157
Views
1
CrossRef citations to date
0
Altmetric
Articles

Metabolic and Metabolomic Effects of Metformin in Murine Model of Pulmonary Adenoma Formation

ORCID Icon, , , ORCID Icon, ORCID Icon, , & show all
Pages 1014-1027 | Received 01 Aug 2022, Accepted 03 Jan 2023, Published online: 23 Jan 2023

References

  • Le S, Lee GC. Emerging trends in metformin prescribing in the United States from 2000 to 2015. Clin Drug Investig. 2019;39(8):757–63. 10.1007/s40261-019-00799-0
  • Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, DeCensi A, Szabo E. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila). 2014;7(9):867–85. 10.1158/1940-6207.CAPR-13-0424
  • Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S. Metformin and cancer risk in diabetic patients: A systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3(11):1451–61. 10.1158/1940-6207.CAPR-10-0157
  • Hou YC, Hu Q, Huang J, Fang JY, Xiong H. Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: A meta-analysis. Oncotarget. 2017;8(5):8843–53. doi:10.18632/oncotarget.13633
  • Zhang Z-J, Zheng Z-J, Shi R, Su Q, Jiang Q, Kip KE. Metformin for liver cancer prevention in patients with type 2 diabetes: A systematic review and meta-analysis. J Clin Endocrinol Metab. 2012;97(7):2347–53. 10.1210/jc.2012-1267
  • Zhou P-T, Li B, Liu F-R, Zhang M-C, Wang Q, Li Y-Y, Xu C, Liu Y-H, Yao Y, Li D, et al. Metformin is associated with survival benefit in pancreatic cancer patients with diabetes: a systematic review and meta-analysis. Oncotarget. 2017;8(15):25242–50. doi:10.18632/oncotarget.15692
  • Zhang Z-J, Zheng Z-J, Kan H, Song Y, Cui W, Zhao G, Kip KE. Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011;34(10):2323–8. doi:10.2337/dc11-0512
  • Kim HS, Kim JH, Jang HJ, Lee J. The addition of metformin to systemic anticancer therapy in advanced or metastatic cancers: a meta-analysis of randomized controlled trials. Int J Med Sci. 2020;17(16):2551–60. doi:10.7150/ijms.50338
  • Wu Z, Qu B, Huang X, Song Y, Gao P, Shi J, Zhou C, Wang Z. The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials. Ann Transl Med. 2020;8(21):1404– 10.21037/atm-20-4441
  • Mogheri F, Jokar E, Afshin R, Akbari AA, Dadashpour M, Firouzi-Amandi A, Serati-Nouri H, Zarghami N. Co-delivery of metformin and silibinin in dual-drug loaded nanoparticles synergistically improves chemotherapy in human non-small cell lung cancer A549 cells. J Drug Delivery Sci Technol. 2021;66:102752. 10.1016/j.jddst.2021.102752
  • El-Mir M-Y, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–8. 10.1074/jbc.275.1.223
  • Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017;27(8):657–69. 10.1016/j.numecd.2017.04.009
  • Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016–23. 10.1038/ncb2329
  • Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9(8):563–75. 10.1038/nrc2676
  • Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care. 1989;12(8):553–64. 10.2337/diacare.12.8.553
  • Salani B, Rio AD, Marini C, Sambuceti G, Cordera R, Maggi D. Metformin, cancer and glucose metabolism. Endocr Relat Cancer. 2014;21(6):R461–R471. 10.1530/ERC-14-0284
  • Yu H, Zhong X, Gao P, Shi J, Wu Z, Guo Z, Wang Z, Song Y. The potential effect of metformin on cancer: An umbrella review. Front Endocrinol (Lausanne). 2019;10:617. doi:10.3389/fendo.2019.00617
  • Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 2007;67(22):10804–12. 10.1158/0008-5472.CAN-07-2310
  • Estensen RD, Jordan MM, Wiedmann TS, Galbraith AR, Steele VE, Wattenberg LW. Effect of chemopreventive agents on separate stages of progression of benzo[alpha]pyrene induced lung tumors in A/J mice. Carcinogenesis. 2004;25(2):197–201. doi:10.1093/carcin/bgg196
