Authors : S. Sarankarthikeyan; Dr. Ariharasivakumar Ganesan; C. Rejina; Harish Kumar E.

Volume/Issue : Volume 10 - 2025, Issue 8 - August

Google Scholar : https://tinyurl.com/24mcfchr

Scribd : https://tinyurl.com/3eyfanjf

DOI : https://doi.org/10.38124/ijisrt/25aug1273

Note : A published paper may take 4-5 working days from the publication date to appear in PlumX Metrics, Semantic Scholar, and ResearchGate.

Note : Google Scholar may take 30 to 40 days to display the article.

Abstract : Inflammatory Bowel Disease (IBD), which includes Crohn’s disease and ulcerative colitis, represents an increasing global health challenge. The traditional process of drug development is both slow and expensive, leading to a growing interest in drug repurposing as a viable alternative strategy. This review emphasizes the therapeutic promise of five repurposed medications quinacrine, febuxostat, dapsone, amitriptyline, and bazedoxifene each of which targets critical inflammatory and oxidative pathways implicated in the pathogenesis of IBD. These drugs, initially approved for different medical conditions, exhibit encouraging anti-inflammatory, antioxidant, and barrier-protective properties in preclinical models of IBD. By modulating signalling pathways such as NF-κB, TLR4, and STAT3, as well as affecting gut microbiota, these agents present novel opportunities for the management of IBD, characterized by enhanced safety profiles and translational significance.

Keywords : Drug Repurposing, Quinacrine, Febuxostat, Dapsone, Amitriptyline, Bazedoxifene, NF-κB signalling, TLR4 Pathway, STAT3 Pathway, Oxidative Stress, Gut Microbiota Modulation.

References :

