Skip to main content

Advertisement

SpringerLink
Log in

Metformin and pancreatic cancer: Is there a role?

  • Review Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA, with a 5-year survival rate of 6 %. Anti-hyperglycemic treatments for type 2 diabetes mellitus that induce hyperinsulinemia (i.e., sulfonylureas) are thought to increase cancer risk, whereas treatments that lower insulin resistance and hyperinsulinemia (i.e., metformin) are considered cancer prevention strategies. Metformin is a cornerstone in the treatment of diabetes mellitus type 2. Retrospective studies have shown a survival benefit in diabetic patients with many solid tumors including pancreatic cancer that have been treated with metformin compared with patients treated with insulin or sulfonylureas. Metformin influences various cellular pathways, including activation of the LKB1/AMPK pathway, inhibition of cell division, promotion of apoptosis and autophagy, down-regulation of circulating insulin, and activation of the immune system. Ongoing research is redefining our understanding about how metformin modulates the molecular pathways implicated in pancreatic cancer. The authors review the topic critically and also give their opinion. Further studies investigating the effect of metformin in combination with chemotherapy, targeted agents, or radiation therapy are undergoing. In addition, the role of metabolic and other biomarkers is needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pannala R, Basu A, Petersen GM, Chari ST (2009) New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 10(1):88–95

    Article  PubMed Central  PubMed  Google Scholar 

  2. Bartosch-Harlid A, Andersson R (2010) Diabetes mellitus in pancreatic cancer and the need for diagnosis of asymptomatic disease. Pancreatology 10(4):423–428

    Article  CAS  PubMed  Google Scholar 

  3. Bowker SL, Majumdar SR, Veugelers P, Johnson JA (2006) Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29:254–258

    Article  PubMed  Google Scholar 

  4. Watanabe CK (1918) Studies in the metabolic changes induced by administration of guanidine bases influence of injected guanidine hydrochloride upon blood sugar content. J Biol Chem 33:253–265

    CAS  Google Scholar 

  5. UKPDS Group (1998) Effects of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes. Lancet 352:854–865

    Article  Google Scholar 

  6. El-Mir M-Y et al (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228

    Article  CAS  PubMed  Google Scholar 

  7. Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348:607–614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Zhou G et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Zhou M, Xia L, Wang J (2007) Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos 35(10):1956–1962

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Gong L, Goswami S, Giacomini KM, Altman RB, Klein TE (2012) Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics 22(11):820–827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M (2005) Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70:1851–1860

    Article  PubMed  Google Scholar 

  12. Chen S, Zhou J, Xi M, Jia Y, Wong Y, Zhao J, Ding L, Zhang J, Wen A (2013) Pharmacogenetic variation and metformin response. Curr Drug Metab 14(10):1070–1082

    Article  CAS  PubMed  Google Scholar 

  13. Zhou K, Donnelly L, Yang J, Li M, Deshmukh H, Van Zuydam N, Ahlqvist E, Wellcome Trust Case Control Consortium, Spencer CC, Groop L, Morris AD, Colhoun HM, Sham PC, McCarthy MI, Palmer CN, Pearson ER (2014) Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2(6):481–487. doi:10.1016/S2213-8587(14)70050-6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Minematsu T, Giacomini KM (2011) Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther 10:531–539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE (1995) Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med 333(9):550–554

    Article  CAS  PubMed  Google Scholar 

  16. Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(Pt 3):607–614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Hinke SA, Martens GA, Cai Y, Finsi J, Heimberg H, Pipeleers D, Van de Casteele M (2007) Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol 150(8):1031–1043

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    Article  CAS  PubMed  Google Scholar 

  19. Frasca F, Pandini G, Sciacca L et al (2008) The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 114:23–37

    Article  CAS  PubMed  Google Scholar 

  20. Mountjoy KG, Finlay GJ, Holdaway IM (1987) Abnormal insulin receptor down regulation and dissociation of down regulation from insulin biological action in cultured human tumor cells. Cancer Res 47:6500–6504

    CAS  PubMed  Google Scholar 

  21. De Meyts P (2004) Insulin and its receptor: structure, function and evolution. Bioessays 26:1351–1362

    Article  PubMed  Google Scholar 

  22. Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK (2000) Insulin regulation of human hepatic growth hormone receptors: divergent effects on biosynthesis and surface translocation. J Clin Endocrinol Metab 85:4712–4720

    CAS  PubMed  Google Scholar 

  23. Housa D, Housova J, Vernerova Z, Haluzik M (2006) Adipocytokines and cancer. Physiol Res 55:233–244

    CAS  PubMed  Google Scholar 

  24. O’Sullivan KE, Reynolds JV, O’Hanlon C, O’Sullivan JN, Lysaght J (2014) Could signal transducer and activator of transcription 3 be a therapeutic target in obesity-related gastrointestinal malignancy? J Gastrointest Cancer 45(1):1–11

