase-3-study-for-futility-in-metastatic-pancreatic-cancer-165476446.html. Accessed 2 Apr 2016
  6. Appleman VA, Ahronian LG, Cai J, Klimstra DS, Lewis BC (2012) KRAS(G12D)- and BRAF(V600E)-induced transformation of murine pancreatic epithelial cells requires MEK/ERK-stimulated IGF1R signaling. Mol Cancer Res 10:1228–1239. doi:10.1158/1541-7786.MCR-12-0340-T PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bailey P, Chang DK, Nones K et al (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531:47–52. doi:10.1038/nature16965 PubMedCrossRefGoogle Scholar
  8. Bao B, Wang Z, Ali S et al (2012) Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res (Phila) 5(3):355–364. doi:10.1158/1940-6207.CAPR-11-0299 CrossRefGoogle Scholar
  9. Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh T-C, Wu E (2012) Advances in biomarker research for pancreatic cancer. Curr Pharm Des 18(17):2439–2451PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bhaw-Luximon A, Jhurry D (2015) New avenues for improving pancreatic ductal adenocarcinoma (PDAC) treatment: selective stroma depletion combined with nano drug delivery. Cancer Lett 369:266–273PubMedCrossRefGoogle Scholar
  11. Biankin AV, Waddell N, Kassahn KS et al (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491:399–405PubMedPubMedCentralCrossRefGoogle Scholar
  12. Braghiroli MI, de Celis Ferrari ACR, Pfiffer TE et al (2015) Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas. ecancer 9:563. doi:10.3332/ecancer.2015.563
  13. Brahimi-Horn MC, Bellot G, Pouysségur J (2011) Hypoxia and energetic tumour metabolism. Curr Opin Genet Dev 21(1):67–72PubMedCrossRefGoogle Scholar
  14. Bridges HR, Jones AJ, Pollak MN, Hirst J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462:475–487. doi:10.1042/BJ20140620 PubMedPubMedCentralCrossRefGoogle Scholar
  15. Cantoria MJ, Patel H, Boros LG, Meuillet EJ (2014) Metformin and pancreatic cancer metabolism, pancreatic cancer—insights into molecular mechanisms and novel approaches to early detection and treatment. In: Dr. Kelly McCall (ed) ISBN: 978-953-51-1375-1, InTech. doi:10.5772/57432. http://www.intechopen.com/books/pancreatic-cancer-insights-into-molecular-mechanisms-and-novel-approaches-to-early-detection-and-treatment/metformin-and-pancreatic-cancer-metabolism
  16. 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/P70S6K signaling. Sci Rep 5: article number 14404. doi:10.1038/srep14404
  17. Chaiteerakij R, Zhen DB, Burch PA et al (2015) Metformin use does not increase survival of pancreatic cancer patients: a cautionary lesson [abstract]. In: Proceedings of the 106th annual meeting of the American Association for Cancer Research; AACR, Cancer Res 75(15 Suppl):Abstract nr LB-183. doi:10.1158/1538-7445.AM2015-LB-183
  18. Chandel N (2014) Four key questions about metformin and cancer. BMC Biol 12:8CrossRefGoogle Scholar
  19. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia. J Biol Chem 275(33):25130–25138PubMedCrossRefGoogle Scholar
  20. Chari ST (2007) Detecting early pancreatic cancer: problems and prospects. Semin Oncol 34:284–294PubMedPubMedCentralCrossRefGoogle Scholar
  21. Chen HX, Sharon E (2013) IGF-IR as an anti-cancer target—trials and tribulations. Chin J Cancer 32(5):242–252PubMedPubMedCentralCrossRefGoogle Scholar
  22. Choi YK, Park K-G (2013) Metabolic roles of AMPK and metformin in cancer cells. Mol Cells 36:279–287. doi:10.1007/s10059-013-0169-8 PubMedPubMedCentralCrossRefGoogle Scholar
