The Application of G2013 (α-L-Guluronic acid) as an Anti-Inflammatory Drug Candidate in Treatment of Disease

10.22122/jims.v39i616.13841

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of different inflammatory disorders, and shown to have many side effects for patients. G2013 or α-L-guluronic acid is a new NSAID candidate made from alginate in the pathobiology department of Tehran University of Medical Sciences, Iran, and it has been proven to be safe. G2013 anti-inflammatory, immunosuppressive, and immunomodulatory effects have been reported in previous studies. In many studies, it has been shown that this drug candidate has good potential for treatment of different diseases, and is going through clinical phases. In this review article, first, toxicity and anti-inflammatory effects of G2013 is mentioned, and then its effects on the treatment of oxidative stress, and diseases including rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and breast cancer is also reviewed.

Keywords


Davis JS, Lee HY, Kim J, Advani SM, Peng HL, Banfield E, et al. Use of non-steroidal anti-inflammatory drugs in US adults: Changes over time and by demographic. Open Heart 2017; 4(1): e000550.
Jin J. JAMA Patient Page. Nonsteroidal anti-inflammatory drugs. JAMA 2015; 314(10): 1084.
Bjarnason I, Hayllar J, MacPherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993; 104(6): 1832-47.
Hosseini F, Hassannia H, Mahdian-Shakib A, Jadidi-Niaragh F, Enderami SE, Fattahi M, et al. Targeting of crosstalk between tumor and tumor microenvironment by beta-D mannuronic acid (M2000) in murine breast cancer model. Cancer Med 2017; 6(3): 640-50.
Mortazavi-Jahromi SS, Nazeri S, Jafarnezhad-Ansariha F, Oraei M, Mirshafiey A. Assessment of immunological profile in ankylosing spondylitis patients following a clinical trial with guluronic acid (G2013), as a new NSAID with immunomodulatory properties. Immunol Res 2019; 67(1): 108-15.
Hossein-Khannazer N, Shabani S, Farokhfar M, Azizi G, Asarzadegan F, Safarpour LB, et al. Pivotal cytokines and their transcription factors are the targets of guluronic acid (G2013) for inhibiting the immunopathogenesis process of multiple sclerosis. Drug Dev Res 2020; 81(4): 511-6.
Afraei S, Azizi G, Zargar SJ, Sedaghat R, Mirshafiey A. New therapeutic approach by G2013 in experimental model of multiple sclerosis. Acta Neurol Belg 2015; 115(3): 259-66.
Nazeri S, Khadem AS, Fattahi MJ, Sedaghat R, Tofighi ZF, Aghazadeh Z, et al. Preclinical and pharmacotoxicology evaluation of alpha-l-guluronic acid (G2013) as a non-steroidal anti-inflammatory drug with immunomodulatory property. Immunopharmacol Immunotoxicol 2017; 39(2): 59-65.
Nazeri S, Jamshidi AR, Mahmoudi M, Vojdanian M, Khadem AS, Afraei S, et al. The safety and efficacy of Guluronic acid (G2013) in ankylosing spondylitis: A randomized controlled parallel clinical trial. Pharmacol Rep 2019; 71(3): 393-8.
Khadem AS, Jafarnezhad-Ansariha F, Nazeri S, Azizi G, Aghazadeh Z, Hosseinzadeh E, et al. Effects of guluronic acid, as a new NSAID with immunomodulatory properties on IL-17, RORgammat, IL-4 and GATA-3 gene expression in rheumatoid arthritis patients. Immunopharmacol Immunotoxicol 2020; 42(1): 22-7.
Khadem AS, Akhlaghi M, Mahmoudi M, Mostafaei S, Jamshidi AR, Nazeri S, et al. A randomized clinical trial for the assessment of the efficacy and safety of guluronic acid (G2013) in patients with rheumatoid arthritis. Immunopharmacol Immunotoxicol 2019; 41(1): 95-101.
Bakhtiari T, Azarian S, Ghaderi A, Ahmadzadeh A, Mirshafiey A. Effect of guluronic acid (G2013), As a new anti-inflammatory drug on gene expression of pro-inflammatory and anti-inflammatory cytokines and their transcription factors in rheumatoid arthritis patients. Iran J Allergy Asthma Immunol 2019; 18(6): 639-48.
Iranian Registry of Clinical Trials (IRCT) [Online]. [cited 2021]; Available from: https://www.irct.ir/search/result?query=%CE%B1-L-guluronic+acid