1. Qiu L, Yan C, Yang Y, Liu K, Yin Y, Zhang Y, Lei Y, Jia X, Li G. Morin alleviates DSS-induced ulcerative colitis in mice via inhibition of inflammation and modulation of intestinal microbiota. International Immunopharmacology. 2024 Oct 25; 140:112846.
2. Fonseca-Camarillo G, Yamamoto-Furusho JK. Immunoregulatory pathways involved in inflammatory bowel disease. Inflammatory bowel diseases. 2015 Sep 1;21(9):2188-93.
3. Ford AC, Bercik P, Morgan DG, Bolino C, Pintos‐Sanchez MI, Moayyedi P. Characteristics of functional bowel disorder patients: a cross‐sectional survey using the Rome III criteria. Alimentary pharmacology & therapeutics. 2014 Feb;39(3):312-21.
4. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. Crohn's disease. The Lancet. 2017 Apr 29;389(10080):1741-55.
5. Feuerstein JD, Cheifetz AS. Crohn disease: epidemiology, diagnosis, and management. In Mayo Clinic Proceedings 2017 Jul 1 (Vol. 92, No. 7, pp. 1088-1103). Elsevier.
6. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World journal of gastroenterology: WJG. 2014 Jan 7;20(1):91.
7. Neurath MF. Targeting immune cell circuits and trafficking in inflammatory bowel disease. Nature immunology. 2019 Aug;20(8):970-9.
8. Oliyaei N, Zekri S, Iraji A, Oliyaei A, Tanideh R, Mussin NM, Tamadon A, Tanideh N. Health benefits of algae and marine-derived bioactive metabolites for modulating ulcerative colitis symptoms. Journal of Functional Foods. 2025 Feb 1; 125:106690.
9. Vavricka SR, Schoepfer A, Scharl M, Lakatos PL, Navarini A, Rogler G. Extraintestinal manifestations of inflammatory bowel disease. Inflammatory bowel diseases. 2015 Aug 1;21(8):1982-92.
10. Deng Y, Jia X, Liu L, He Q, Liu L. The role of intestinal macrophage polarization in colitis-associated colon cancer. Frontiers in Immunology. 2025 Mar 5; 16:1537631.
11. Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Frontiers in immunology. 2012 May 8; 3:107.
12. Ryan BM, Wolff RK, Valeri N, Khan M, Robinson D, Paone A, Bowman ED, Lundgreen A, Caan B, Potter J, Brown D. An analysis of genetic factors related to risk of inflammatory bowel disease and colon cancer. Cancer epidemiology. 2014 Oct 1;38(5):583-90.
13. Lin D, Jin Y, Shao X, Xu Y, Ma G, Jiang Y, Xu Y, Jiang Y, Hu D. Global, regional, and national burden of inflammatory bowel disease, 1990–2021: Insights from the global burden of disease 2021. International Journal of Colorectal Disease. 2024 Sep 7;39(1):139.
14. Dou Z, Zheng H, Shi Y, Li Y, Jia J. Analysis of global prevalence, DALY and trends of inflammatory bowel disease and their correlations with sociodemographic index: Data from 1990 to 2019. Autoimmunity Reviews. 2024 Nov 1;23(11):103655.
15. Zhang Y, Chu X, Wang L, Yang H. Global patterns in the epidemiology, cancer risk, and surgical implications of inflammatory bowel disease. Gastroenterology report. 2024;12: goae053.
16. Alatab S, Sepanlou SG, Ikuta K, Vahedi H, Bisignano C, Safiri S, Sadeghi A, Nixon MR, Abdoli A, Abolhassani H, Alipour V. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet gastroenterology & hepatology. 2020 Jan 1;5(1):17-30.
17. Krishnamurthy N, Grimshaw AA, Axson SA, Choe SH, Miller JE. Drug repurposing: a systematic review on root causes, barriers and facilitators. BMC health services research. 2022 Jul 29;22(1):970.
18. Sharma K, Shrivastava H, Kumar A. 13 Advantages, opportunities, and challenges to drug repurposing. Drug Repurposing. 2023 Oct 4:283.
19. Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A. Drug repurposing: progress, challenges and recommendations. Nature reviews Drug discovery. 2019 Jan;18(1):41-58.
20. Parvathaneni V, Gupta V. Utilizing drug repurposing against COVID-19–efficacy, limitations, and challenges. Life sciences. 2020 Oct 15; 259:118275.
21. Chumanevich AA, Witalison EE, Chaparala A, Chumanevich A, Nagarkatti P, Nagarkatti M, Hofseth LJ. Repurposing the anti-malarial drug, quinacrine: new anti-colitis properties. Oncotarget. 2016 Jul 14;7(33):52928.
22. Ehsanian R, Van Waes C, Feller SM. Beyond DNA binding-a review of the potential mechanisms mediating quinacrine's therapeutic activities in parasitic infections, inflammation, and cancers. Cell Communication and Signaling. 2011 May 15;9(1):13.
