Author(s):
Ulfa Kholili, Alvin Hartanto Kurniawan, Choirina Winda, Ummi Maimunah, Poernomo Budi Setiawan
Email(s):
ulfakholili1975@gmail.com
DOI:
10.52711/0974-360X.2023.00065
Address:
Ulfa Kholili1*, Alvin Hartanto Kurniawan2, Choirina Winda2, Ummi Maimunah1, Poernomo Budi Setiawan1
1Gastroenterology-Hepatology Division, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya 60131, Indonesia.
2Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya 60131, Indonesia.
*Corresponding Author
Published In:
Volume - 16,
Issue - 1,
Year - 2023
ABSTRACT:
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies globally, while its mortality rate is the second-highest in the world. HCC has mostly been involved by some underlying issues, such as the hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, and non-alcohol fatty liver disease (NAFLD). Metabolic syndrome and diabetes mellitus currently are independent risk factors to develop HCC in these patients by chronic inflammation and insulin resistance. The next issues following HCC were lack of a good surveillance system, which will result in delayed diagnosis establishment, limited therapeutical option, poor prognosis, and poor survival rates. These problems allow chemoprevention can be a worth to try option in the management of chronic hepatitis patients. Metformin has been known as one of the most often used anti-diabetic agents worldwide and provided many benefits. Based on several recent studies, metformin induces the prevention effect toward the development of HCC with several mechanisms either by the AMPK-dependent or AMPK-independent pathway. In this review article, we will discuss metformin as a promising chemoprevention agent against HCC from mechanisms, current limitations, and future prospects.
Cite this article:
Ulfa Kholili, Alvin Hartanto Kurniawan, Choirina Winda, Ummi Maimunah, Poernomo Budi Setiawan. The Role of Metformin as Chemopreventive Strategies for Hepatocellular Carcinoma. Research Journal of Pharmacy and Technology 2023; 16(1):377-4. doi: 10.52711/0974-360X.2023.00065
Cite(Electronic):
Ulfa Kholili, Alvin Hartanto Kurniawan, Choirina Winda, Ummi Maimunah, Poernomo Budi Setiawan. The Role of Metformin as Chemopreventive Strategies for Hepatocellular Carcinoma. Research Journal of Pharmacy and Technology 2023; 16(1):377-4. doi: 10.52711/0974-360X.2023.00065 Available on: https://www.rjptonline.org/AbstractView.aspx?PID=2023-16-1-65
REFERENCES:
1. Valery PC, Laversanne M, Clark PJ, Petrick JL, McGlynn KA, Bray F. Projections of primary liver cancer to 2030 in 30 countries worldwide. Hepatology. 2018;67(2):600–11. doi.org/10.1002/hep.29498
2. Giannitrapani L, Zerbo M, Amodeo S, Pipitone E, Galia M, Li Cavoli TV, et al. The Changing Epidemiology of Hepatocellular Carcinoma: Experience of a Single Center. Biomed Res Int. 2020;2020. doi.org/10.1155/2020/5309307
3. Petrick JL, Florio AA, Znaor A, Ruggieri D, Laversanne M, Alvarez CS, et al. International trends in hepatocellular carcinoma incidence, 1978–2012. Int J Cancer. 2019;147(2):317-330. doi.org/10.1002/ijc.32723.
4. Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology. 2019;156(2):477-491. doi.org/10.1053/j.gastro.2018.08.065.
5. Sayiner M, Golabi P, Younossi ZM. Disease Burden of Hepatocellular Carcinoma: A Global Perspective. Dig Dis Sci. 2019;64(4):910–7.doi.org/ 10.1007/s10620-019-05537-2.
6. Kim H seok, El-Serag HB. The Epidemiology of Hepatocellular Carcinoma in the USA. Curr Gastroenterol Rep. 2019;21(4):17.doi.org/ 10.1007/s11894-019-0681-x
7. Tsoulfas G. Hepatocellular carcinoma and metabolic syndrome: The times are changing and so should we. World J Gastroenterol. 2019;25(29):3842–8.doi.org/10.3748/wjg.v25.i29.3842
8. Li X, Wang X, Gao P. Diabetes Mellitus and Risk of Hepatocellular Carcinoma. Biomed Res Int. 2017;2017:5202684.doi.org/10.1155/2017/5202684
9. Harris PS, Hansen RM, Gray ME, Massoud OI, McGuire BM, Shoreibah MG. Hepatocellular carcinoma surveillance: An evidence-based approach. World J Gastroenterol. 2019;25(13):1550–9.doi.org/10.3748/wjg.v25.i13.1550
10. Pazgan-Simon M, Serafinska S, Janocha-Litwin J, Simon K, Zuwala-Jagiello J. Diagnostic Challenges in Primary Hepatocellular Carcinoma: Case Reports and Review of the Literature. Case Rep Oncol Med. 2015;2015:878763.doi.org/ 10.1155/2015/878763
11. Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J Hepatol. 2015;7(26):2648–63.doi.org/10.4254/wjh.v7.i26.2648
12. Athuluri-Divakar SK, Hoshida Y. Generic chemoprevention of hepatocellular carcinoma. Ann N Y Acad Sci. 2019;1440(1):23–35.doi.org/ 10.1111/nyas.13971.