Mahdian-Shakib A, Hashemzadeh MS, Anissian A, Oraei M, Mirshafiey A. Evaluation of the acute and 28-day sub-acute intravenous toxicity of alpha-l-guluronic acid (ALG; G2013) in mice. Drug Chem Toxicol 2019; 1-10.
Sharifi L, Mohsenzadegan M, Aghamohammadi A, Rezaei N, Zavareh FT, Bokaie S, et al. Immunomodulatory Effect of G2013 (alpha-L-Guluronic Acid) on the TLR2 and TLR4 in Human Mononuclear Cells. Curr Drug Discov Technol 2018; 15(2): 123-31.
Mortazavi-Jahromi SS, Farazmand A, Motamed N, Navabi SS, Mirshafiey A. Effects of guluronic acid (G2013) on SHIP1, SOCS1 induction and related molecules in TLR4 signaling pathway. Int Immunopharmacol 2018; 55: 323-9.
Hajivalili M, Pourgholi F, Majidi J, Aghebati-Maleki L, Movassaghpour AA, Samadi KH, et al. G2013 modulates TLR4 signaling pathway in IRAK-1 and TARF-6 dependent and miR-146a independent manner. Cell Mol Biol (Noisy -le -grand) 2016; 62(4): 1-5.
Mirshafiey A, Mortazavi-Jahromi SS, Taeb M, Cuzzocrea S, Esposito E. Evaluation of the Effect of alpha-L-Guluronic Acid (G2013) on COX-1, COX-2 Activity and Gene Expression for Introducing this Drug as a Novel NSAID with Immunomodulatory Property. Recent Pat Inflamm Allergy Drug Discov 2018; 12(2): 162-8.
Mirshafiey A, Hosseini S, Afraei S, Rastkari N, Zavareh FT, Azizi G. Anti-aging property of G2013 molecule as a novel immunosuppressive agent on enzymatic and non-enzymatic oxidative stress determinants in Rat model. Curr Drug Discov Technol 2016; 13(1): 25-33.
Mohsenzadegan M, Seif F, Farajollahi MM, Khoshmirsafa M. Anti-oxidants as chemopreventive agents in prostate cancer: A gap between preclinical and clinical studies. Recent Pat Anticancer Drug Discov 2018; 13(2): 224-39.
Taeb M, Mortazavi-Jahromi SS, Jafarzadeh A, Mirzaei MR, Mirshafiey A. An in vitro evaluation of anti-aging effect of guluronic acid (G2013) based on enzymatic oxidative stress gene expression using healthy individuals PBMCs. Biomed Pharmacother 2017; 90: 262-7.
McFarland HF, Martin R. Multiple sclerosis: A complicated picture of autoimmunity. Nat Immunol 2007; 8(9): 913-9.
Noorbakhsh SM, Razavi A, Moghadam NB, Saadat P, Hoseini M, Aghazadeh Z, et al. Effects of guluronic acid (G2013) on gene expression of TLR2, TLR4, MyD88, TNF-alpha and CD52 in multiple sclerosis under in vitro conditions. Immunopharmacol Immunotoxicol 2019; 41(6): 586-90.
Elyan M, Khan MA. The role of nonsteroidal anti-inflammatory medications and exercise in the treatment of ankylosing spondylitis. Curr Rheumatol Rep 2006; 8(4): 255-9.
Maksymowych WP. Update on the treatment of ankylosing spondylitis. Ther Clin Risk Manag 2007; 3(6): 1125-33.
Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159(21): 2542-50.
Azadpour M, Farajollahi M M, Varzi A M, Hadipour F, Barati M. The evaluation of cytotoxicity effects of Rheum ribes L (rubarb) extract on cancer cell lines and its antibacterial and mutagenicity activity. Entomol Appl Sci Lett 2020; 7(3): 7-12.
Zhang Q, Zhu B, Li Y. Resolution of cancer-promoting inflammation: A new approach for anticancer therapy. Front Immunol 2017; 8: 71.
Pereg D, Lishner M. Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. J Intern Med 2005; 258(2): 115-23.
Sondhi SM, Rani R, Singh J, Roy P, Agrawal SK, Saxena AK. Solvent free synthesis, anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives. Bioorg Med Chem Lett 2010; 20(7): 2306-10.
Wojtkowiak JW, Verduzco D, Schramm KJ, Gillies RJ. Drug resistance and cellular adaptation to tumor acidic pH microenvironment. Mol Pharm 2011; 8(6): 2032-8.
Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer 2006; 6(8): 583-92.
Hosseini F, Mahdian-Shakib A, Jadidi-Niaragh F, Enderami SE, Mohammadi H, Hemmatzadeh M, et al. Anti-inflammatory and anti-tumor effects of alpha-l-guluronic acid (G2013) on cancer-related inflammation in a murine breast cancer model. Biomed Pharmacother 2018; 98: 793-800.