  • Wattenberg LW, Estensen RD. Studies of chemopreventive effects of budenoside on benzo[a]pyrene-induced neoplasia of the lung of female A/J mice. Carcinogenesis. 1997;18(10):2015–7. doi:10.1093/carcin/18.10.2015
  • Wattenberg LW, Wiedmann TS, Estensen RD, Zimmerman CL, Galbraith AR, Steele VE, Kelloff GJ. Chemoprevention of pulmonary carcinogenesis by brief exposures to aerosolized budesonide or beclomethasone dipropionate and by the combination of aerosolized budesonide and dietary myo-inositol. Carcinogenesis. 2000;21(2):179–82. doi:10.1093/carcin/21.2.179
  • Chambers MC, Maclean B, Burke R, Amodei D, Ruderman DL, Neumann S, Gatto L, Fischer B, Pratt B, Egertson J, et al. A cross-platform toolkit for mass spectrometry and proteomics. Nat Biotechnol. 2012;30(10):918–20. 10.1038/nbt.2377
  • Pluskal T, Castillo S, Villar-Briones A, Oresic M. MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinf. 2010;11(1):395. doi:10.1186/1471-2105-11-395 10.1186/1471-2105-11-395
  • Dunn WB, Broadhurst D, Begley P, Zelena E, Francis-McIntyre S, Anderson N, Brown M, Knowles JD, Halsall A, Haselden JN, Human Serum Metabolome (HUSERMET) Consortium, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc. 2011;6(7):1060–83. doi:10.1038/nprot.2011.335
  • Benjamini Y, Hochberg Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J Roy Stat Soc Ser B (Methodological). 1995;57(1):289–300. 10.1111/j.2517-6161.1995.tb02031.x
  • R: A language and environment for statistical computing. Version 4.1.0. R Foundation for Statistical Computing; 2020. www.R-project.org.
  • Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart DS, Xia J. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018;46(W1):W486–W494. 10.1093/nar/gky310
  • Pang Z, Chong J, Zhou G, de Lima Morais DA, Chang L, Barrette M, Gauthier C, Jacques P-É, Li S, Xia J, et al. MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 2021;49(W1):W388–W396. 10.1093/nar/gkab382
  • Trilla-Fuertes L, Gámez-Pozo A, López-Camacho E, Prado-Vázquez G, Zapater-Moros A, López-Vacas R, Arevalillo JM, Díaz-Almirón M, Navarro H, Maín P, et al. Computational models applied to metabolomics data hints at the relevance of glutamine metabolism in breast cancer. BMC Cancer. 2020;20(1):307. doi:10.1186/s12885-020-06764-x
  • Iglay K, Sawhney B, Fu AZ, Fernandes G, Crutchlow MF, Rajpathak S, Khunti K. Dose distribution and up-titration patterns of metformin monotherapy in patients with type 2 diabetes. Endocrinol Diabetes Metab. 2020;3(1):e00107. 10.1002/edm2.107
  • Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81–98. 10.2165/11534750-000000000-00000
  • Chandel NS, Avizonis D, Reczek CR, Weinberg SE, Menz S, Neuhaus R, Christian S, Haegebarth A, Algire C, Pollak M, et al. Are metformin doses used in murine cancer models clinically relevant? Cell Metabolism. 2016;23(4):569–70. 10.1016/j.cmet.2016.03.010
  • Sutkowska E, Fortuna P, Wisniewski J, Sutkowska K, Hodurek P, Gamian A, Kaluza B. Low metformin dose and its therapeutic serum concentration in prediabetes. Sci Rep. 2021;11(1):11684.
  • Wattenberg LW. Studies of polycyclic hydrocarbon hydroxylases of the intestine possibly related to cancer: Effect of diet on benzpyrene hydroxylase activity. Cancer. 1971;28(1):99–102. 10.1002/1097-0142(197107)28:1<99::AID-CNCR2820280118>3.0.CO;2-M
  • Wattenberg LW. Exogenous factors affecting polycyclic hydrocarbon hydroxylase activity. Adv Enzyme Regul. 1973;11:193–201. doi:10.1016/0065-2571(73)90016-2
  • Sonnet DS, O’Leary MN, A, Gutierrez M, et al. Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD. Sci Rep. 2016;6(1):28775.