23. Spisni E, Valerii MC, De Fazio L, Cavazza E, Borsetti F, Sgromo A, Candela M, Centanni M, Rizello F, Strillacci A. Cyclooxygenase-2 silencing for the treatment of colitis: a combined in vivo strategy based on RNA interference and engineered Escherichia coli. Molecular Therapy. 2015 Feb 1;23(2):278-89.
24. Mukawa K, Fujii S, Tominaga K, Yoshitake N, Abe A, Kono T, Sekikawa A, Fukui H, Ichikawa K, Tomita S, Imura J. Inhibitory effects of the cyclooxygenase-2 inhibitor, etodolac, on colitis-associated tumorigenesis in p53-deficient mice treated with dextran sulfate sodium. Oncology reports. 2008 Feb 1;19(2):393-9.
25. Bondeson J, Sundler R. Antimalarial drugs inhibit phospholipase A2 activation and induction of interleukin lβ and tumor necrosis factor α in macrophages: implications for their mode of action in rheumatoid arthritis. General Pharmacology: The Vascular System. 1998 Mar 1;30(3):357-66.
26. Horrobin DF, Manku MS, Karmazyn M, Ally AI, Morgan RO, Karmali RA. Quinacrine is a prostaglandin antagonist. Biochemical and biophysical research communications. 1977 Jun 20;76(4):1188-93.
27. Jani TS, DeVecchio J, Mazumdar T, Agyeman A, Houghton JA. Inhibition of NF-κB signaling by quinacrine is cytotoxic to human colon carcinoma cell lines and is synergistic in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or oxaliplatin. Journal of Biological Chemistry. 2010 Jun 18;285(25):19162-72.
28. Eckmann L, Nebelsiek T, Fingerle AA, Dann SM, Mages J, Lang R, Robine S, Kagnoff MF, Schmid RM, Karin M, Arkan MC. Opposing functions of IKKβ during acute and chronic intestinal inflammation. Proceedings of the National Academy of Sciences. 2008 Sep 30;105(39):15058-63.
29. Krishnamurthy B, Rani N, Bharti S, Golechha M, Bhatia J, Nag TC, Ray R, Arava S, Arya DS. Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats. Chemico-biological interactions. 2015 Jul 25; 237:96-103.
30. Fahmi AN, Shehatou GS, Shebl AM, Salem HA. Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury. Naunyn-Schmiedeberg's archives of pharmacology. 2016 Aug;389(8):819-30.
31. Millar AD, Rampton DS, Chander CL, Claxson AW, Blades S, Coumbe A, Panetta J, Morris CJ, Blake DR. Evaluating the antioxidant potential of new treatments for inflammatory bowel disease using a rat model of colitis. Gut. 1996 Sep 1;39(3):407-15.
32. Rubin DC, Shaker A, Levin MS. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Frontiers in immunology. 2012 May 8; 3:107.
33. Kannan N, Guruvayoorappan C. Protective effect of Bauhinia tomentosa on acetic acid induced ulcerative colitis by regulating antioxidant and inflammatory mediators. International immunopharmacology. 2013 May 1;16(1):57-66.
34. Ferrat M, Moulahoum H, Boumaza BM, Mouzaoui S, Périanin A, Djerdjouri B. Gadolinium chloride attenuates acetic acid-evoked colitis in mice by reducing neutrophil infiltration and pro-oxidative enzyme activity. Naunyn-Schmiedeberg's Archives of Pharmacology. 2019 Mar 5;392(3):299-311.
35. Atreya I, Atreya R, Neurath MF. NF‐κB in inflammatory bowel disease. Journal of internal medicine. 2008 Jun;263(6):591-6.
36. Jafari RM, Shayesteh S, Ala M, Yousefi-Manesh H, Rashidian A, Hashemian SM, Sorouri M, Dehpour AR. Dapsone ameliorates colitis through TLR4/NF-kB pathway in TNBS induced colitis model in rat. Archives of medical research. 2021 Aug 1;52(6):595-602.
37. Dejban P, Rahimi N, Takzare N, Jahansouz M, Haddadi NS, Dehpour AR. Beneficial effects of dapsone on ischemia/reperfusion injury following torsion/detorsion in ipsilateral and contralateral testes in rat. Theriogenology. 2019 Dec 1; 140:136-42.
38. Brunton LL, Knollmann BC, Hilal-Dandan R, editors. Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill Education; 2018.
39. Antoniou E, Margonis GA, Angelou A, Pikouli A, Argiri P, Karavokyros I, Papalois A, Pikoulis E. The TNBS-induced colitis animal model: An overview. Annals of medicine and surgery. 2016 Nov 1; 11:9-15.
40. Cui L, Feng L, Zhang ZH, Jia XB. The anti-inflammation effect of baicalin on experimental colitis through inhibiting TLR4/NF-κB pathway activation. International Immunopharmacology. 2014 Nov 1;23(1):294-303.
41. Rashidian A, Rashki A, Abdollahi A, Haddadi NS, Chamanara M, Mumtaz F, Dehpour AR. Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway. Immunopharmacology and immunotoxicology. 2019 Nov 2;41(6):607-13.
42. Ford AC, Wright-Hughes A, Alderson SL, Ow PL, Ridd MJ, Foy R, Bianco G, Bishop FL, Chaddock M, Cook H, Cooper D. Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2023 Nov 11;402(10414):1773-85.