  23. Choi Y, Kim T-Y, Oh D-Y et al (2016) The impact of diabetes mellitus and metformin treatment on survival of patients with advanced pancreatic cancer undergoing chemotherapy. Cancer Res Treat 48(1):171–179PubMedCrossRefGoogle Scholar
  24. Conroy T, Desseigne F, Ychou M et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. doi:10.1056/NEJMoa1011923 PubMedCrossRefGoogle Scholar
  25. De Souza A, Khawaja KI, Masud F, Saif MW (2016) Metformin and pancreatic cancer: is there a role? Cancer Chemother Pharmacol. doi:10.1007/s00280-015-2948-8 Google Scholar
  26. DeCensi A, Puntoni M, Goodwin P et al (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res 3:1451–1461. doi:10.1158/1940-6207.CAPR-10-0157 CrossRefGoogle Scholar
  27. Dell’Antone P (2012) Energy metabolism in cancer cells: how to explain the Warburg and Crabtree effects? Med Hypotheses 79(3):388–392. doi:10.1016/j.mehy.2012.06.002 CrossRefGoogle Scholar
  28. Denduluri SK, Idowu O, Wang Z et al (2015) Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes Dis 2:13e25Google Scholar
  29. Deus CM, Santos GL, Loureiro R, Vega-Naredo I, Faneca H, Oliveira PJ (2015) Shutting down the furnace: preferential killing of cancer cells with mitochondrial-targeting molecules. Curr Med Chem 22(20):2438–2457PubMedCrossRefGoogle Scholar
  30. Esbah O, Eren T, Helvaci K et al (2014) The effect of metformin use on prognosis in pancreatic cancer patients. Acta Med Mediterr 30:465–471Google Scholar
  31. Eser S, Schnieke A, Schneider G, Saur D (2014) Oncogenic KRAS signalling in pancreatic cancer. Br J Cancer 111:817–822. doi:10.1038/bjc.2014.215 PubMedPubMedCentralCrossRefGoogle Scholar
  32. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305PubMedPubMedCentralCrossRefGoogle Scholar
  33. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA (2012) The pancreas cancer microenvironment. Clin Cancer Res 18:4266–4276PubMedPubMedCentralCrossRefGoogle Scholar
  34. Feng Y, Ke C, Tang Q et al (2014) Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis 5:e1088. doi:10.1038/cddis.2014.59 PubMedPubMedCentralCrossRefGoogle Scholar
  35. Fong ZV, Winter JM (2012) Biomarkers in pancreatic cancer: diagnostic, prognostic, and predictive. Cancer J 18(6):530–538. doi:10.1097/PPO.0b013e31827654ea PubMedCrossRefGoogle Scholar
  36. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E (2014) Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res 7(9):867–885CrossRefGoogle Scholar
  37. Gao Z-Y, Liu Z, Bi M-H et al (2016) Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med 11:1700–1706PubMedPubMedCentralGoogle Scholar
  38. García-Jiménez C, Gutiérrez-Salmerón M, Chocarro-Calvo A, García-Martinez JM, Castaño A, De la Vieja A (2016) From obesity to diabetes and cancer: epidemiological links and role of therapies. Br J Cancer 114:716–722. doi:10.1038/bjc.2016.37 PubMedPubMedCentralCrossRefGoogle Scholar
  39. Gong J, Robbins LA, Lugea A, Waldron RT, Jeon CY, Pandol SJ (2014) Diabetes, pancreatic cancer, and metformin therapy. Front Physiol. doi:10.3389/fphys.2014.00426 PubMedPubMedCentralGoogle Scholar
  40. Gong J, Kelekar G, Shen J, Shen J, Kaur S, Mita M (2016) The expanding role of metformin in cancer: an update on antitumor mechanisms and clinical development. Target Oncol. doi:10.1007/s11523-016-0423-z PubMedGoogle Scholar
  41. Griss T, Vincent EE, Egnatchik R et al (2015) Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol. doi:10.1371/journal.pbio.1002309 PubMedPubMedCentralGoogle Scholar
  42. Hakam A, Fang Q, Karl R, Coppola D (2003) Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig Dis Sci 48:1972–1978. doi:10.1023/A:1026122421369 PubMedCrossRefGoogle Scholar