  • Silamiķele L, Silamiķelis I, Ustinova M, Kalniņa Z, Elbere I, Petrovska R, Kalniņa I, Kloviņš J. Metformin strongly affects gut microbiome composition in high-fat diet-induced type 2 diabetes mouse model of both sexes. Front Endocrinol (Lausanne). 2021;12:626359. doi:10.3389/fendo.2021.626359
  • Preiss D, Rankin N, Welsh P, Holman RR, Kangas AJ, Soininen P, Würtz P, Ala-Korpela M, Sattar N. Effect of metformin therapy on circulating amino acids in a randomized trial: the CAMERA study. Diabet Med. 2016;33(11):1569–74. doi:10.1111/dme.13097
  • Chen Q, Yang X, Zhang H, Kong X, Yao L, Cui X, Zou Y, Fang F, Yang J, Chang Y, et al. Metformin impairs systemic bile acid homeostasis through regulating SIRT1 protein levels. Biochim Biophys Acta Mol Cell Res. 2017;1864(1):101–12. 10.1016/j.bbamcr.2016.10.020
  • Abbas NAT, El. Salem A. Metformin, sitagliptin, and liraglutide modulate serum retinol-binding protein-4 level and adipocytokine production in type 2 diabetes mellitus rat model. Can J Physiol Pharmacol. 2018;96(12):1226–31. 10.1139/cjpp-2017-0650
  • Hirsch A, Hahn D, Kempná P, Hofer G, Nuoffer J-M, Mullis PE, Flück CE. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology. 2012;153(9):4354–66. doi:10.1210/en.2012-1145
  • Yang M, Darwish T, Larraufie P, Rimmington D, Cimino I, Goldspink DA, Jenkins B, Koulman A, Brighton CA, Ma M, et al. Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells. Sci Rep. 2021;11(1):2529.
  • Dahabiyeh LA, Mujammami M, Arafat T, Benabdelkamel H, Alfadda AA, Abdel Rahman AM. A metabolic pattern in healthy subjects given a single dose of metformin: A metabolomics approach. Front Pharmacol. 2021;12:705932. doi:10.3389/fphar.2021.705932
  • Park Sang G, Schimmel P, Kim S. Aminoacyl tRNA synthetases and their connections to disease. Proceedings of the National Academy of Sciences. 2008;105:11043–11049.
  • Matthews DE. Review of lysine metabolism with a focus on humans. J Nutr. 2020;150(Suppl 1):2548S–55S. 10.1093/jn/nxaa224
  • Flanagan JL, Simmons PA, Vehige J, Willcox MDP, Garrett Q. Role of carnitine in disease. Nutr Metab (Lond). 2010;7(1):30. 10.1186/1743-7075-7-30
  • Engel KM, Schiller J, Galuska CE, Fuchs B. Phospholipases and reactive oxygen species derived lipid biomarkers in healthy and diseased humans and animals - A focus on lysophosphatidylcholine. Front Physiol. 2021;12:732319. doi:10.3389/fphys.2021.732319
  • Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S, Steele VE, Rao CV. Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol. 2013;6(6):649–59. doi:10.1593/tlo.13556
  • Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen–induced lung tumorigenesis. Cancer Prev Res (Phila). 2010;3(9):1066–76. doi:10.1158/1940-6207.capr-10-0055
  • Thompson MD, Grubbs CJ, Bode AM, Reid JM, McGovern R, Bernard PS, Stijleman IJ, Green JE, Bennett C, Juliana MM, et al. Lack of effect of metformin on mammary carcinogenesis in nondiabetic rat and mouse models. Cancer Prev Res (Phila). 2015;8(3):231–9. 10.1158/1940-6207.CAPR-14-0181-T
  • Hull RL, Shen Z-P, Watts MR, Kodama K, Carr DB, Utzschneider KM, Zraika S, Wang F, Kahn SE. Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes. 2005;54(7):2235–44. doi:10.2337/diabetes.54.7.2235
  • Seabloom DE, Galbraith AR, Haynes AM, Antonides JD, Wuertz BR, Miller WA, Miller KA, Steele VE, Miller MS, Clapper ML, et al. Fixed-dose combinations of pioglitazone and metformin for lung cancer prevention. Cancer Prev Res (Phila). 2017;10(2):116–23. doi:10.1158/1940-6207.capr-16-0232
  • Pomatto-Watson LCD, Bodogai M, Bosompra O, Kato J, Wong S, Carpenter M, Duregon E, Chowdhury D, Krishna P, Ng S, et al. Daily caloric restriction limits tumor growth more effectively than caloric cycling regardless of dietary composition. Nat Commun. 2021;12(1):6201.
