Abstract
Background
Intestinal mucositis is a major concern related with cancer therapy. It is well established that overproduction of reactive oxygen species and inflammatory mediators plays vital role in the pathogenesis of mucositis. The aim of the study was to investigate the modulatory effect of vitamin E (vit. E) on 5-fluorouracil (5-FU)-induced intestinal mucositis by targeting oxidative stress and inflammatory markers in rats.
Methods
Rats were randomly divided into four groups of six animals each. All four-group animals received normal standard diet and water throughout the experimental period which last up to 10 days. Rats were gavaged with vit. E (300 mg/kg b. wt.) daily for 10 days (day 1–10) and were given intraperitoneal injection of 5-FU (150 mg/kg b. wt.) or saline (control) on day 8 to induce mucositis.
Results
We found that vit. E supplementation ameliorated 5-FU-induced lipid peroxidation, myeloperoxidase activity, activation of nuclear factor κB, expression of cyclooxygenase-2, inducible nitric oxide synthase and mucin depletion. Vit. E administration also attenuated 5-FU-induced histological anomalies such as neutrophil infiltration, loss of cellular integrity, villus and crypt deformities.
Conclusions
Findings of the study suggest that vit. E inhibits 5-FU-induced mucositis via modulation of oxidative stress, activation of redox sensitive transcription factor and its downstream targets.
Acknowledgments
Authors thank the Research Centre, PSMMC, kingdom of Saudi Arabia for financial support to carry out this work.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the report for publication.
References
1. Peterson DE, Keefe DM, Sonis ST. New frontiers in mucositis. Am Soc Clin Oncol Educ Book 2012:545–51.10.14694/EdBook_AM.2012.32.46Search in Google Scholar PubMed
2. Harris DJ. Cancer treatment-induced mucositis pain: strategies for assessment and management. Ther Clin Risk Manage 2006;2:251.10.2147/tcrm.2006.2.3.251Search in Google Scholar PubMed PubMed Central
3. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, et al. Clinical practice guidelines for the prevention and treatment of cancer therapy–induced oral and gastrointestinal mucositis. Cancer 2004; 100 (S9):2026–46.10.1002/cncr.20163Search in Google Scholar PubMed
4. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB. The burdens of cancer therapy. Cancer 2003;98:1531–9.10.1002/cncr.11671Search in Google Scholar PubMed
5. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003;3:330–8.10.1038/nrc1074Search in Google Scholar PubMed
6. Lalla RV, Peterson DE. Treatment of mucositis, including new medications. Cancer J 2006;12:348–54.10.1097/00130404-200609000-00004Search in Google Scholar PubMed
7. Yasuda M, Kato S, Yamanaka N, Iimori M, Matsumoto K, Utsumi D, et al. 5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. Br J Pharmacol 2013;168:1388–400.10.1111/bph.12019Search in Google Scholar PubMed PubMed Central
8. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer–Jensen M, et al. Perspectives on cancer therapy–induced mucosal injury. Cancer 2004;100(S9):1995–2025.10.1002/cncr.20162Search in Google Scholar PubMed
9. Kwon Y. Mechanism-based management for mucositis: option for treating side effects without compromising the efficacy of cancer therapy. Onco Targets Ther 2016:9;2007–16.10.2147/OTT.S96899Search in Google Scholar PubMed PubMed Central
10. Conklin KA. Chemotherapy-associated oxidative stress: impact on chemotherapeutic effectiveness. Integr Cancer Ther 2004;3:294–300.10.1177/1534735404270335Search in Google Scholar PubMed
11. Yoshino F, Yoshida A, Nakajima A, Wada-Takahashi S, Takahashi S-S, Lee MC-I. Alteration of the redox state with reactive oxygen species for 5-fluorouracil-induced oral mucositis in hamsters. PloS One 2013;8:e82834.10.1371/journal.pone.0082834Search in Google Scholar
12. Chang C-T, Ho T-Y, Lin H, Liang J-A, Huang H-C, Li C-C, et al. 5-Fluorouracil induced intestinal mucositis via nuclear factor-κB activation by transcriptomic analysis and in vivo bioluminescence imaging. PLoS One 2012;7:e31808.10.1371/journal.pone.0031808Search in Google Scholar