  43. Hardie DG, Alessi DR (2013) LKB1 and AMPK and the cancer-metabolism link—ten years after. BMC Biol 11:36. doi:10.1186/1741-7007-11-36 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Higurashi T, Hosono K, Takahashi H, Komiya Y et al (2016) Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol 17(4):475–483PubMedCrossRefGoogle Scholar
  45. Hirakawa T, Yashiro M, Murata A et al (2013) IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer. BMC Cancer 13:392PubMedPubMedCentralCrossRefGoogle Scholar
  46. Hur KY, Lee M-S (2015) New mechanisms of metformin action: focusing on mitochondria and the gut. J Diabetes Investig 6(6):600–609. doi:10.1111/jdi.12328 PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hwang AL, Haynes K, Hwang WT, Yang YX (2013) Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas 42(7):1054–1059PubMedPubMedCentralCrossRefGoogle Scholar
  48. Incio J, Suboj P, Chin SM et al (2015) Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages. PLoS ONE 10(12):e0141392. doi:10.1371/journal.pone.0141392 PubMedPubMedCentralCrossRefGoogle Scholar
  49. Jeon S-M, Hay N (2012) The dark face of AMPK as an essential tumor promoter. Cell Logist 2(4):197–202PubMedPubMedCentralCrossRefGoogle Scholar
  50. Jeon S-M, Chandel NS, Hay N (2012) AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485(7400):661–665. doi:10.1038/nature11066 PubMedPubMedCentralCrossRefGoogle Scholar
  51. Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE, Kang KS (2011) Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS ONE 6(11):e28068. doi:10.1371/journal.pone.0028068 PubMedPubMedCentralCrossRefGoogle Scholar
  52. Karna E, Surazynski A, Orlowski K, Laszkiewicz J, Puchalski Z, Nawrat P, Palka J (2002) Serum and tissue level of insulin-like growth factor-I (IGF-I) and IGF-I binding proteins as an index of pancreatitis and pancreatic cancer. Int J Exp Pathol 83:239–245. doi:10.1046/j.1365-2613.2002.00237.x PubMedPubMedCentralCrossRefGoogle Scholar
  53. Karnevi E, Said K, Andersson R, Rosendahl AH (2013) Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. BMC Cancer 13:235. doi:10.1186/1471-2407-13-235 PubMedPubMedCentralCrossRefGoogle Scholar
  54. Keane MG, Horsfall L, Rait G, Pereira SP (2014) A case–control study comparing the incidence of early symptoms inpancreatic and biliary tract cancer. BMJ Open 4:e005720. doi:10.1136/bmjopen-2014-005720 PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. doi:10.1038/ncb2152 PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kim JG, Kang MJ, Yoon YK et al (2012) Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. PLoS ONE 7(3):e33322. doi:10.1371/journal.pone.0033322 PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E (2009) Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res 69(16):6539–6545. doi:10.1158/0008-5472.CAN-09-0418 PubMedPubMedCentralCrossRefGoogle Scholar
  58. Kisfalvi K, Moro A, Sinnett-Smith J, Eibl G, Rozengurt E (2013) Metformin inhibits the growth of human pancreatic cancer xenografts. Pancreas 42(5):781–785. doi:10.1097/MPA.0b013e31827aec40 PubMedCrossRefGoogle Scholar
  59. Korc M (1998) Role of growth factors in pancreatic cancer. Surg Oncol Clin N Am 7:25–41PubMedGoogle Scholar
  60. Kordes S, Pollak MN, Zwinderman AH et al (2015) Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. doi:10.1016/S1470-2045(15)00027-3 PubMedGoogle Scholar
  61. Kwon M, Choi YA, Choi MK, Song IS (2015) Organic cation transporter-mediated drug-drug interaction potential between berberine and metformin. Arch Pharm Res 38(5):849–856. doi:10.1007/s12272-014-0510-6 PubMedCrossRefGoogle Scholar
