Oral sub mucous fibrosis: Exploring therapeutic strategies using -Anti TGF β drugs

sheshaprasad R, anuradha pai

Abstract


Objective: Oral submucous fibrosis (OSMF) is a chronic irreversible potentially malignant condition causing morbidity. Transforming Growth Factor beta (TGF-β1) plays the central role in its development. Hence early intervention is the key to limit progress of disease.

The aim of this paper was to review the effective therapeutic agents available to neutralize the pathological effect of TGF-β1 in OSMF.

Methods: An electronic search was conducted and we reviewed the records of the https://clinicaltrials.gov/, the registry of clinical trials that have been conducted internationally and in the United States in order to look for drugs associated with different types of fibrotic disorder. The studies related to pulmonary fibrosis were also included. We performed another search in the PubMed database and chose the successfully tested drugs from the result of our previous search and used the keywords "Name of the selected drug” "TGF” “Fibrosis."

Results: A total of 89 studies were listed in the search and finally 9 studies were considered for the analysis. The search results indicated the potential benefit of two drugs namely nintedanib and pirfenidone. It was noted that nintedanib reversed TGF-β1-induced EMT in non-small cell lung cancer cells and pirfenidone treatment inhibited TGF-β1-induced up-regulation of phosphorylation of ERK1/2, p38 and Jun amino-terminal kinases (JNK) in a renal fibrosis rat model.

Conclusion: It was concluded that pirfenidone and nintedanib were found to have promising role in treatment of pulmonary fibrosis also linked to pathological effect of TGF-β pathway. Therefore, we put forward the suggestion of designing preclinical studies, as well as clinical trials to test the effectiveness of these drugs in treating oral submucous fibrosis.

Keywords: OSMF, potentially malignant condition, TGF-β1, Pirfenidone


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References


Cox SC, Walker DM. Oral submucous fibrosis. A review. Australian dental journal. 1996;41(5):294-9.

Schnaper HW, Kopp JB. Renal fibrosis. Frontiers in bioscience : a journal and virtual library. 2003;8:e68-86.

Denton CP, Black CM. Scleroderma--clinical and pathological advances. Best practice & research Clinical rheumatology. 2004;18(3):271-90.

Bataller R, Brenner DA. Liver fibrosis. The Journal of clinical investigation. 2005;115(2):209-18.

Mendoza FA, Artlett CM, Sandorfi N, Latinis K, Piera-Velazquez S, Jimenez SA. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Seminars in arthritis and rheumatism. 2006;35(4):238-49.

Noble PW. Idiopathic pulmonary fibrosis: natural history and prognosis. Clinics in chest medicine. 2006;27(1 Suppl 1):S11-6, v.

Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. The Journal of clinical investigation. 2007;117(3):557-67.

White JM, Creamer D, du Vivier AW, Pagliuca A, Ho AY, Devereux S, et al. Sclerodermatous graft-versus-host disease: clinical spectrum and therapeutic challenges. The British journal of dermatology. 2007;156(5):1032-8.

Cowper SE. Nephrogenic systemic fibrosis: an overview. Journal of the American College of Radiology : JACR. 2008;5(1):23-8.

Rosenbloom J, Mendoza FA, Jimenez SA. Strategies for anti-fibrotic therapies. Biochimica et biophysica acta. 2013;1832(7):1088-103.

Patil S, Maheshwari S. Proposed new grading of oral submucous fibrosis based on cheek flexibility. Journal of clinical and experimental dentistry. 2014;6(3):e255-8.

Wynn TA. Cellular and molecular mechanisms of fibrosis. The Journal of pathology. 2008;214(2):199-210.

Meng X-M, Tang PM-K, Li J, Lan HY. TGF-β/Smad signaling in renal fibrosis. Frontiers in Physiology. 2015;6(82).

Lepparanta O, Sens C, Salmenkivi K, Kinnula VL, Keski-Oja J, Myllarniemi M, et al. Regulation of TGF-beta storage and activation in the human idiopathic pulmonary fibrosis lung. Cell and tissue research. 2012;348(3):491-503.

Varga J, Pasche B. Transforming growth factor beta as a therapeutic target in systemic sclerosis. Nature reviews Rheumatology. 2009;5(4):200-6.

Kale AD, Mane DR, Shukla D. Expression of transforming growth factor beta and its correlation with lipodystrophy in oral submucous fibrosis: an immunohistochemical study. Medicina oral, patologia oral y cirugia bucal. 2013;18(1):e12-8.

Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. The European Respiratory Journal. 2015;45(5):1434-45.

Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in fibrosis. Current rheumatology reports. 2006;8(2):145-50.

Wynn TA. Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. The Journal of clinical investigation. 2007;117(3):524-9.

Desmouliere A, Gabbiani G. Myofibroblast differentiation during fibrosis. Experimental nephrology. 1995;3(2):134-9.

Abraham DJ, Eckes B, Rajkumar V, Krieg T. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Current rheumatology reports. 2007;9(2):136-43.

Krieg T, Abraham D, Lafyatis R. Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis research & therapy. 2007;9 Suppl 2:S4.

McAnulty RJ. Fibroblasts and myofibroblasts: their source, function and role in disease. The international journal of biochemistry & cell biology. 2007;39(4):666-71.

Kirk TZ, Mark ME, Chua CC, Chua BH, Mayes MD. Myofibroblasts from scleroderma skin synthesize elevated levels of collagen and tissue inhibitor of metalloproteinase (TIMP-1) with two forms of TIMP-1. The Journal of biological chemistry. 1995;270(7):3423-8.

Piera-Velazquez S, Jimenez SA. Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis & Tissue Repair. 2012;5(Suppl 1):S7-S.

Li Z, Jimenez SA. Protein kinase Cdelta and c-Abl kinase are required for transforming growth factor beta induction of endothelial-mesenchymal transition in vitro. Arthritis and rheumatism. 2011;63(8):2473-83.

Medici D, Potenta S, Kalluri R. Transforming growth factor-beta2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. The Biochemical journal. 2011;437(3):515-20.

Piera-Velazquez S, Jimenez SA. Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis Tissue Repair. 2012;5(Suppl 1):S7.

van Meeteren LA, ten Dijke P. Regulation of endothelial cell plasticity by TGF-beta. Cell and tissue research. 2012;347(1):177-86.

Goumans MJ, Liu Z, ten Dijke P. TGF-beta signaling in vascular biology and dysfunction. Cell research. 2009;19(1):116-27.

Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cellular and molecular life sciences : CMLS. 2009;66(5):773-87.

Piera-Velazquez S, Mendoza FA, Jimenez SA. Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases. Journal of clinical medicine. 2016;5(4).

Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Deuel TF. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science (New York, NY). 1987;237(4820):1333-6.

Lin RY, Sullivan KM, Argenta PA, Meuli M, Lorenz HP, Adzick NS. Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair. Annals of surgery. 1995;222(2):146-54.

Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2004;18(7):816-27.

Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 1999;13(13):1774-86.

Khan I, Agarwal P, Thangjam GS, Radhesh R, Rao SG, Kondaiah P. Role of TGF-beta and BMP7 in the pathogenesis of oral submucous fibrosis. Growth factors (Chur, Switzerland). 2011;29(4):119-27.

Haque MF, Meghji S, Khitab U, Harris M. Oral submucous fibrosis patients have altered levels of cytokine production. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2000;29(3):123-8.

Utsunomiya H, Tilakaratne WM, Oshiro K, Maruyama S, Suzuki M, Ida-Yonemochi H, et al. Extracellular matrix remodeling in oral submucous fibrosis: its stage-specific modes revealed by immunohistochemistry and in situ hybridization. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2005;34(8):498-507.

Ila Pant NK, Imran Khan, Somanahalli Girish Rao, Paturu Kondaiah Role of Areca Nut Induced TGF-β and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis. PLOS ONE. Published: June 24, 2015https://doi.org/10.1371/journal.pone.0129252.

Maria S, Kamath VV, Satelur K, Rajkumar K. Evaluation of transforming growth factor beta1 gene in oral submucous fibrosis induced in Sprague-Dawley rats by injections of areca nut and pan masala (commercial areca nut product) extracts. Journal of cancer research and therapeutics. 2016;12(1):379-85.

Rajendran R. Oral submucous fibrosis: etiology, pathogenesis, and future research. Bulletin of the World Health Organization. 1994;72(6):985-96.

Pandiar D, Shameena P. Immunohistochemical expression of CD34 and basic fibroblast growth factor (bFGF) in oral submucous fibrosis. Journal of Oral and Maxillofacial Pathology. 2014;18(2):155-61.

Sinor PN, Gupta PC, Murti PR, Bhonsle RB, Daftary DK, Mehta FS, et al. A case-control study of oral submucous fibrosis with special reference to the etiologic role of areca nut. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 1990;19(2):94-8.