    Article  PubMed  Google Scholar 

  25. Krechler T, Zeman M, Vecka M, Macasek J, Jachymova M, Zima T, Zak A (2011) Leptin and adiponectin in pancreatic cancer: connection with diabetes mellitus. Neoplasma 58(1):58–64

    Article  CAS  PubMed  Google Scholar 

  26. Dalamaga M et al (2009) Pancreatic cancer expresses adiponectin receptors and is associated with hypoleptinemia and hyperadiponectinemia: a case–control study. Cancer Causes Control 20(5):625–633

    Article  PubMed Central  PubMed  Google Scholar 

  27. Bao B, Wang Z, Li Y, Kong D, Ali S, Banerjee S, Ahmad A, Sarkar FH (2011) The complexities of obesity and diabetes with the development and progression of pancreatic cancer. Biochim Biophys Acta 1815(2):135–146

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, Wang Z, Philip PA, Sarkar FH (2010) Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res 70:3606–3617

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Olson P, Lu J, Zhang H, Shai A, Chun MG, Wang Y, Libutti SK, Nakakura EK, Golub TR, Hanahan D (2009) MicroRNA dynamics in the stages of tumorigenesis correlate with hallmark capabilities of cancer. Genes Dev 23:2152–2165

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Kong L, Zhu J, Han W, Jiang X, Xu M, Zhao Y, Dong Q, Pang Z, Guan Q, Gao L, Zhao J, Zhao L (2011) Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. Acta Diabetol 48(1):61–69

    Article  CAS  PubMed  Google Scholar 

  31. Kolfschoten IG, Roggli E, Nesca V, Regazzi R (2009) Role and therapeutic potential of microRNAs in diabetes. Diabetes Obes Metab 11(Suppl. 4):118–129

    Article  CAS  PubMed  Google Scholar 

  32. Lovis P, Roggli E, Laybutt DR, Gattesco S, Yang JY, Widmann C, Abderrahmani A, Regazzi R (2008) Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction. Diabetes 57:2728–2736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kent OA, Mullendore M, Wentzel EA, Lopez-Romero P, Tan AC, Alvarez H, West K, Ochs MF, Hidalgo M, Arking DE, Maitra A, Mendell JT (2009) A resource for analysis of microRNA expression and function in pancreatic ductal adenocarcinoma cells. Cancer Biol Ther 8:2013–2024

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Zhang B, Pan X, Cobb GP, Anderson TA (2007) microRNAs as oncogenes and tumor suppressors. Dev Biol 302:1–12

    Article  CAS  PubMed  Google Scholar 

  35. Rachagani S, Kumar S, Batra SK (2010) MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett 292:8–16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Hardie DG (2007) AMP-activated/SNF1protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8:774–785

    Article  CAS  PubMed  Google Scholar 

  37. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Yue W, Yang CS, Dipaola RS, Tan XL (2014) Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prev Res (Phila) 7(4):388–397

    Article  CAS  Google Scholar 

  39. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67:10804–10812

    Article  CAS  PubMed  Google Scholar 

  41. Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN, Bruchim I (2008) In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 110:246–250

    Article  CAS  PubMed  Google Scholar 

  42. Zhang Y, Yang J, Cui X, Chen Y et al (2013) A novel epigenetic CREB-miR-373 axis mediates ZIP4-induced pancreatic cancer growth. EMBO Mol Med 5(9):1322–1334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Li W, Yuan Y, Huang L, Qiao M, Zhang Y (2012) Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells. Diabetes Res Clin Pract 96(2):187–195

    Article  CAS  PubMed  Google Scholar 

  44. Kalender A, Selvaraj A, Kim SY et al (2010) Metformin, independent of AMPK, inhibits mTORC1 in rag GTPase-dependent manner. Cell Metab 11:390–401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Nakamura M, Ogo A, Yamura M, Yamaguchi Y, Nakashima H (2014) Metformin suppresses sonic hedgehog expression in pancreatic cancer cells. Anticancer Res 34(4):1765–1769

    CAS  PubMed  Google Scholar 

  46. Morran DC, Wu J, Jamieson NB, Mrowinska A, Kalna G, Karim SA, Au AY, Scarlett CJ, Chang DK, Pajak MZ, Australian Pancreatic Cancer Genome Initiative (APGI), Oien KA, McKay CJ, Carter CR, Gillen G, Champion S, Pimlott SL, Anderson KI, Evans TR, Grimmond SM, Biankin AV, Sansom OJ, Morton JP (2014) Targeting mTOR dependency in pancreatic cancer. Gut 63(9):1481–1489

