Development and Reproduction (한국발생생물학회지:발생과생식)

The Korean Society of Developmental Biology (한국발생생물학회)
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Antitumor Activity of Combination Therapy with Metformin and Trametinib in Non-Small Cell Lung Cancer Cells

  • Ko, Eunjeong (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Baek, Seungjae (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Kim, Jiwon (Dept. of Medicine, Jeju National University School of Medicine) ;
  • Park, Deokbae (Histology, Jeju National University School of Medicine) ;
  • Lee, Youngki (Histology, Jeju National University School of Medicine)
  • Received : 2020.05.02
  • Accepted : 2020.05.27
  • Published : 2020.06.30
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Abstract

Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutically important, since metformin could enhance cell proliferation through RAS/RAF/MEK/ERK pathway and lead to impairment of its anticancer activity suppressing PI3K/AKT/mTOR pathway, requiring blockade of both signaling pathways for more efficient antitumor effect. The present study tested the combination therapy of metformin and trametinib by monitoring the alterations of regulatory effector proteins of cell signaling pathways and the effect of the combination on cell viability in NCI-H2087 NSCLC cells with NRAS and BRAF mutations. We show that metformin alone blocks PI3K/AKT/mTOR signaling pathway but induces the activation and phosphorylation of ERK. The combination therapy synergistically decreased cell viability in treatment with low doses of two drugs, while it gave antagonistic effect with high doses. These findings suggest that the efficacy of metformin and trametinib combination therapy may depend on the alteration of ERK activity induced by metformin and specific cellular context of cancer cells.