  62. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC (2011) 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 2011:11–20Google Scholar
  63. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL (2009) Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137(2):482–488PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lipner MB, Marayati R, Deng Y, Wang X, Raftery L, O’Neil BH, Yeh JJ (2016) Metformin treatment does not inhibit growth of pancreatic cancer patient-derived xenografts. PLoS ONE 11(1):e0147113. doi:10.1371/journal.pone.0147113 PubMedPubMedCentralCrossRefGoogle Scholar
  65. Liu Z, Jia X, Duan Y, Xiao H, Sundqvist KG, Permert J et al (2013) Excess glucose induces hypoxia-inducible factor-1alpha in pancreatic cancer cells and stimulates glucose metabolism and cell migration. Cancer Biol Ther 14:428–435PubMedPubMedCentralCrossRefGoogle Scholar
  66. Lodhia KA, Tienchaiananda P, Haluska P (2015) Understanding the key to targeting the IGF axis in cancer: a biomarker assessment. Front Oncol 5:142PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lonarardo E, Cioffi M, Sancho P et al (2013) Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS ONE. doi:10.1371/journal.pone.0076518 Google Scholar
  68. Lu Y, Rodrıguez LAG, Malgerud L et al (2015) New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer. Br J Cancer. doi:10.1038/bjc.2015.353 Google Scholar
  69. Madiraju AK, Eion DM, Rahimi Y et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546. doi:10.1038/nature13270 PubMedPubMedCentralCrossRefGoogle Scholar
  70. Magruder JT, Elahi D, Andersen DK (2011) Diabetes and pancreatic cancer chicken or egg? Pancreas 40:339–351PubMedCrossRefGoogle Scholar
  71. Mann KM, Ward JM, Yew CC et al (2012) Sleeping beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc Natl Acad Sci USA 109:5934–5941PubMedPubMedCentralCrossRefGoogle Scholar
  72. Maris C, D’Haene N, Trépant A-L et al (2015) IGF-IR: a new prognostic biomarker for human glioblastoma. Br J Cancer 113:729–737. doi:10.1038/bjc.2015.242 PubMedPubMedCentralCrossRefGoogle Scholar
  73. MAST Study—Metformin Active Surveillance Trial, ClinicalTrials.gov Identifier: NCT01864096Google Scholar
  74. Mayer MJ, Klotz LH, Venkateswaran V (2015) Metformin and prostate cancer stem cells: a novel therapeutic target. Prostate Cancer Prostatic Dis 18:303–309PubMedCrossRefGoogle Scholar
  75. Ming M, Sinnett-Smith J, Wang J et al (2014) Dose-dependent AMPK-dependent and independent mechanisms of berberine and metformin inhibition of mTORC1, ERK, DNA synthesis and proliferation in pancreatic cancer cells. PLoS ONE 9(12):e114573. doi:10.1371/journal.pone.0114573 PubMedPubMedCentralCrossRefGoogle Scholar
  76. Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S, Steele VE, Rao CV (2013) Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol 6(6):649–659PubMedPubMedCentralCrossRefGoogle Scholar
  77. Momi N, Kaur S, Krishn SR, Batra SK (2012) Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol 58:283–297PubMedPubMedCentralGoogle Scholar
  78. Morran DC, Wu J, Jamieson NB et al (2014) Targeting mTOR dependency in pancreatic cancer. Gut 63:1481–1489. doi:10.1136/gutjnl-2013-306202 PubMedPubMedCentralCrossRefGoogle Scholar
  79. Nair V, Sreevalsan S, Basha R, Abdelrahim M, Abudayyeh A, Rodrigues Hoffman A, Safe S (2014) Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) transcription factors. J Biol Chem 289(40):27692–27701. doi:10.1074/jbc.M114.592576 PubMedPubMedCentralCrossRefGoogle Scholar