13. Park JW, Lee JS, Suh KS, Chung JW, Seong J, Kim DY, et al. 2018 Korean Liver Cancer Association-National Cancer Center Korea practice guidelines for the management of hepatocellular carcinoma. Vol. 13, Gut and Liver. 2019. 227–299.doi.org/10.5009/gnl19024
14. Balogh J, Victor III D, Ahsam EH, Gordon S, Burroughs, Boktour M, et al. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016;3:41–53.doi.org/10.2147/JHC.S61146.eCollection 2016
15. Axley P, Ahmed Z, Ravi S, Singal AK. Hepatitis C Virus and Hepatocellular Carcinoma: A Narrative Review. J Clin Transl Hepatol. 2018;6(1):79–84.doi.org/10.14218/JCTH.2017.00067
16. Mantovani A, Targher G. Type 2 diabetes mellitus and risk of hepatocellular carcinoma: Spotlight on nonalcoholic fatty liver disease. Ann Transl Med. 2017;5(13):270.doi.org/10.21037/atm.2017.04.41
17. Bhat A, Sebastiani G, Bhat M. Systematic review: Preventive and therapeutic applications of metformin in liver disease. World J Hepatol. 2015;7(12):1652–9.doi.org/10.4254/wjh.v7.i12.1652
18. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog. 2017;16:1.doi.org/10.4103/jcar.JCar_9_16. eCollection 2017.
19. Yang YM, Kim SY, Seki E. Inflammation and Liver Cancer: Molecular Mechanisms and Therapeutic Targets. Semin Liver Dis. 2019;39(1):26–42.doi.org/10.1055/s-0038-1676806. Epub 2019 Jan 17.
20. Ferrín G, Guerrero M, Amado V, Rodríguez-Perálvarez M, De la Mata M. Activation of mTOR signaling pathway in hepatocellular carcinoma. Int J Mol Sci. 2020;21(4):1266.doi.org/ 10.3390/ijms21041266
21. Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2014;11(1):45–54.doi.org/ 10.1038/nrgastro.2013.143
22. Li A, Zhang R, Zhang Y, Liu X, Wang R, Liu J, et al. BEZ235 increases sorafenib inhibition of hepatocellular carcinoma cells by suppressing the PI3K/AKT/mTOR pathway. Am J Transl Res. 2019;11(9):5573–85.
23. Ampuero J, Romero-Gomez M. Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: Role of statins and metformin. World J Hepatol. 2015;7(8):1105–11.doi.org/10.4254/wjh.v7.i8.1105
24. Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016;22(2):823–32.doi.org/10.3748/wjg.v22.i2.823
25. Cunha V, Cotrim HP, Rocha R, Carvalho K, Lins-Kusterer L. Metformin in the prevention of hepatocellular carcinoma in diabetic patients: A systematic review. Ann Hepatol. 2019;S1665-2681(19):32272–0.doi.org/10.1016/j.aohep.2019.10.005
26. Li W, Saud SM, Young MR, Chen G, Hua B. Targeting AMPK for cancer prevention and treatment. Oncotarget. 2015;6(10):7365–78.doi.org/10.18632/oncotarget.3629.
27. Yang S, Liu G. Targeting the RAS/RAF/MEK/ERK pathway in hepatocellular carcinoma. Oncol Lett. 2017;13(3):1041–7.doi.org/ 10.3892/ol.2017.5557. Epub 2017 Jan 2.
28. Kutlu O, Kaleli HN, Ozer E. Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2018;2018:8543763.doi.org/10.1155/2018/8543763. eCollection 2018.
29. Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances [version 1; referees: 4 approved]. F1000Research. 2016;5:F1000 Faculty Rev-879. doi.org/ https://doi.org/10.12688/f1000research.6946.1
30. Vacante F, Senesi P, Montesano A, Paini S, Luzi L, Terruzzi I. Metformin counteracts HCC progression and metastasis enhancing KLF6/p21 expression and downregulating the IGF axis. Int J Endocrinol. 2019;2019:7570146.doi.org/ 10.1155/2019/7570146
31. Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, et al. Metformin: A review of its potential indications. Drug Des Devel Ther. 2017;11:2421–9.doi.org/10.2147DDDT.S141675
32. Fujita K, Iwama H, Miyoshi H, Tani J, Oura K, Tadokoro T, et al. Diabetes mellitus and metformin in hepatocellular carcinoma. World J Gastroenterol. 2016;22(27):611–6113.doi.org/10.3748/wjg.v22.i27.6100
33. Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, et al. Clinical trial: Pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29(2):172–82.doi.org/10.1111/j.1365-2036.2008.03869.x
34. Heckman-Stoddard BM, Gandini S, Puntoni M, Dunn BK, Decensi A, Szabo E. Repurposing old drugs to chemoprevention: The case of metformin. Semin Oncol. 2016;43(1):123–33.doi.org/ 10.1053/j.seminoncol.2015.09.009
35. Zhang ZJ, Zheng ZJ, 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.doi.org/10/1210/jc.2012-1267
36. Ma S, Zheng Y, Xiao Y, Zhou P, Tan H. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients. Med. 2017;96:19(e6888).doi.org/ 10.1097/MD.0000000000006888
37. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: A systematic review and meta-analysis. Am J Gastroenterol. 2013;108(6):881–91.doi.org/10.1038/ajg.2013.5
38. Suissa S, Azoulay L. Metformin and the risk of cancer: Time-related biases in observational studies. Diabetes Care. 2012;35(2):2665–73.doi.org/ 10.2337/dc12-0788
39. Bosetti C, Franchi M, Nicotra F, Asciutto R, Merlino L, La Vecchia C, et al. Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: A nested case-control study based on Italian healthcare utilization databases. Pharmacoepidemiol Drug Saf. 2015;24(7):771–8.doi.org/ 10.1002/pds.3801
40. Kasmari AJ, Welch A, Liu G, Leslie D, McGarrity T, Riley T. Independent of Cirrhosis, Hepatocellular Carcinoma Risk Is Increased with Diabetes and Metabolic Syndrome. Am J Med. 2017;130(6):746.e1-746.e7.doi.org/ 10.1016/j.amjmed.2016.12.029
41. Zhou YY, Zhu GQ, Liu T, Zheng JN, Cheng Z, Zou TT, et al. Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma. Sci Rep. 2016;6:33743.doi.org/10.1038/srep33743
42. Baba H, Kurano M, Nishida T, Hatta H, Hokao R, Tsuneyama K. Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes. BMC Res Notes. 2017;10:478.doi.org/ 10.1186/s13104-017-2783-6
43. Niwa Y, Ishikawa K, Ishigami M, Honda T, Achiwa K, Izumoto T, et al. Effect of hyperglycemia on hepatocellular carcinoma development in diabetes. Biochem Biophys Res Commun. 2015;463(3):344–50.doi.org/10.1016/j.bbrc.2015.05.066
44. Huang MY, Chung CH, Chang WK, Lin CS, Chen KW, Hsieh TY, et al. The role of thiazolidinediones in hepatocellular carcinoma risk reduction: A population-based cohort study in Taiwan. Am J Cancer Res. 2017;7(7):1606–16. PMID: 28744408; PMCID: PMC5523039.