43. Xia BT, Beckmann N, Winer LK, Kim Y, Goetzman HS, Veile RE, Gulbins E, Goodman MD, Nomellini V, Caldwell CC. Amitriptyline treatment mitigates sepsis-induced tumor necrosis factor expression and coagulopathy. Shock. 2019 Mar 1;51(3):356-63.
44. Kiesler P, Fuss IJ, Strober W. Experimental models of inflammatory bowel diseases. Cellular and molecular gastroenterology and hepatology. 2015 Mar 1;1(2):154-70.
45. Neurath MF. Cytokines in inflammatory bowel disease. Nature Reviews Immunology. 2014 May;14(5):329-42.
46. Martini E, Krug SM, Siegmund B, Neurath MF, Becker C. Mend your fences: the epithelial barrier and its relationship with mucosal immunity in inflammatory bowel disease. Cellular and molecular gastroenterology and hepatology. 2017 Jul 1;4(1):33-46.
47. McGuckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G. Intestinal barrier dysfunction in inflammatory bowel diseases. Inflammatory bowel diseases. 2009 Jan 1;15(1):100-13.
48. Cader MZ, Kaser A. Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation. Gut. 2013 Nov 1;62(11):1653-64.
49. Hutchinson MR, Loram LC, Zhang Y, Shridhar M, Rezvani N, Berkelhammer D, Phipps S, Foster PS, Landgraf K, Falke JJ, Rice KC. Evidence that tricyclic small molecules may possess toll-like receptor and myeloid differentiation protein 2 activity. Neuroscience. 2010 Jun 30;168(2):551-63.
50. Franco‐Trepat E, Alonso‐Pérez A, Guillán‐Fresco M, Jorge‐Mora A, Crespo‐Golmar A, López‐Fagúndez M, Pazos‐Pérez A, Gualillo O, Belen Bravo S, Gomez Bahamonde R. Amitriptyline blocks innate immune responses mediated by toll‐like receptor 4 and IL‐1 receptor: Preclinical and clinical evidence in osteoarthritis and gout. British Journal of Pharmacology. 2022 Jan;179(2):270-86.
51. Ke X, Zhou F, Gao Y, Xie B, Hu G, Fang W, Peng J, Chen Y, Sferra TJ. Qing Hua Chang Yin exerts therapeutic effects against ulcerative colitis through the inhibition of the TLR4/NF-κB pathway. International journal of molecular medicine. 2013 Oct;32(4):926-30.
52. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb 24;124(4):783-801.
53. Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005 Sep 1;146(9):3999-4008.
54. Wang J, Liu T, Chen X, Jin Q, Chen Y, Zhang L, Han Z, Chen D, Li Y, Lv Q, Xie M. Bazedoxifene regulates Th17 immune response to ameliorate experimental autoimmune myocarditis via inhibition of STAT3 activation. Frontiers in pharmacology. 2021 Feb 10; 11:613160.
55. Lobo RA, Pinkerton JV, Gass ML, Dorin MH, Ronkin S, Pickar JH, Constantine G. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertility and sterility. 2009 Sep 1;92(3):1025-38.
56. Rzemieniec J, Litwa E, Wnuk A, Lason W, Krzeptowski W, Kajta M. Selective aryl hydrocarbon receptor modulator 3, 3′-diindolylmethane impairs AhR and ARNT signaling and protects mouse neuronal cells against hypoxia. Molecular neurobiology. 2016 Oct;53(8):5591-606.
57. Matsushima-Nishiwaki R, Yamada N, Hattori Y, Hosokawa Y, Tachi J, Hori T, Kozawa O. SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway. Plos one. 2022 Jan 10;17(1): e0262485.
58. Li H, Xiao H, Lin L, Jou D, Kumari V, Lin J, Li C. Drug design targeting protein–protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. Journal of medicinal chemistry. 2014 Feb 13;57(3):632-41.
59. Guo W, Xiang Q, Mao B, Tang X, Cui S, Li X, Zhao J, Zhang H, Chen W. Protective effects of microbiome-derived inosine on lipopolysaccharide-induced acute liver damage and inflammation in mice via mediating the TLR4/NF-κB pathway. Journal of Agricultural and Food Chemistry. 2021 Jun 22;69(27):7619-28.
60. Shi N, Xue W, Liu P, Zeng C, Yue S, Xie W, Yu W, Lu W, Fan H, Wang Y, Tang Y. Atomically Dispersed Ru on NiFeV Layered Triple Hydroxides for Enhanced Water Oxidation. Advanced Functional Materials. 2025 Feb 26:2421740.
61. Weth FR, Hoggarth GB, Weth AF, Paterson E, White MP, Tan ST, Peng L, Gray C. Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy. British journal of cancer. 2024 Mar 23;130(5):703-15.
62. Saranraj K, Kiran PU. Drug repurposing: Clinical practices and regulatory pathways. Perspectives in Clinical Research. 2025 Apr 1;16(2):61-8.
63. Talevi A, Bellera CL. Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics. Expert opinion on drug discovery. 2020 Apr 2;15(4):397-401.