13. Lalla RV, Sonis ST, Peterson DE. Management of oral mucositis in patients who have cancer. Dent Clin North Am 200852:61–77.10.1016/j.cden.2007.10.002Search in Google Scholar
14. Nazrun A, Norazlina M, Norliza M, Nirwana S. The anti-inflammatory role of vitamin E in prevention of osteoporosis. Adv Pharmacol Sci 2011;2012:142702.Search in Google Scholar
15. Singh U, Devaraj S. Vitamin E: inflammation and atherosclerosis. Vitamins Hormones 2007;76:519–49.10.1016/S0083-6729(07)76020-XSearch in Google Scholar
16. Yang CS, Lu G, Ju J, Li GX. Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols. Ann New York Acad Sci 2010;1203:29–34.10.1111/j.1749-6632.2010.05561.xSearch in Google Scholar
17. Bhartiya US, Raut YS, Joseph LJ, Hawaldar RW, Rao BS. Evaluation of the radioprotective effect of turmeric extract and vitamin E in mice exposed to therapeutic dose of radioiodine. Indian J Clin Biochem 2008;23:382–6.10.1007/s12291-008-0084-5Search in Google Scholar
18. Amin KA, Hashem KS, Al-muzafar HM, Taha EM. Oxidative hepatotoxicity effects of monocrotaline and its amelioration by lipoic acid, S-adenosyl methionine and vitamin E. J Complement Integr Med 2014;11:35–41.10.1515/jcim-2013-0041Search in Google Scholar
19. Al-Asmari AK, Khan AQ, Al-Qasim AM, Al-Yousef Y. Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators. Toxicology Reports 2015;2:908–16.10.1016/j.toxrep.2015.06.006Search in Google Scholar
20. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 1982;78:206–9.10.1111/1523-1747.ep12506462Search in Google Scholar
21. Utley HG, Bernheim F, Hochstein P. Effect of sulfhydryl reagents on peroxidation in microsomes. Arch Biochem Biophys 1967;118:29–32.10.1016/0003-9861(67)90273-1Search in Google Scholar
22. Shiota A, Hada T, Baba T, Sato M, Yamanaka-Okumura H, Yamamoto H, et al. Protective effects of glycoglycerolipids extracted from spinach on 5-fluorouracil induced intestinal mucosal injury. J Med Invest 2010;57:314–20.10.2152/jmi.57.314Search in Google Scholar
23. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004;4:277–84.10.1038/nrc1318Search in Google Scholar
24. Wu JT, Kral JG, The NF-. κB/IκB signaling system: a molecular target in breast cancer therapy. J Surg Res 2005;123:158–69.10.1016/j.jss.2004.06.006Search in Google Scholar
25. Yeoh AS, Gibson RJ, Yeoh EE, Bowen JM, Stringer AM, Giam KA, et al. A novel animal model to investigate fractionated radiotherapy-induced alimentary mucositis: the role of apoptosis, p53, nuclear factor-κB, COX-1, and COX-2. Mol Cancer Ther 2007;6:2319–27.10.1158/1535-7163.MCT-07-0113Search in Google Scholar
26. Sonis ST. The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Crit Rev Oral Biol Med 2002;13:380–9.10.1177/154411130201300502Search in Google Scholar
27. Calfee-Mason KG, Spear BT, Glauert HP. Effects of vitamin E on the NF-κB pathway in rats treated with the peroxisome proliferator, ciprofibrate. Toxicol Appl Pharmacol 2004;199:1–9.10.1016/j.taap.2004.03.006Search in Google Scholar
28. Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, Charnock-Jones DS, Burton GJ. Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Am J Pathol 2007;170:1511–20.10.2353/ajpath.2007.061035Search in Google Scholar
29. Ekstrand-Hammarstrom B, Osterlund C, Lilliehook B, Vitamin BA. E down-modulates mitogen-activated protein kinases, nuclear factor-kappaB and inflammatory responses in lung epithelial cells. Clin Exp Immunol 2007;147:359–69.10.1111/j.1365-2249.2006.03285.xSearch in Google Scholar
30. Pal A, Alam S, Singhal J, Kumar R, Ansari KM, Protective DM. Effect of topical application of α-tocopherol and/or N-acetyl cysteine on argemone oil/alkaloid-induced skin tumorigenesis in mice. Nutr Cancer 2013;65:78–87.10.1080/01635581.2013.785005Search in Google Scholar
31. Sonis S, O‘Donnell K, Popat R, Bragdon C, Phelan S, Cocks D, et al. The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. Oral Oncol 2004;40:170–6.10.1016/S1368-8375(03)00148-9Search in Google Scholar
32. Freitas APF, Bitencourt FS, Brito GAC, de Alencar NMN, Ribeiro RA, Lima-Júnior RCP, et al. Protein fraction of Calotropis procera latex protects against 5-fluorouracil-induced oral mucositis associated with downregulation of pivotal pro-inflammatory mediators. Naunyn-Schmiedeberg’s Arch Pharmacol 2012;385:981–90.10.1007/s00210-012-0778-3Search in Google Scholar PubMed
