title: Pitavastatin inhibits azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db obese mice.
abstract: Obesity and related metabolic abnormalities are risk factors for colorectal cancer. A state of chronic inflammation and adipocytokine imbalance may play a role in colorectal carcinogenesis. Statins, which are commonly used for the treatment of hyperlipidemia, are known to possess anti-inflammatory effects. Statins also exert chemopreventive properties against various cancers. The present study examined the effects of pitavastatin, a recently developed lipophilic statin, on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administrated weekly subcutaneous injections of AOM (15 mg/kg body weight) for 4 weeks and then were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 8 weeks. Feeding with either dose of pitavastatin significantly reduced the number of colonic premalignant lesions, beta-catenin accumulated crypts, by inhibiting proliferation and the surrounding inflammation. Pitavastatin increased the serum levels of adiponectin while conversely decreasing the serum levels of total cholesterol, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-18, and leptin. Pitavastatin also caused a significant increase in the expression of phosphorylated form of the AMP-activated kinase (AMPK) protein on the colonic mucosa of AOM-treated mice. In addition, the expression levels of TNF-alpha, IL-6, IL-18, and COX-2 mRNAs on the colonic mucosa of AOM-treated mice were decreased by treatment with this agent. These findings suggest that pitavastatin attenuates chronic inflammation and improves the imbalance of adipocytokines, both of which are caused by the presence of excess adipose tissues, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model. Therefore, some types of statins, including pitavastatin, may be a useful chemoprevention modality for colon cancer in obese individuals.
authors.affiliation: Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.forename: Yohei
authors.initials: Y
authors.lastname: Shirakami
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sakai
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hata
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hirose
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: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000188:drug therapy; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011804:Quinolines / Q000627:therapeutic use*
chemical_list: D002273:Carcinogens; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; C108475:pitavastatin; D001397:Azoxymethane
references.citation: Int J Oncol. 2009 Feb;34(2):339-44
references.pmid: 19148467
references.citation: Gut. 2008 Nov;57(11):1531-8
references.pmid: 18676419
references.citation: JAMA. 2008 Oct 1;300(13):1523-31
references.pmid: 18827209
references.citation: Clin Chim Acta. 2007 May 1;380(1-2):24-30
references.pmid: 17343838
references.citation: Carcinogenesis. 2008 May;29(5):1057-63
references.pmid: 18375960
references.citation: Int J Cancer. 2007 Jan 15;120(2):252-8
references.pmid: 17066427
references.citation: Cancer Res. 2007 Jul 15;67(14):6745-52
references.pmid: 17638885
references.citation: J Natl Cancer Inst. 2005 Nov 16;97(22):1688-94
references.pmid: 16288122
references.citation: Clin Cancer Res. 2009 May 1;15(9):3068-75
references.pmid: 19366832
references.citation: Obes Rev. 2007 Sep;8(5):395-408
references.pmid: 17716297
references.citation: Nat Rev Cancer. 2001 Oct;1(1):11-21
references.pmid: 11900248
references.citation: Gut. 2006 Feb;55(2):285-91
references.pmid: 16239255
references.citation: Carcinogenesis. 2004 May;25(5):821-5
references.pmid: 14729596
references.citation: Int J Cancer. 2008 Aug 15;123(4):951-7
references.pmid: 18521906
references.citation: Carcinogenesis. 2003 Jun;24(6):1015-9
references.pmid: 12807742
references.citation: Science. 1996 Feb 2;271(5249):665-8
references.pmid: 8571133
references.citation: Circulation. 2001 Jan 23;103(3):357-62
references.pmid: 11157685
references.citation: Int J Cancer. 2004 Mar;109(1):149-52
references.pmid: 14735482
references.citation: JAMA. 1997 Jul 23-30;278(4):313-21
references.pmid: 9228438
references.citation: N Engl J Med. 2005 May 26;352(21):2184-92
references.pmid: 15917383
references.citation: Nat Rev Cancer. 2005 Dec;5(12):930-42
references.pmid: 16341084
references.citation: Cancer Prev Res (Phila). 2008 Oct;1(5):369-75
references.pmid: 19138981
references.citation: Cancer Res. 2001 Mar 1;61(5):1874-8
references.pmid: 11280741
references.citation: Eur J Cancer. 2006 Apr;42(6):745-50
references.pmid: 16517151
references.citation: Endocr Rev. 2005 May;26(3):439-51
references.pmid: 15897298
references.citation: Carcinogenesis. 2003 Jan;24(1):107-11
references.pmid: 12538355
references.citation: Lancet. 2005 Oct 8;366(9493):1267-78
references.pmid: 16214597
references.citation: Expert Opin Pharmacother. 2007 Oct;8(14):2315-27
references.pmid: 17927486
references.citation: Toxicol Lett. 2000 Mar 15;112-113:395-402
references.pmid: 10720758
references.citation: Am J Physiol Endocrinol Metab. 2001 May;280(5):E745-51
references.pmid: 11287357
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 May;282(5):R1429-35
references.pmid: 11959686
references.citation: Cancer Prev Res (Phila). 2009 Apr;2(4):301-9
references.pmid: 19336731
references.citation: Mutat Res. 2004 May;566(3):191-208
references.pmid: 15082237
references.citation: Circulation. 2004 Jun 1;109(21 Suppl 1):II18-26
references.pmid: 15173059
references.citation: Jpn J Cancer Res. 2002 Mar;93(3):242-6
references.pmid: 11927004
references.citation: Atherosclerosis. 2009 Jun;204(2):483-90
references.pmid: 18977478
references.citation: Science. 1993 Jan 1;259(5091):87-91
references.pmid: 7678183
references.citation: Am J Pathol. 1993 Jun;142(6):1858-65
references.pmid: 8506954
references.citation: Cancer Res. 2007 May 1;67(9):4079-87
references.pmid: 17483318
references.citation: J Nutr Biochem. 2006 Mar;17(3):145-56
references.pmid: 16426829
references.citation: Int J Cancer. 2007 Nov 15;121(10):2331-9
references.pmid: 17657716
references.citation: Cancer Prev Res (Phila). 2008 Sep;1(4):298-304
references.pmid: 19138973
references.citation: Chem Biol Interact. 2005 Jun 30;155(1-2):1-9
references.pmid: 15904905
references.citation: Horm Metab Res. 2007 Apr;39(4):250-5
references.pmid: 17447161
references.citation: Mol Med Rep. 2008 May-Jun;1(3):355-61
references.pmid: 21479417
references.citation: Cancer Lett. 2007 Mar 8;247(1):115-21
references.pmid: 16797120
references.citation: J Cell Biochem. 2009 Apr 15;106(6):975-83
references.pmid: 19224538
references.citation: Biomed Pharmacother. 2004 Dec;58(10):614-8
references.pmid: 15589072
references.citation: Diabetologia. 2003 May;46(5):595-607
references.pmid: 12764580
references.citation: Cancer Sci. 2004 Apr;95(4):316-20
references.pmid: 15072589
references.citation: Gastroenterology. 2007 May;132(6):2208-25
references.pmid: 17498513
references.citation: Obes Surg. 2003 Aug;13(4):615-21
references.pmid: 12935365