45. Zhao B, Luo J, Yu T. Anticancer mechanisms of metformin : A review of the current evidence. Life Sci. 2020;254(January):117717.doi.org/10.1016/j.lfs.2020.117717
46. Choi J, Roberts LR. Statins and metformin for chemoprevention of hepatocellular carcinoma. Clin Liver Dis. 2016;8(2):48–52.doi.org/10.1002/cld.568
47. Li S, Ogawa W, Emi A, Hayashi K, Senga Y, Nomura K, et al. Role of S6K1 in regulation of SREBP1c expression in the liver. Biochem Biophys Res Commun. 2011;412(2):197–202.doi.org/10.1016/j.bbrc.2011.07.038
48. Zhou Y, Yu S, Cai C, Zhong L, Yu H, Shen W. LXRα participates in the mTOR/S6K1/SREBP-1c signaling pathway during sodium palmitate-induced lipogenesis in HepG2 cells. Nutr Metab. 2018;15:31.doi.org/10.1186/s12986-018-0268-9
49. Lin CP, Liu CR, Lee CN, Chan TS, Liu HE. Targeting c-Myc as a novel approach for hepatocellular carcinoma. World J Hepatol. 2010;2(1):16–20.doi/org/10.4254/wjh.v2.i1.16
50. Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget. 2017;8(28):46691–703.doi.org/ 10.18632/oncotarget.17358
51. Park SY, Kim D, Kee SH. Metformin-activated AMPK regulates β-catenin to reduce cell proliferation in colon carcinoma RKO cells. Oncol Lett. 2019;17(3):2695–702.doi.org/ 10.3892/ol.2019.9892
52. Sun Y, Tao C, Huang X, He H, Shi H, Zhang Q, et al. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. Onco Targets Ther. 2016;9:2845–53.doi.org/ 10.2147/OTT.S99770
53. Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, et al. Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res. 2012;5(4):536–43.doi.org/ 10.1158/1940-6207.CAPR-11-0536
54. Lee M, Katerelos M, Gleich K, Galic S, Kemp BE, Mount PF, et al. Phosphorylation of acetyl-CoA carboxylase by AMPK reduces renal fibrosis and is essential for the anti-fibrotic effect of metformin. J Am Soc Nephrol. 2018;29(9):2326–36.doi.org/ 10.1681/ASN.2018010050
55. Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med. 2013;19(12):1649–54.doi.org/ 10.1038/nm.3372
56. Jiang X, Tan HY, Teng S, Chan YT, Wang D, Wang N. The role of AMP-activated protein kinase as a potential target of treatment of hepatocellular carcinoma. Cancers (Basel). 2019;11(5):647.doi.org/10.3390/cancers11050647
57. Kato K, Iwama H, Yamashita T, Kobayashi K, Fujihara S, Fujimori T, et al. The anti-diabetic drug metformin inhibits pancreatic cancer cell proliferation in vitro and in vivo: Study of the microRNAs associated with the antitumor effect of metformin. Oncol Rep. 2016;35(3):1582–92.doi.org/ 10.3892/or.2015.4496
58. Moiseeva O, Deschênes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar AE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013;12(3):489–98.doi.org/ 10.1111/acel.12075
59. Li J, Yang Z, Tuo B. Role of OCT1 in hepatocellular carcinoma. Onco Targets Ther. 2019;12:6013–22.doi.org/10.2147/OTT.S212088
60. Gangopadhyay KK, Singh P. Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment. Indian J Endocrinol Metab. 2017;21(2):341–54.doi.org/ 10.4103/ijem.IJEM_512_16
61. Bhat M, Chaiteerakij R, Harmsen WS, Schleck CD, Yang JD, Giama NH, et al. Metformin does not improve survival in patients with hepatocellular carcinoma. World J Gastroenterol. 2014;20(42):15750–5.doi.org/10.3748/wjg.v20.i42.15750
62. American-Diabetes-Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetesd2019. Diabetes Care. 2019;42(Suppl 1):S90-S102.doi.org/10.2337/dc19-S009
63. Gunton JE, Cheung NW, Davis TME, Zoungas S, Colagiuri S. A new blood glucose management algorithm for type 2 diabetes: A position statement of the Australian Diabetes Society. Med J Aust. 2014;201(11):650–3.doi.org/ 10.5694/mja14.01187
64. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. 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;11:20.doi.org/ 10.1186/1471-2407-11-20
65. Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. Cancer Manag Res. 2019;11:3295–313.doi.org/ 10.2147/CMAR.S200059
66. Deperalta DK, Wei L, Ghoshal S, Schmidt B, Lauwers GY, Lanuti M, et al. Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis. Cancer. 2016;122(8):1216–27.doi.org/ 10.1002/cncr.29912
67. Schulte L, Scheiner B, Voigtländer T, Koch S, Schweitzer N, Marhenke S, et al. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int. 2019;39(4):714–26.doi.org/ 10.1111/liv.14048
68. Shankaraiah RC, Callegari E, Guerriero P, Rimessi A, Pinton P, Gramantieri L, et al. Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma. Oncogene. 2019;38(45):7035–45.doi.org/ 10.1038/s41388-019-0942-z
69. Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96(8):2601–8.doi.org/ 10.1210/jc.2010-241570.
70. Schulte L, Scheiner B, Voigtländer T, Koch S, Schweitzer N, Marhenke S, et al. Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma. Liver Int. 2019;39(4):714–26.doi.org/ 10.1111/liv.14048
71. Shankaraiah RC, Callegari E, Guerriero P, Rimessi A, Pinton P, Gramantieri L, et al. Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma. Oncogene. 2019;38(45):7035–45.doi.org/10.1038/s41388-019-0942-z
72. Nkontchou G, Cosson E, Aout M, Mahmoudi A, Bourcier V, Charif I, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab. 2011;96(8):2601–8. doi.org/10.1210/jc.2010-2415