Keywords

References

  1. Ashinuma H, Takiguchi Y, Kitazono S, Kitazono-Saitoh M, Kitamura A, Chiba T, Tada Y, Kurosu K, Sakaida E, Sekine I, Tanabe N, Iwama A, Yokosuka O, Tatsumi K (2012) Antiproliferative action of metformin in human lung cancer cell lines. Oncol Rep 28:8-14. https://doi.org/10.3892/or.2012.1763
  2. Chan BA, Hughes BGM (2015) Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future. Transl Lung Cancer Res 4:36-54. https://doi.org/10.3978/j.issn.2218-6751.2014.05.01
  3. Chou TC, Talalay P (1981) Generalized equations for the analysis of inhibitions of Michaelis-Menten and higher-order kinetic systems with two or more mutually exclusive and nonexclusive inhibitors. Eur J Biochem 115:207-216. https://doi.org/10.1111/j.1432-1033.1981.tb06218.x
  4. Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, Beer DG Cope L, Creighton CJ, Danilova L, Ding L, Getz G, Hammerman PS, Neil Hayes D, Hernandez B, Herman JG, Heymach JV, Jurisica I, Kucherlapati R, Kwiatkowski D, Ladanyi M, Robertson G, Schultz N, Shen R, Sinha R, Sougnez C, Tsao MS, Travis WD, Weinstein JN, Wigle DA, Wilkerson MD, Chu A, Cherniack AD, Hadjipanayis A, Rosenberg M, Weisenberger DJ, Laird PW, Radenbaugh A, Ma S, Stuart S, Byers LA, Baylin SB, Govindan R, Meyerson M (2014) Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-550. https://doi.org/10.1038/nature13385
  5. Corte CMD, Ciaramella V, Di Mauro C, Castellone MD, Papaccio F, Fasno M, Sasso FC, Martinelli E, Troiani T, De Vita F, Orditura M, Bianco R, Ciardiello F, Morgillo F (2016) Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cells. Oncotarget 7:4265-4278. https://doi.org/10.18632/oncotarget.6559
  6. De Luca A, Maiello MR, D'Alessio A, Pergameno M, Normanno N (2012) The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: Role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets 16:S17-S27.
  7. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069-1075. https://doi.org/10.1038/nature07423
  8. Do MT, Kim HG, Khanal T, Choi JH, Kim DH, Jeong TC, Jeong HG (2013) Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of RAF-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol Appl Pharmacol 271:229-238. https://doi.org/10.1016/j.taap.2013.05.010
  9. Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304-1305. https://doi.org/10.1136/bmj.38415.708634.F7
  10. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling DJ, Watson M, Mardis ER, Wilson RK (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150:1121-1134. https://doi.org/10.1016/j.cell.2012.08.024
  11. Griss T, Vincent EE, Egnatchik R, Chen J, Ma EH, Faubert B, Viollet B, DeBerardinis RJ, Jones RG (2015) Metformin antagonizes cancer cell proliferation by suppressing mitochondrialdependent biosynthesis. Plos Biol 13:e1002309. https://doi.org/10.1371/journal.pbio.1002309
  12. Hall GC, Roberts CM, Boulis M, Mo J, MacRae KD (2005) Diabetes and the risk of lung cancer. Diabetes Care 28:590-594. https://doi.org/10.2337/diacare.28.3.590
  13. Holderfield M, Deuker MM, McCormick F, McMahon M (2014) Targeting RAF kinases for cancer therapy: BRAF mutated melanoma and beyond. Nat Rev Cancer 14:455-467. https://doi.org/10.1038/nrc3760
  14. Kim T, Kim T, Choi S, Ko H, Park D, Lee Y (2018) Combination of BEZ235 and metformin has synergistic effect on cell viability in colorectal cancer cells. Dev Reprod 22:133-142. https://doi.org/10.12717/DR.2018.22.2.133
  15. Ko G, Kim T, Ko E, Park D, Lee Y (2019) Synergistic enhancement of paclitaxel-induced inhibition of cell growth by metformin in melanoma cells. Dev Reprod 23:119-128. https://doi.org/10.12717/dr.2019.23.2.119
  16. Ko JC, Huang YC, Chen HJ, Tseng SC, Chiu HC, Wo TY, Huang YJ, Weng SH, Chiou RYY, Lin YW (2013) Metformin induces cytotoxicity by down-regulating thymidine phosphorylase and excision repair cross-complementation 1 expression in non-small cell lung cancer cells. Basic Clin Pharmacol Toxicol 113:56-65. https://doi.org/10.1111/bcpt.12052
  17. Lai SW, Liao KF, Chen PC, Tsai PY, Hsieh DPH, Chen CC (2012) Antidiabetes drugs correlate with decreased risk of lung cancer: A population-based observation in Taiwan. Clin Lung Cancer 13:143-148. https://doi.org/10.1016/j.cllc.2011.10.002
  18. Liu W, Du Y, Wen R, Yang M, Xu J (2020) Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol Ther 206:107438. https://doi.org/10.1016/j.pharmthera.2019.107438
  19. Martin MJ, Hayward R, Viros A, Marais R (2012) Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A. Cancer Discov 2:344-355. https://doi.org/10.1158/2159-8290.CD-11-0280
  20. Morgillo F, Sasso FC, Corte CMD, 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 19:3508-3519. https://doi.org/10.1158/1078-0432.CCR-12-2777
  21. Planchard D, Popat S, Kerk K, Novello E, Smit EF, Faivre-Finn C, Mok TS, Reck M, Van Schil PE, Hellmann MD, Peters S (2018) Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol iv192-iv237.
  22. Sayed R, Saad AS, El Wakeel L, Elkholy E, Badary O (2015) Metformin addition to chemotherapy in stage IV non-small cell lung cancer: An open label randomized controlled study. Asian Pac J Cancer Prev 16:6621-6626. https://doi.org/10.7314/APJCP.2015.16.15.6621
  23. Schrank Z, Chhabra G, Lin L, Iderzorig T, Osude C, Khan N, Kuckovic A, Singh S, Miller RJ, Puri N (2018) Current molecular-targeted therapies in NSCLC and their mechanism of resistance. Cancers 10:224. https://doi.org/10.3390/cancers10070224
  24. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, DePinho RA, Montiminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642-1646. https://doi.org/10.1126/science.1120781
  25. Stinchcombe TE, Bogart J, Wigle DA, Govindan R (2010) Annual review of advances in lung cancer clinical research: A report for the year of 2009. J Thorac Oncol 5:935-939. https://doi.org/10.1097/JTO.0b013e3181e3a2e6
  26. Tseng SC, Huang YC, Chen HJ, Chiu HC, Huang YJ, Wo TY, Weng SH, Lin YW (2013) Metformin-mediated downregulation of p38 mitogen-activated proteinkinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Biochem Pharmacol 85:583-594. https://doi.org/10.1016/j.bcp.2012.12.001
  27. Vancura A, Bu P, Bhagwat M, Zeng J, Vancurova I (2018) Metformin as an anticancer agent. Trends Pharmacol Sci 39:867-878. https://doi.org/10.1016/j.tips.2018.07.006
  28. World Health Organization [WHO] (2020) WHO outlines steps to save 7 million lives from cancer. Available online: https://www.who.int/news-room/detail/04-02-2020-who-outlinessteps-to-save-7-million-lives-from-cancer
  29. Yousef M, Tsiani E (2017) Metformin in lung cancer: Review of in vitro and in vivo animal studies. Cancers 9:45. https://doi.org/10.3390/cancers9050045