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Barrett's Esophagus and β-carotene Therapy: Symptomatic Improvement in GERD and Enhanced HSP70 Expression in Esophageal Mucosa

  • Dutta, Sudhir K. (Department of Medicine, University of Maryland School of Medicine and Division Director of Gastroenterology) ;
  • Agrawal, Kireet (Department of Internal Medicine, John Stroger Hospital of Cook County) ;
  • Girotra, Mohit (Department of Medicine, Johns Hopkins University/Sinai Hospital Program in Internal Medicine) ;
  • Fleisher, A. Steven (Division of Gastroenterology, Franklin Square Hospital) ;
  • Motevalli, Mahnaz (Research Co-ordinator, Division of Gastroenterology, Sinai Hospital of Baltimore) ;
  • Mah'moud, Mitchell A. (Duke University School of Medicine) ;
  • Nair, Padmanabhan P. (Johns Hopkins Bloomberg School of Public Health)
  • Published : 2012.12.31

Abstract

Introduction: Epidemiological studies suggest a protective role for ${\beta}$-carotene with several malignancies. Esophageal adenocarcinoma frequently arises from Barrett's esophagus (BE). We postulated that ${\beta}$-carotene therapy maybe protective in BE. Materials and Method: We conducted a prospective study in which 25 mg of ${\beta}$-carotene was administered daily for six-months to six patients. Each patient underwent upper endoscopy before and after therapy and multiple mucosal biopsies were obtained. Additionally, patients completed a gastroesophageal reflux disease (GERD) symptoms questionnaire before and after therapy and severity score was calculated. To study the effect of ${\beta}$-carotene at molecular level, tissue extracts of the esophageal mucosal biopsy were subjected to assessment of heat-shock protein 70 (HSP70). Results: A significant (p<0.05) reduction in mean GERD symptoms severity score from $7.0{\pm}2.4$ to $2.7{\pm}1.7$ following ${\beta}$-carotene therapy was noted. Measurement of Barrett's segment also revealed a significant reduction in mean length after therapy. In fact, two patients had complete disappearance of intestinal metaplasia. Furthermore, marked enhancement of HSP70 expression was demonstrated in biopsy specimens from Barrett's epithelium in four cases that were tested. Conclusions: Long-term ${\beta}$-carotene therapy realizes amelioration of GERD symptoms along with restitution of the histological and molecular changes in esophageal mucosa of patients with BE, associated with concurrent increase in mucosal HSP70 expression.