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Liang J, Shao SH, Xu ZX et al (2007) The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9:218–224

    Article  CAS  PubMed  Google Scholar 

  48. Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares AH, Smulson ME (1998) Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J Biol Chem 273(22):13703–13712

    Article  CAS  PubMed  Google Scholar 

  49. Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, Smulson M (1999) Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis: caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem 274(33):22932–22940

    Article  CAS  PubMed  Google Scholar 

  50. Fasih A, Elbaz HA, Hüttemann M, Konski AA, Zielske SP (2014) Radiosensitization of pancreatic cancer cells by metformin through the AMPK pathway. Radiat Res 182(1):50–59

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Zhang JG, Hong DF, Zhang CW, Sun XD, Wang ZF, Shi Y, Liu JW, Shen GL, Zhang YB, Cheng J, Wang CY, Zhao G (2014) Sirtuin 1 facilitates chemoresistance of pancreatic cancer cells by regulating adaptive response to chemotherapy-induced stress. Cancer Sci 105(4):445–454

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. 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):649–659

    Article  PubMed Central  PubMed  Google Scholar 

  53. Lonardo E, Cioffi M, Sancho P, Sanchez-Ripoll Y, Trabulo SM, Dorado J, Balic A, Hidalgo M, Heeschen C (2013) Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells. PLoS One 8(10):e76518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Semple RK (2009) From bending DNA to diabetes: the curious case of HMGA1. J Biol 8(7):64

    Article  PubMed Central  PubMed  Google Scholar 

  55. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL (2009) Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137(2):482–488

    Article  PubMed Central  PubMed  Google Scholar 

  56. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. 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 18(10):2905–2912

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461

    Article  CAS  Google Scholar 

  59. Hwang AL, Haynes K, Hwang WT, Yang YX (2013) Metformin and survival in pancreatic cancer: a retrospective cohort study. Pancreas 42(7):1054–1059

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    Article  PubMed Central  PubMed  Google Scholar 

  61. 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 11:20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Bodmer M, Becker C, Meier C, Jick SS, Meier CR (2012) Use of antidiabetic agents and the risk of pancreatic cancer: a case–control analysis. Am J Gastroenterol 107(4):620–626

    Article  CAS  PubMed  Google Scholar 

  63. Zhang P, Li H, Tan X, Chen L, Wang S (2013) Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer Epidemiol 37(3):207–218

    Article  PubMed  Google Scholar 

  64. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, Ren ZG, Jiang GL (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):19–26

    Article  CAS  PubMed  Google Scholar 

  65. Stolzenberg-Solomon RZ, Graubard BI, Chari S, Limburg P, Taylor PR, Virtamo J, Albanes D (2005) Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294(22):2872–2878

    Article  CAS  PubMed  Google Scholar 

  66. Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST (2013) Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol 108(4):510–519; quiz 520

  67. Soranna D, Scotti L, Zambon A, Bosetti C, Grassi G, Catapano A, La Vecchia C, Mancia G (2012) Corrao G Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis. Oncologist 17(6):813–822

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Pollak M (2012) Metformin and pancreatic cancer: a clue requiring investigation. Clin Cancer Res 18(10):2723–2725

    Article  CAS  PubMed  Google Scholar 

  69. Motoo Y, Shimasaki T, Ishigaki Y, Nakajima H, Kawakami K, Minamoto T (2011) Metabolic disorder, inflammation, and deregulated molecular pathways converging in pancreatic cancer development: implications for new therapeutic strategies. Cancers 3(1):446–460. doi:10.3390/cancers3010446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of GI Cancers and Experimental Therapeutics, Department of Hematology and Oncology, Tufts University School of Medicine and Tufts Cancer Center, Tufts Medical Center, 800 Washington Street, Boston, MA, 02111, USA

    Andre De Souza & Muhammad Wasif Saif

  2. Department of Endocrinology and Metabolism, Services Institute of Medical Sciences, Lahore, Pakistan

    Khadija Irfan Khawaja

  3. King Edward Medical University, Lahore, Pakistan

    Faisal Masud

Authors
  1. Andre De Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Khadija Irfan Khawaja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Faisal Masud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad Wasif Saif
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muhammad Wasif Saif.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Souza, A., Khawaja, K.I., Masud, F. et al. Metformin and pancreatic cancer: Is there a role?. Cancer Chemother Pharmacol 77, 235–242 (2016). https://doi.org/10.1007/s00280-015-2948-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2948-8

Keywords

Search

Navigation