Jacob BJ, Straif K, Thomas G, Ramadas K, Mathew B, Zhang ZF, et al. Betel quid without tobacco as a risk factor for oral precancers. Oral Oncol. 2004;40(7):697-704.

Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2005;34(6):321-8.

Hsieh YP, Chen HM, Lin HY, Yang H, Chang JZ. Epigallocatechin-3-gallate inhibits transforming-growth-factor-beta1-induced collagen synthesis by suppressing early growth response-1 in human buccal mucosal fibroblasts. Journal of the Formosan Medical Association = Taiwan yi zhi. 2017;116(2):107-13.

Yang SF, Hsieh YS, Tsai CH, Chou MY, Chang YC. The upregulation of type I plasminogen activator inhibitor in oral submucous fibrosis. Oral Oncol. 2003;39(4):367-72.

Prime SS, Pring M, Davies M, Paterson IC. TGF-beta signal transduction in oro-facial health and non-malignant disease (part I). Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists. 2004;15(6):324-36.

Cutroneo KR. TGF-beta-induced fibrosis and SMAD signaling: oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2007;15 Suppl 1:S54-60.

Feres-Filho EJ, Choi YJ, Han X, Takala TE, Trackman PC. Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells. The Journal of biological chemistry. 1995;270(51):30797-803.

Hong HH, Uzel MI, Duan C, Sheff MC, Trackman PC. Regulation of lysyl oxidase, collagen, and connective tissue growth factor by TGF-beta1 and detection in human gingiva. Laboratory investigation; a journal of technical methods and pathology. 1999;79(12):1655-67.

Moutasim KA, Jenei V, Sapienza K, Marsh D, Weinreb PH, Violette SM, et al. Betel-derived alkaloid up-regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis. The Journal of pathology. 2011;223(3):366-77.

Prabhu RV, Prabhu V, Chatra L, Shenai P, Suvarna N, Dandekeri S. Areca nut and its role in oral submucous fibrosis. Journal of clinical and experimental dentistry. 2014;6(5):e569-e75.

Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among gutkha chewers of Patna, Bihar, India. Journal of the Indian Society of Pedodontics and Preventive Dentistry. 2006;24(2):84-9.

Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community dentistry and oral epidemiology. 1985;13(6):340-1.

Angadi PV, Rao S. Management of oral submucous fibrosis: an overview. Oral and maxillofacial surgery. 2010;14(3):133-42.

Krishnamoorthy B, Khan M. Management of oral submucous fibrosis by two different drug regimens: A comparative study. Dental Research Journal. 2013;10(4):527-32.

Eickelberg O, Pansky A, Koehler E, Bihl M, Tamm M, Hildebrand P, et al. Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2001;15(3):797-806.

Nishijima N, Seike M, Soeno C, Chiba M, Miyanaga A, Noro R, et al. miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. International journal of oncology. 2016;48(3):937-44.

Li Z, Liu X, Wang B, Nie Y, Wen J, Wang Q, et al. Pirfenidone suppresses MAPK signalling pathway to reverse epithelial-mesenchymal transition and renal fibrosis. Nephrology (Carlton, Vic). 2017;22(8):589-97.

Yoithapprabhunath TR, Maheswaran T, Dineshshankar J, Anusushanth A, Sindhuja P, Sitra G. Pathogenesis and therapeutic intervention of oral submucous fibrosis. Journal of Pharmacy & Bioallied Sciences. 2013;5(Suppl 1):S85-S8.

Chole RH, Gondivkar SM, Gadbail AR, Balsaraf S, Chaudhary S, Dhore SV, et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol. 2012;48(5):393-8.

Gadekar SM. 5-Methyl-1-phenyl-2-(1H)-pyridone compositions and methods of use. 1976. Aug 10 iUp, 974,281.

Margolin SB. Composition and method for reparation and prevention of fibrotic lesions. 1994. May 10 iUp, 310,562.

Lee BS, Margolin SB, Nowak RA. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production. The Journal of clinical endocrinology and metabolism. 1998;83(1):219-23.

Zhang S, Shiels IA, Ambler JS, Taylor SM. Pirfenidone reduces fibronectin synthesis by cultured human retinal pigment epithelial cells. Australian and New Zealand journal of ophthalmology. 1998;26 Suppl 1:S74-6.

Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. The Journal of pharmacology and experimental therapeutics. 1999;289(1):211-8.