  • Malin SK, Kashyap SR. Effects of metformin on weight loss: potential mechanisms. Curr Opin Endocrinol Diabetes Obesity. 2014;21(5):323–9.
  • Albanes D. Total calories, body weight, and tumor incidence in mice. Cancer Res. 1987;47(8):1987–92.
  • Stevanovic D, Janjetovic K, Misirkic M, Vucicevic L, Sumarac-Dumanovic M, Micic D, Starcevic V, Trajkovic V. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signalling and food intake. Neuroendocrinology. 2012;96(1):24–31. 10.1159/000333963
  • Lv W-S, Wen J-P, Li L, Sun R-X, Wang J, Xian Y-X, Cao C-X, Wang Y-L, Gao Y-Y. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012;1444:11–9. doi:10.1016/j.brainres.2012.01.028
  • Lee CK, Choi YJ, Park SY, Kim JY, Won KC, Kim YW. Intracerebroventricular injection of metformin induces anorexia in rats. Diabetes Metab J. 2012;36(4):293–9. doi:10.4093/dmj.2012.36.4.293
  • Li B, Zhou P, Xu K, Chen T, Jiao J, Wei H, Yang X, Xu W, Wan W, Xiao J, et al. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci. 2020;16(1):74–84. 10.7150/ijbs.33787
  • Liberti MV, Locasale JW. The warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 2016;41(3):211–8. 10.1016/j.tibs.2015.12.001
  • Marini C, Salani B, Massollo M, Amaro A, Esposito AI, Orengo AM, Capitanio S, Emionite L, Riondato M, Bottoni G, et al. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle. 2013;12(22):3490–9. 10.4161/cc.26461
  • Harada K, Ferdous T, Harada T, Ueyama Y. Metformin in combination with 5-fluorouracil suppresses tumor growth by inhibiting the Warburg effect in human oral squamous cell carcinoma. Int J Oncol. 2016;49(1):276–84. doi:10.3892/ijo.2016.3523
  • Wang WM, Yang SS, Shao SH, Nie HQ, Zhang J, Su T. Metformin downregulates the expression of epidermal growth factor receptor independent of lowering blood glucose in oral squamous cell carcinoma. Front Endocrinol (Lausanne). 2022;13:828608. doi:10.3389/fendo.2022.828608
  • Jang S-K, Hong S-E, Lee DA-H, Kim JY, Kim J-Y, Hong J, Park I-C, Jin H-O. Inhibition of AKT enhances the sensitivity of NSCLC cells to metformin. Anticancer Res. 2021;41(7):3481–7. 10.21873/anticanres.15135
  • Huang WC, Hung MC. Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009;108(3):180–94. doi:10.1016/s0929-6646(09)60051-6
  • Lee DK, Szabo E. Repurposing drugs for cancer prevention. Curr Top Med Chem. 2016;16(19):2169–78. doi:10.2174/1568026616666160216154946
  • Hart T, Dider S, Han W, Xu H, Zhao Z, Xie L. Toward repurposing metformin as a precision anti-cancer therapy using structural systems pharmacology. Sci Rep. 2016;6:20441. doi:10.1038/srep20441
  • Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol. 2012;30:39–68. 10.1146/annurev-immunol-020711-075024
  • Nie C, He T, Zhang W, Zhang G, Ma X. Branched chain amino acids: Beyond nutrition metabolism. IJMS. 2018;19(4):954. doi:10.3390/ijms19040954 10.3390/ijms19040954