  80. Niraula S, Dowling RJO, Ennis M et al (2012) Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study. Breast Cancer Res Treat 135:821–830. doi:10.1007/s10549-012-2223-1 PubMedCrossRefGoogle Scholar
  81. O’Reilly T, McSheehy PMJ (2010) Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol 3(2):65–79PubMedPubMedCentralCrossRefGoogle Scholar
  82. Owonikoko TK, Khuri FR (2013) Targeting the PI3K/AKT/mTOR pathway: biomarkers of success and tribulation. Am Soc Clin Oncol Educ Book. doi:10.1200/EdBook_AM.2013.33.e395 PubMedPubMedCentralGoogle Scholar
  83. Paplomata E, O’Regan R (2014) The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol 6(4):154–166. doi:10.1177/1758834014530023 PubMedPubMedCentralCrossRefGoogle Scholar
  84. Park D-B (2015) Metformin promotes apoptosis but suppresses autophagy in glucose-deprived H4IIE hepatocellular carcinoma cells. Diabetes Metab J 39:518–527. doi:10.4093/dmj.2015.39.6.518 PubMedPubMedCentralCrossRefGoogle Scholar
  85. Pollak MN (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928. doi:10.1038/nrc2536 PubMedCrossRefGoogle Scholar
  86. Pollak MN (2012) Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov 2(9):778–790PubMedCrossRefGoogle Scholar
  87. Pryor R, Cabreiro F (2015) Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J 471(Pt 3):307–322. doi:10.1042/BJ20150497 PubMedPubMedCentralCrossRefGoogle Scholar
  88. Qin R, Smyrk TC, Reed NR, Schmidt RL, Schnelldorfer T, Chari ST, Petersenand GM, Tang AH (2015) Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1a pathway to predict survival in resectable pancreatic cancer. Br J Cancer 112:514–522. doi:10.1038/bjc.2014.659 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Reni M, Dugnani E, Cereda S et al (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 PubMedGoogle Scholar
  90. Rieder S, Michalski CW, Friess H, Kleeff J (2011) Insulin-like growth factor signaling as a therapeutic target in pancreatic cancer. Anti Cancer Agents Med Chem 11:427–433. doi:10.2174/187152011795677454 CrossRefGoogle Scholar
  91. Rozengurt E, Sinnett-Smith J, Kisfalvi K (2010) 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):2505–2511PubMedPubMedCentralCrossRefGoogle Scholar
  92. Sadeghi N, Abbruzzese JL, Yeung SC, Hassan M, Li D (2012) Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res 8:2905–2912CrossRefGoogle Scholar
  93. Sahra I, Laurent K, Loubat A et al (2008) The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27:3576–3586PubMedCrossRefGoogle Scholar
  94. Sancho P, Burgos-Ramos E, Tavera A et al (2015) MYC/PGC-1a balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells. Cell Metab 22:1–16CrossRefGoogle Scholar
  95. Soares HP, Ni Y, Kisfalvi K, Sinnett-Smith J, Rozengurt E (2013) Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS ONE 8(2):e57289. doi:10.1371/journal.pone.0057289 PubMedPubMedCentralCrossRefGoogle Scholar
  96. Song R (2016) Mechanism of metformin: a tale of two sites. Diabetes Care 39:187–189PubMedCrossRefGoogle Scholar
  97. Stark A, Eibl G (2015) Pancreatic ductal adenocarcinoma, pancreatic ductal adenocarcinoma. Pancreapedia: Exocrine Pancreas Knowledge Base. doi:10.3998/panc.2015.14
  98. Subramani R, Lopez-Valdez R, Arumugam A et al (2014) Targeting insulin-like growth factor 1 receptor inhibits pancreatic cancer growth and metastasis. PLoS ONE 9(5):e97016. doi:10.1371/journal.pone.0097016 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Suissa S, Azoulay L (2012) Metformin and the risk of cancer: time-related biases in observational studies. Diabetes Care 35(12):2665–2673PubMedPubMedCentralCrossRefGoogle Scholar