Keywords

${\beta}$-arotene;HSP70;Barrett's esophagus;GERD

References

  1. Wetscher GJ, Hinder PR, Bagchi D, et al (1995). Reflux esophagitis in humans is mediated by oxygen-derived free radicals. Am J Surg, 170, 552-6. https://doi.org/10.1016/S0002-9610(99)80014-2
  2. Yagui-Beltran A, Craig AL, Lawrie L, et al (2001). The human oesophageal squamous epithelium exhibits a novel type of heat shock protein response. Eur J Biochem, 268, 5343-55. https://doi.org/10.1046/j.0014-2956.2001.02468.x
  3. Yang PC, Davis S (1988). Incidence of cancer of the esophagus in the US by histologic type. Cancer, 61, 612-7. https://doi.org/10.1002/1097-0142(19880201)61:3<612::AID-CNCR2820610332>3.0.CO;2-Q
  4. Pal D, Banerjee S, Ghosh AK (2012). Dietary-induced cancer prevention: an expanding research arena of emerging diet related to healthcare system. J Adv Pharm Technol Res, 3, 16-24.
  5. Prabhala RH, Garewal HS, Hicks MJ, Sampliner RE, Watson RR (1991). The effects of 13-cis-retinoic acid and ${\beta}$-carotene on cellular immunity in humans. Cancer, 67, 1556-60. https://doi.org/10.1002/1097-0142(19910315)67:6<1556::AID-CNCR2820670616>3.0.CO;2-O
  6. Saluja A, Dudeja V (2008). Heat shock proteins in pancreatic diseases. J Gastroenterol Hepatol, 23, 42-5 https://doi.org/10.1111/j.1440-1746.2007.05272.x
  7. Sankaranarayanan R, Mathew B, Varghese C, et al (1997). Chemoprevention of oral leukoplakia with vitamin A and ${\beta}$-carotene: an assessment. Oral Oncol, 33, 231-6. https://doi.org/10.1016/S0964-1955(97)00010-9
  8. Sarkar A, Bishayee A, Chatterjee M (1995). Beta-carotene prevents lipid peroxidation and red blood cell membrane protein damage in experimental hepatocarcinogenesis. Cancer Biochem Biophys, 15, 111-25.
  9. Schwartz JL, Singh RP, Teicher B, et al (1990). Induction of a 70 kD protein associated with the selective cytotoxicity of ${\beta}$-carotene in human epidermal carcinoma. Biochem Biophys Res Commun, 169, 941-6. https://doi.org/10.1016/0006-291X(90)91984-Z
  10. Shirvani VN, Outu-Lascar R, Kaur BS, Omary B, Triadafilopoulos G (2000). Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: ex vivo induction by bile salts and acid exposure. Gastroenterology, 118, 487-96. https://doi.org/10.1016/S0016-5085(00)70254-X
  11. Sihvo EI, Salminen JT, Rantanen TK, et al (2002). Oxidative stress has a role in malignant transformation in Barrett's esophagus. Int J Cancer, 102, 551-5. https://doi.org/10.1002/ijc.10755
  12. Solaymani-Dodaran M, Logan RF, West J, Card T, Coupland C (2004). Risk of extra-oesophageal malignancies and colorectal cancer in Barrett's oesophagus and gastrooesophageal reflux. Scand J Gastroenterol, 39, 680-5. https://doi.org/10.1080/00365520410004802
  13. Souza RF, Shewmake K, Terada LS, Spechler SJ (2002). Acid exposure activates the mitogen-activated protein kinase pathways in Barrett's esophagus. Gastroenterology, 122, 299-307. https://doi.org/10.1053/gast.2002.30993
  14. Stich HF, Hornby AP, Mathew B, Sankaranarayanan R, Nair MK (1998). Response of oral leukoplakias to the administration of vitamin A. Cancer Lett, 40, 93-101.
  15. Terry P, Lagergren J, Ye W, Nyren O, Wolk A (2000). Antioxidants and cancers of the esophagus and gastric cardia. Int J Cancer, 87, 750-4. https://doi.org/10.1002/1097-0215(20000901)87:5<750::AID-IJC19>3.0.CO;2-6
  16. Toba T, Shidoji Y, Fujii J, et al (1997). Growth suppression and induction of heat-shock protein-70 by 9-cis ${\beta}$-carotene in cervical dysplasia-derived cells. Life Sci, 61, 839-45. https://doi.org/10.1016/S0024-3205(97)00566-3
  17. Triadafilopoulos G, Sharma R (1997). Features of symptomatic gastroesophageal reflux disease in elderly patients. Am J Gastroenterol, 92, 2007-11.
  18. Tsuda H, Uehara N, Iwahori Y, et al (1994). Chemoprotective effect of ${\beta}$-carotene, alpha-tocopherol and five naturally occurring antioxidants on initiation of hepatocarcinogenesis by 2-amino,3-methylimidazo (4,5-f)quinoline in the rat. Jpn J Cancer Res, 85, 1214-9. https://doi.org/10.1111/j.1349-7006.1994.tb02932.x
  19. Gerson LB, Edson R, Lavori PW, Triadafilopoulos G (2001). Use of a simple symptom questionnaire to predict Barrett's esophagus in patients with symptoms of gastroesophageal reflux. Am J Gastroenterol, 96, 2005-12. https://doi.org/10.1111/j.1572-0241.2001.03933.x
  20. Hillman LC, Chiragakis L, Shadbolt B, Kaye GL, Clarke AC (2004). Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett's oesophagus. Med J Aust, 180, 387-91.
  21. Hopwood D, Moitra S, Vojtesek B, et al (1997). Biochemical analysis of the stress protein response in human oesophageal epithelium. Gut, 41, 156-63. https://doi.org/10.1136/gut.41.2.156
  22. Joly AL, Wettstein G, Mignot G, Ghiringhelli F, Garrido C (2010). Dual role of heat shock proteins as regulators of apoptosis and innate immunity. J Innate Immun, 2, 238-47. https://doi.org/10.1159/000296508
  23. Katz D, Rothstein R, Schned A, et al (1998). The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett's esophagus. Am J Gastroenterol, 93, 536-41. https://doi.org/10.1111/j.1572-0241.1998.161_b.x
