Chemopreventive effects of an HDAC2-selective inhibitor on rat colon carcinogenesis and APCmin/+ mouse intestinal tumorigenesis.
Epigenetic modulators, particularly histone deacetylases (HDACs), are valid targets for cancer prevention and therapy. Recent studies report that HDAC2 overexpression is associated with colon tumor progression and is a potential target for colon cancer prevention. This study tested chemopreventive and dose-response effects of Ohio State University HDAC42 (OSU-HDAC42), a selective HDAC2 inhibitor, using a rat colon carcinogenesis model to assess aberrant crypt foci inhibition and a familial adenomatous polyposis model to assess intestinal tumor inhibition. Colonic aberrant crypt foci were induced by azoxymethane (AOM) (15 mg/kg body weight, once-weekly subcutaneous injections at 8 and 9 weeks age). One week after AOM treatment, groups of rats were fed an AIN-76A diet containing 0, 75, 150, and 300 ppm OSU-HDAC42 for 8 weeks, and colonic aberrant crypt foci were evaluated. To assess the inhibitory effect of OSU-HDAC42 on small-intestinal polyps and colon tumor growth, 6-week-old male C57Bl/6J-APC(min/+)mice were fed an AIN-76A diet containing 150 ppm OSU-HADC42 or 300 ppm pan-HDAC inhibitor suberoylanilide hydroxyamic acid (SAHA) for 80 days. Our results demonstrate that dietary OSU-HDAC42 produced dose-dependent inhibition of AOM-induced colonic aberrant crypt foci formation (13-50%; P < 0.01 to < 0.0001) and reduced multiple crypts with ≥ 4 crypts per focus (25-57%; P < 0.01 to < 0.0001) in F344 rats. Our findings show that 150 ppm OSU-HDAC42 significantly inhibited small-intestinal polyps (>46%; P < 0.001), with polyp size measuring >1 mm (P < 0.001), and colon tumors (>26%) in APC(min/+)mice, whereas 300 ppm SAHA showed nonsignificant inhibition. Mice fed 150 ppm OSU-HDAC42 had significantly decreased HDAC2, proliferating cell nuclear antigen, B cell lymphoma 2, cyclin-dependent kinase 2, and cell division cycle homolog 25C expression levels and increased p53 expression levels. These observations demonstrate the chemopreventive efficacy of OSU-HDAC42 against chemically induced and polyposis models of intestinal tumorigenesis.
Hematology-Oncology Section, Department of Medicine, Center for Cancer Prevention and Drug Development, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (D.R., A.M., L.Q., M.B., Y.Z., L.B., C.V.R.); and Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Institutes of Health National Cancer Institute, Bethesda, Maryland (V.E.S.).
Durgadevi
D
Ravillah
Altaf
A
Mohammed
Li
L
Qian
Misty
M
Brewer
Yuting
Y
Zhang
Laura
L
Biddick
Vernon E
VE
Steele
Chinthalapally V
CV
Rao
D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D045325:HCT116 Cells; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007414:Intestinal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2