Tada S, Nakamuta M, Enjoji M, Sugimoto R, Iwamoto H, Kato M, et al. Pirfenidone inhibits dimethylnitrosamine-induced hepatic fibrosis in rats. Clinical and experimental pharmacology & physiology. 2001;28(7):522-7.

Nguyen DT, Ding C, Wilson E, Marcus GM, Olgin JE. Pirfenidone mitigates left ventricular fibrosis and dysfunction after myocardial infarction and reduces arrhythmias. Heart rhythm. 2010;7(10):1438-45.

Gan Y, Herzog EL, Gomer RH. Pirfenidone treatment of idiopathic pulmonary fibrosis. Therapeutics and Clinical Risk Management. 2011;7:39-47.

Garcia L, Hernandez I, Sandoval A, Salazar A, Garcia J, Vera J, et al. Pirfenidone effectively reverses experimental liver fibrosis. Journal of hepatology. 2002;37(6):797-805.

Yu CC, Tsai CH, Hsu HI, Chang YC. Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: involvement in the pathogenesis of oral submucous fibrosis. PLoS One. 2013;8(1):e55122.

Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel anti-fibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. European journal of pharmacology. 2002;446(1-3):177-85.

Kaur J, Jacobs R. Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis. Journal of the Korean Association of Oral and Maxillofacial Surgeons. 2015;41(4):171-5.

Bishen KA, Radhakrishnan R, Satyamoorthy K. The role of basic fibroblast growth factor in oral submucous fibrosis pathogenesis. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2008;37(7):402-11.

Gan Y, Herzog EL, Gomer RH. Pirfenidone treatment of idiopathic pulmonary fibrosis. Ther Clin Risk Manag. 2011;7:39-47.

Tsai CH, Lee SS, Chang YC. Hypoxic regulation of plasminogen activator inhibitor-1 expression in human buccal mucosa fibroblasts stimulated with arecoline. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2015;44(9):669-73.

Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer research. 2008;68(12):4774-82.

Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, Seidel P, et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respiratory research. 2014;15:157.

Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. The Journal of pharmacology and experimental therapeutics. 2014;349(2):209-20.

Rangarajan S, Kurundkar A. Novel Mechanisms for the Antifibrotic Action of Nintedanib. 2016;54(1):51-9.

Seema Nayak MMG, Annu Makker, Vikram Bhatia, Saumya Chandra, Sandeep Kumar, S. P. Agarwal. Fibroblast Growth Factor (FGF-2) and Its Receptors FGFR-2 and FGFR-3 May Be Putative Biomarkers of Malignant Transformation of Potentially Malignant Oral Lesions into Oral Squamous Cell Carcinoma. PLOS ONE. Published: October 14, 2015https://doi.org/10.1371/journal.pone.0138801.

Hajari Case A, Johnson P. Clinical use of nintedanib in patients with idiopathic pulmonary fibrosis. BMJ Open Respiratory Research. 2017;4(1).

Lancaster LH, de Andrade JA, Zibrak JD, Padilla ML, Albera C, Nathan SD, et al. Pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis. European Respiratory Review. 2017;26(146).

Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011;377(9779):1760-9.

Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82.

Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, Hunninghake GW. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620-8.

Noth I, Anstrom KJ, Calvert SB, de Andrade J, Flaherty KR, Glazer C, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95.

King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-92.

Lederer DJ, Bradford WZ, Fagan EA, Glaspole I, Glassberg MK, Glasscock KF, et al. Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis. Chest. 2015;148(1):196-201.

King TE, Jr., Brown KK, Raghu G, du Bois RM, Lynch DA, Martinez F, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(1):92-9.

Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann Intern Med. 2013;158(9):641-9.

Martinez FJ, de Andrade JA, Anstrom KJ, King TE, Jr., Raghu G. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2093-101.

Raghu G, Anstrom KJ, King TE, Jr., Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-77.

Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655-66.

Theodore AC, Tseng CH, Li N, Elashoff RM, Tashkin DP. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study. Chest. 2012;142(3):614-21.

Roth MD, Tseng CH, Clements PJ, Furst DE, Tashkin DP, Goldin JG, et al. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011;63(9):2797-808.

Goldin J, Elashoff R, Kim HJ, Yan X, Lynch D, Strollo D, et al.

Treatment of scleroderma-interstitial lung disease with cyclophosphamide is associated with less progressive fibrosis on serial thoracic high-resolution CT scan than placebo: findings from the scleroderma lung study. Chest. 2009;136(5):1333-40.




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