  • Rivera ME, Lyon ES, Vaughan RA. Effect of metformin on myotube BCAA catabolism. J Cell Biochem. 2020;121(1):816–27. 10.1002/jcb.29327
  • Zhao Y, Sun H, Feng M, Zhao J, Zhao X, Wan Q, Cai D. Metformin is associated with reduced cell proliferation in human endometrial cancer by inbibiting PI3K/AKT/mTOR signaling. Gynecol Endocrinol. 2018;34(5):428–32. doi:10.1080/09513590.2017.1409714
  • Wang Z, Guo J, Han X, Xue M, Wang W, Mi L, Sheng Y, Ma C, Wu J, Wu X, et al. Metformin represses the pathophysiology of AAA by suppressing the activation of PI3K/AKT/mTOR/autophagy pathway in ApoE(-/-) mice. Cell Biosci. 2019;9:68. doi:10.1186/s13578-019-0332-9
  • Novin ZS, Ghavamzadeh S, Mehdizadeh A. The weight loss effects of branched chain amino acids and vitamin B6: A randomized controlled trial on obese and overweight women. Int J Vitam Nutr Res. 2018;88(1–2):80–9. doi:10.1024/0300-9831/a000511
  • Reuter SE, Evans AM. Carnitine and acylcarnitines. Clin Pharmacokinet. 2012;51(9):553–72. 10.1007/BF03261931
  • Houten SM, Wanders RJA. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation. J Inher Metab Disea. 2010;33(5):469–77. 10.1007/s10545-010-9061-2
  • Jain S, Singh SN. Effect of L-carnitine supplementation on nutritional status and physical performance under calorie restriction. Ind J Clin Biochem. 2015;30(2):187–93. doi:10.1007/s12291-014-0437-1 10.1007/s12291-014-0437-1
  • Brandsch C, Eder K. Effect of L-carnitine on weight loss and body composition of rats fed a hypocaloric diet. Ann Nutr Metab. 2002;46(5):205–10. doi:10.1159/000065408
  • Mingorance C, Duluc L, Chalopin M, Simard G, Ducluzeau P-H, Herrera MD, Alvarez de Sotomayor M, Andriantsitohaina R. Propionyl-L-carnitine corrects metabolic and cardiovascular alterations in diet-induced obese mice and improves liver respiratory chain activity. PLoS One. 2012;7(3):e34268. doi:10.1371/journal.pone.0034268
  • Wang C, Kong H, Guan Y, Yang J, Gu J, Yang S, Xu G. Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. Anal Chem. 2005;77(13):4108–16. doi:10.1021/ac0481001
  • Cai S, Huo T, Li N, Xiong Z, Li F. Lysophosphatidylcholine–biomarker of Metformin action: studied using UPLC/MS/MS. Biomed Chromatogr. 2009;23(7):782–6. doi:10.1002/bmc.1185
  • Kim H-S, Ren G, Kim T, Bhatnagar S, Yang Q, Bahk YY, Kim J-A. Metformin reduces saturated fatty acid-induced lipid accumulation and inflammatory response by restoration of autophagic flux in endothelial cells. Sci Rep. 2020;10(1):13523. 10.1038/s41598-020-70347-w
  • Dahabiyeh LA, Mujammami M, Arafat T, Benabdelkamel H, Alfadda AA, Abdel Rahman AM. A metabolic pattern in healthy subjects given a single dose of metformin: A metabolomics approach. Front Pharmacol. 2021 Jul 15;12:705932.
  • Aretz I, Meierhofer D. Advantages and pitfalls of mass spectrometry based metabolome profiling in systems biology. IJMS. 2016;17(5):632. 10.3390/ijms17050632

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.