title: Renin-angiotensin system inhibitors suppress azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice.
abstract: Obesity-related metabolic abnormalities, including chronic inflammation and oxidative stress, increase the risk of colorectal cancer. Dysregulation of the renin-angiotensin system (RAS) also plays a critical role in obesity-related metabolic disorders and in several types of carcinogenesis. In the present study, we examined the effects of an angiotensin-converting enzyme (ACE) inhibitor and angiotensin-II type 1 receptor blocker (ARB), both of which inhibit the RAS, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were given 4 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then, they received drinking water containing captopril (ACE inhibitor, 5mg/kg/day) or telmisartan (ARB, 5mg/kg/day) for 7 weeks. At sacrifice, administration of either captopril or telmisartan significantly reduced the total number of colonic premalignant lesions, i.e., aberrant crypt foci and β-catenin accumulated crypts, compared to that observed in the control group. The expression levels of TNF-α mRNA in the colonic mucosa of AOM-treated db/db mice were decreased by captopril and telmisartan. Captopril lowered the expression levels of TNF-α, IL-1β, IL-6, and PAI-1 mRNAs, while telmisartan lowered the expression levels of COX-2, IL-1β, IL-6, and PAI-1 mRNAs in the white adipose tissues of these mice. In addition, these agents significantly reduced the levels of urinary 8-OHdG, a surrogate marker of oxidative damage to DNA, in the experimental mice. These findings suggested that both ACE inhibitor and ARB suppress chemically-induced colon carcinogenesis by attenuating chronic inflammation and reducing oxidative stress in obese mice. Therefore, targeting dysregulation of the RAS might be an effective strategy for chemoprevention of colorectal carcinogenesis in obese individuals.
authors.affiliation: Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kochi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D057911:Angiotensin Receptor Antagonists / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D002216:Captopril / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011230:Precancerous Conditions / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000077333:Telmisartan; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D053583:Interleukin-1beta; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002216:Captopril; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D003849:Deoxyguanosine; D001397:Azoxymethane; D000077333:Telmisartan