  24. Klaunig JE, Kamendulis LM (2004). The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol, 44, 239-67. https://doi.org/10.1146/annurev.pharmtox.44.101802.121851
  25. Kubo A, Levin TR, Block G, et al (2008). Dietary antioxidants, fruits and vegetables and the risk of Barrett's esophagus. Am J Gastroenterol, 103, 1614-23. https://doi.org/10.1111/j.1572-0241.2008.01838.x
  26. Kubo A, Corley DA, Jensen CD, Kaur R (2010). Dietary factors and the risks of oesophageal adenocarcinoma and Barrett's oesophagus. Nutr Res Rev, 23, 230-46. https://doi.org/10.1017/S0954422410000132
  27. Lagergren J, Bergstrom R, Lindgren A, Nyren O (1999). Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med, 340, 825-31. https://doi.org/10.1056/NEJM199903183401101
  28. Lee JS, Oh TY, Ahn BO, et al (2001). Involvement of oxidative stress in experimentally induced reflux esophagitis: clue for the chemoprevention of esophageal carcinoma by antioxidants. Mutat Res, 480, 189-200.
  29. Majima T, Tsutsumi M, Nishino H, Tsunoda T, Konishi Y (1998). Inhibitory effects of ${\beta}$-carotene, palm carotene, and green tea polyphenols on pancreatic arcinogenesis initiated by N-nitorsobis(2-oxoprpyl)amine in Syrian golden hamsters. Pancreas, 16, 13-8. https://doi.org/10.1097/00006676-199801000-00003
  30. Mayne ST, Risch HA, Dubrow R, et al (2001). Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev, 10, 1055-62.
  31. Murphy SJ, Anderson LA, Ferguson HR, et al (2010). Dietary antioxidant and mineral intake in humans is associated with reduced risk of esophageal adenocarcinoma but not reflux esophagitis or Barrett's esophagus. J Nutr, 140, 1757-63. https://doi.org/10.3945/jn.110.124362
  32. Nguyen DM, El-Serag HB, Henderson L, et al (2009). Medication usage and the risk of neoplasia in patients with Barrett's esophagus. Clin Gastroenterol Hepatol, 7, 1299-304. https://doi.org/10.1016/j.cgh.2009.06.001
  33. Nkondjock A, Ghadirian P (2004). Intake of specific carotenoids and essential fatty acids and breast cancer risk in Montreal, Canada. Am J Clin Nutr, 79, 857-64.
  34. Oh TY, Lee JS, Ahn BO, et al (2001). Oxidative stress is more important than acid in the pathogenesis of reflux esophagitis in rats. Gut, 49, 364-71. https://doi.org/10.1136/gut.49.3.364
  35. Appel MJ, Woutersen RA (1996) Effects of dietary ${\beta}$-carotene and selenium on initiation and promotion of pancreatic carcinogenesis in azaserine-trested rats. Carcinogenesis, 17, 1411-6. https://doi.org/10.1093/carcin/17.7.1411
  36. Avidan B, Sonnenberg A, Schnell TG, et al (2002). Hiatal hernia size, Barrett's length, and severity of acid reflux are all risk factors for esophageal adenocarcinoma. Am J Gastroenterol, 97, 1930-6. https://doi.org/10.1111/j.1572-0241.2002.05902.x
  37. Bosetti C, Talamini R, Montella M (2004). Retinol, carotenoids and the risk of prostate cancer: a case control study from Italy. Int J Cancer, 112, 689-92. https://doi.org/10.1002/ijc.20486
  38. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr (1991). Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA, 265, 1287-9. https://doi.org/10.1001/jama.1991.03460100089030
  39. Bytzer P, Christensen PB, Damkier P, Vinding K, Seersholm N (1999). Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study. Am J Gastroenterol, 94, 86-91. https://doi.org/10.1111/j.1572-0241.1999.00776.x
  40. Cameron AJ, Lomboy CT, Pera M, Carpenter HA (1995). Adenocarcinoma of the esophagogastric junction and Barrett's esophagus. Gastroenterology, 109, 1541-6. https://doi.org/10.1016/0016-5085(95)90642-8
  41. Chen X, Ding YW, Yang G, et al (2000). Oxidative damage in an esophageal adenocarcinoma model with rats. Carcinogenesis, 21, 257-63. https://doi.org/10.1093/carcin/21.2.257
  42. Clarkson PM, Thompson HS (2000). Antioxidants: what role do they play in physical activity and health? Am J Clin Nutr, 72, 637-46
  43. Clements DM, Oleesky DA, Smith SC, et al (2005). A study to determine plasma antioxidant concentrations in patients with Barrett's esophagus. J Clin Pathol, 58, 490-2. https://doi.org/10.1136/jcp.2004.023721
  44. Cooper BT, Chapman W, Neumann CS, Gearty JC (2006). Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence. Aliment Pharmacol Ther, 23, 727-33. https://doi.org/10.1111/j.1365-2036.2006.02825.x
  45. Correa P, Fontham ET, Bravo JC, et al (2000). Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst, 92, 1881-8. https://doi.org/10.1093/jnci/92.23.1881
  46. Dagli ML, Guerra JL, Sinhorini IL, et al (1998). Beta-carotene reduces the ductal (oval) cell reaction in the liver of Wistar rats submitted to the resistant hepatocyte model of carcinogenesis. Pathology, 30, 259-66. https://doi.org/10.1080/00313029800169416
  47. Devesa SS, Blot WJ, Fraumeni JF Jr (1998). Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer, 83, 2049-53. https://doi.org/10.1002/(SICI)1097-0142(19981115)83:10<2049::AID-CNCR1>3.0.CO;2-2
  48. Garewal HS, Katz RV, Meyskens F, et al (1999). ${\beta}$-carotene produces sustained remissions in patients with oral leukoplakia: results of a multicenter prospective trial. Arch Otolaryngol Head Neck Surg, 125, 1305-10. https://doi.org/10.1001/archotol.125.12.1305

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