33. Lalla RV, Pilbeam CC, Walsh SJ, Sonis ST, Keefe DM, Peterson DE. Role of the cyclooxygenase pathway in chemotherapy-induced oral mucositis: a pilot study. Support Care Cancer 2010;18:95–103.10.1007/s00520-009-0635-1Search in Google Scholar PubMed PubMed Central
34. Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, et al. Cyclooxygenase in biology and disease. FASEB J 1998;12:1063–73.10.1096/fasebj.12.12.1063Search in Google Scholar
35. Egger T, Schuligoi R, Wintersperger A, Amann R, Malle E, Sattler W. Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia. Biochem J 2003;370:459–67.10.1042/bj20021358Search in Google Scholar
36. Huang T-Y, Chu H-C, Lin Y-L, Ho W-H, Hou H-S, Chao Y-C, et al. Minocycline attenuates 5-fluorouracil-induced small intestinal mucositis in mouse model. Biochem Biophys Res Commun 2009;389:634–9.10.1016/j.bbrc.2009.09.041Search in Google Scholar PubMed
37. Leitão RF, Ribeiro RA, Bellaguarda EA, Macedo FD, Silva LR, Oriá RB, et al. Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster. Cancer Chemother Pharmacol 2007;59:603–12.10.1007/s00280-006-0301-ySearch in Google Scholar PubMed
38. Leitão RF, Brito GA, Oriá RB, Braga-Neto MB, Bellaguarda EA, Silva JV, et al. Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents. BMC Gastroenterol 2011;11:90.10.1186/1471-230X-11-90Search in Google Scholar PubMed PubMed Central
39. Lima-Júnior RC, Figueiredo AA, Freitas HC, Melo ML, Wong DV, Leite CA, et al. Involvement of nitric oxide on the pathogenesis of irinotecan-induced intestinal mucositis: role of cytokines on inducible nitric oxide synthase activation. Cancer Chem Pharmacol 2012;69:931–42.10.1007/s00280-011-1780-zSearch in Google Scholar PubMed
40. Ohta Y, Imai Y, Kaida S, Kamiya Y, Kawanishi M, Hirata I. Vitamin E protects against stress‐induced gastric mucosal lesions in rats more effectively than vitamin C. Biofactors 2010;36:60–9.10.1002/biof.73Search in Google Scholar PubMed
41. Khanduja KL, Avti PK, Kumar VP, Chander Mohan Pathak S. Inhibitory effect of vitamin E on proinflammatory cytokines-and endotoxin-induced nitric oxide release in alveolar macrophages. Life Sci 2005;76:2669–80.10.1016/j.lfs.2004.09.037Search in Google Scholar PubMed
42. Calvisi DF, Ladu S, Hironaka K, Factor VM, Thorgeirsson SS. Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer. J Hepatol 2004;41:815–22.10.1016/j.jhep.2004.07.030Search in Google Scholar PubMed
43. Heinecke JW. Pathways for oxidation of low density lipoprotein by myeloperoxidase: tyrosyl radical, reactive aldehydes, hypochlorous acid and molecular chlorine. Biofactors 1997;6:145–55.10.1002/biof.5520060208Search in Google Scholar PubMed
44. Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukocyte Biol 2005;77:598–625.10.1189/jlb.1204697Search in Google Scholar PubMed
45. Davies MJ, Hawkins CL, Pattison DI, Rees MD. Mammalian heme peroxidases: from molecular mechanisms to health implications. Antioxid Redox Signaling 2008;10:1199–234.10.1089/ars.2007.1927Search in Google Scholar PubMed
46. Mashtoub S, Tran CD, Howarth GS. Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats. Exp Biol Med 2013;238:1305–17.10.1177/1535370213493718Search in Google Scholar PubMed
47. Rahman S, Bhatia K, Khan AQ, Kaur M, Ahmad F, Rashid H, et al. Topically applied vitamin E prevents massive cutaneous inflammatory and oxidative stress responses induced by double application of 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Chem Biol Interact 2008;172:195–205.10.1016/j.cbi.2007.11.017Search in Google Scholar PubMed
48. Sapmaz-Metin M, Topcu-Tarladacalisir Y, Uz YH, Inan M, Omurlu IK, Cerkezkayabekir A, et al. Vitamin E modulates apoptosis and c-jun N-terminal kinase activation in ovarian torsion–detorsion injury. Exp Mol Pathol 2013;95:213–19.10.1016/j.yexmp.2013.07.007Search in Google Scholar PubMed
49. Thorpe D, Stringer A, Butler R. Chemotherapy-induced mucositis: The role of mucin secretion and regulation, and the enteric nervous system. Neurotoxicology 2013;38:101–5.10.1016/j.neuro.2013.06.007Search in Google Scholar PubMed
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