Journal of Medical Academics

Register      Login

VOLUME 1 , ISSUE 1 ( January-June, 2018 ) > List of Articles


Effect of Metformin in Preventing Insulin-Mediated Proliferation of p53 and Liver Kinase B1 Mutant and Wild-Type Lung Cancer Cell Lines

Manu Krishnan, Kavita Sahai

Keywords : Diabetes mellitus (DM), Metformin, Lung cancer, Liver kinase B1, p53

Citation Information : Krishnan M, Sahai K. Effect of Metformin in Preventing Insulin-Mediated Proliferation of p53 and Liver Kinase B1 Mutant and Wild-Type Lung Cancer Cell Lines. Journal of Medical Academics 2018; 1 (1):35-42.

DOI: 10.5005/jp-journals-10070-0007

License: NA

Published Online: 01-04-2018

Copyright Statement:  NA


Background: Lung cancer and diabetes mellitus (DM) are diseases of high occurrence worldwide. Increased incidence of lung cancer in DM patients is frequently observed. In this context, an insulin-sensitizing drug, metformin (biguanides) may have inhibitory effects on the proliferation of lung cancer cells. Aim: The present study was aimed to evaluate the growth proliferation effect of insulin on nonsmall cell lung carcinoma (NSCLC) cell lines. It also proposed to assess the preventive role of metformin in insulin-mediated proliferation in p53 and liver kinase B1 (LKB1) mutant and wild-type cell lines. Materials and methods: Two non small cell lung carcinoma cell lines, A549 and H1299 (p53 and LKB1 wild-type and mutant) were used to analyze the mitogenic role of insulin by incubating for 24 hours with human recombinant insulin at concentrations of 1nM to 10μM and followed by the addition of metformin (concentrations from 1μM to 50mM) for 24 hours along with insulin (500nM for A549 and 1μM for H1299). The proliferation was assessed by MTT dye reduction test. Results: Both the cell lines exhibited a significant and dosedependent growth proliferation (p < 0.001) with different concentrations of insulin. This was effectively (p < 0.001) inhibited by metformin treatment for 24 hours. The maximum reduction in growth was 73% and 67% for A549 and H1299 respectively. Conclusions: Insulin in high circulating concentrations can augment the growth proliferation of lung cancer cells. Metformin can inhibit this in a multifaceted way, wherein the mechanism of action is independent of p53 and liver kinase B1. Clinical significance: Metformin could inhibit the insulinmediated proliferation of cells, and hence it may be considered for the new therapeutic policies for treatment of human NSCLC.

PDF Share
  1. World Health Organization. Diabetes facts sheets [Internet]. Geneva: World Health Organization; 15 Nov 2017. Available from
  2. World Health Organization. Cancer facts sheets [Internet]. Geneva: World Health Organization; 1 Feb 2018. Available from
  3. Zhu L, Cao H, Zhang T, Shen H, Dong W, Wang L, et al. The effect of diabetes mellitus on lung cancer prognosis: A PRISMA- complaint meta analysis of cohort studies. Medicine (Baltimore). 2016 Apr; 95(17):e3528.
  4. Giovannucci E, Harlan DM, Michael CA, Bergenstal RM, Gapstur SM, Laurel AH, et al. Diabetes and Cancer. Diabetes Care. 2010 Jul;33(7):1674-168.
  5. Kurushima K, Watanabe H, Ishikawa H, Satoh H, Hizawa N. Survoval of patients with lung cancer and diabetes mellitus. Mol Clin Oncol. 2017 Jun;6(6):907-910.
  6. Park SM, Lim MK, Shin SA, Yun YH. Impact of prediagnosis smoking, alcohol, obesity, and insulin resistance on survival in male cancer patients: National Health Insurance Corporation Study. J Clin Oncol. 2006 Nov; 24(31): 5017-5024.
  7. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008 Dec; 8(12): 915-928.
  8. Bosenberg LH, van Zyl DG. The mechanism of action of oral antidiabetic drugs: A review of recent literature. JEMDSA. 2008 Dec; 13(3): 80-88.
  9. Andujar-Plata P, Pi-Sunyer X, Laferrere B. Metformin effects revisited. Diabetes Res Clin Pract. 2012 Jan; 95(1): 1-9.
  10. Yousef M, Tsiani E. Metformin in lung cancer: Review of in viro and in vivo animal studies. Cancers. 2017 May ; 9(5): E45.
  11. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010 Feb; 33(2): 322-326.
  12. Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, et al. Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer Res. 2010 Mar; 70(6): 2465-2475.
  13. Memmott RM, Dennis PA. LKB1 and mammalian target of rapamycin as predictive factors for the anticancer efficacy of metformin. J Clin Oncol. 2009 Dec; 27(34):226–227.
  14. Argirion I, Weistein SJ, Mannisto S, Albanes D, Modu AM. Serum insulin, glucose, indices of insulin resistance and risk of lung cancer. Cancer Epidemio Biomarkers Prev. 2017 Oct; 26(10): 1519-1524.
  15. Mitri J, Pittas AG. Inhaled insulin--what went wrong. Nat Clin Pract Endocrinol Metab. 2009 Jan;5(1):24-25.
  16. Farhan SY, Jankowski M, Hanbali A, Wang D. The use of insulin and the effect on survival of non-small cell lung cancer patients. Paper presented at the 2009 ASCO Annual Meeting Orlando, Florida.
  17. Kurishima K, Watanabe H, Ishikawa H, Satoh H, Hizawa N. Survival of patients with lung cancer and diabetes mellitus. Mol Clin Oncol. 2017 Jun;6(6):907-910.
  18. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res (Phila). 2010 Sept; 3(9): 1066-1076.
  19. Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 2007 Jul;67(14):6745-675229.
  20. Zakikhani M, Dowling R, Frantus IG, Sonenberg N, Pollak MN. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 2006 Nov; 66(21): 10269-73.
  21. Granja S, Marchiq I, Le Floch R, Moura CS, Baltazar F, Pouyssegur J. Disruption of BASIGIN decreases lactic acid export and sensitizes non-small cell lung cancer to biguanides independently of the LKB1 status. Oncotarget. 2015 Mar; 6(9): 6708-6721.
  22. Guo Q, Liu Z, Jiang L, Liu M, Ma J, Yang C, et al. Metformin inhibits growth of human non-small cell lung cancer cells via liver kinaseB-1-independent activation of adenosine monophosphate-activated protein kinase. Mol Med Rep. 2016 Mar; 13(3): 2590-6.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.