  100. Takahashi A, Kimura F, Yamanaka A et al (2014) Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int 14:53. doi:10.1186/1475-2867-14-53 PubMedPubMedCentralCrossRefGoogle Scholar
  101. Tan X-L, Bhattacharyya KK, Dutta SK et al (2015) Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. Pancreas 44(4):636–647, This article has a delayed release (embargo) and will be available in PMC on May 1, 2016Google Scholar
  102. Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR (2001) AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 61:589–593PubMedGoogle Scholar
  103. Tomic T, Botton T, Cerezo M et al (2011) Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis 2:e199. doi:10.1038/cddis.2011.86 PubMedPubMedCentralCrossRefGoogle Scholar
  104. Trajkovic-Arsic M, Kalideris E, Siveke JT (2013) The role of insulin and IGF system in pancreatic cancer. J Mol Endocrinol 50:R67–R74PubMedCrossRefGoogle Scholar
  105. Utomo WK, Narayanan V, Biermann K, van Eijck CHJ, Bruno MJ, Peppelenbosch MP, Braat H (2014) mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma. Cancer Lett 346:309–317PubMedCrossRefGoogle Scholar
  106. Vasseur S, Tomasini R, Tournaire R, Iovanna JL (2010) Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers 2:2138–2152. doi:10.3390/cancers2042138 PubMedPubMedCentralCrossRefGoogle Scholar
  107. Vazquez-Martin A, Oliveras-Ferraros C, Cufí S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9(18):3807–3814PubMedCrossRefGoogle Scholar
  108. Verma M (2010) Pancreatic cancer biomarkers and their implication in cancer diagnosis and epidemiology. Cancers 2:1830–1837. doi:10.3390/cancers2041830 PubMedPubMedCentralCrossRefGoogle Scholar
  109. Von Hoff DD, Ramanathan RK, Borad MJ et al (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29:4548–4554CrossRefGoogle Scholar
  110. Wahdan-Alaswad R, Fan Z, Edgerton SM et al (2013) Glucose promotes breast cancer aggression and reduces metformin efficacy. Cell Cycle 12(24):3759–3769PubMedPubMedCentralCrossRefGoogle Scholar
  111. Wang F, Herrington M, Larsson J, Permert J (2003) The relationship between diabetes and pancreatic cancer. Mol Cancer 2:4. doi:10.1186/1476-4598-2-4 PubMedPubMedCentralCrossRefGoogle Scholar
  112. Wang Z, Lai ST, Xie L et al (2014) Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 106(1):19–26PubMedCrossRefGoogle Scholar
  113. Wheaton WW, Weinberg SE, Hamanaka RB et al (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. doi:10.7554/eLife.02242 PubMedPubMedCentralGoogle Scholar
  114. White E (2013) Exploiting the bad eating habits of Ras-driven cancers. Genes Dev 27:2065–2071PubMedPubMedCentralCrossRefGoogle Scholar
  115. Xu J-W, Wang T-X, You L et al (2014) Insulin-like growth factor 1 receptor (IGF-1R) as a target of MiR-497 and plasma IGF-1R levels associated with TNM stage of pancreatic cancer. PLoS ONE 9(3):e92847. doi:10.1371/journal.pone.0092847 PubMedPubMedCentralCrossRefGoogle Scholar
  116. Zhou X, Chen J, Yi G, Deng M, Liu H, Liang M, Shi B, Fu X, Chen Y, Chen L, He Z, Wang J, Liu J (2016) Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 7(1):873–884. doi:10.18632/oncotarget.6418 PubMedGoogle Scholar
  117. Zulato E, Bergamo F, De Paoli A et al (2014) Prognostic significance of AMPK activation in advanced stage colorectal cancer treated with chemotherapy plus bevacizumab. Br J Cancer 111:25–32. doi:10.1038/bjc.2014.274 PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Centre for Biomedical and Biomaterials Research (CBBR)University of MauritiusRéduitMauritius

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