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Research ArticleDrug Discovery and Translational Medicine

Chemopreventive Effects of an HDAC2-Selective Inhibitor on Rat Colon Carcinogenesis and APCmin/+ Mouse Intestinal Tumorigenesis

Durgadevi Ravillah, Altaf Mohammed, Li Qian, Misty Brewer, Yuting Zhang, Laura Biddick, Vernon E. Steele and Chinthalapally V. Rao
Journal of Pharmacology and Experimental Therapeutics January 2014, 348 (1) 59-68; DOI: https://doi.org/10.1124/jpet.113.208645
Durgadevi Ravillah
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.)
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Altaf Mohammed
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.)
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Li Qian
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.)
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Misty Brewer
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.)
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Yuting Zhang
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.)
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Laura Biddick
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.)
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Vernon E. Steele
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.)
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Chinthalapally V. Rao
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.)
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Abstract

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-APCmin/+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 APCmin/+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.

Footnotes

    • Received August 19, 2013.
    • Accepted November 7, 2013.
  • dx.doi.org/10.1124/jpet.113.208645.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • This research was supported by the National Institutes of Health National Cancer Institute [Grant N01-CN53300]; and the Kerley-Cade Endowment.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 348 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 1
1 Jan 2014
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Research ArticleDrug Discovery and Translational Medicine

Chemoprevention of Colon Carcinogenesis by an HDAC2-Selective Inhibitor

Durgadevi Ravillah, Altaf Mohammed, Li Qian, Misty Brewer, Yuting Zhang, Laura Biddick, Vernon E. Steele and Chinthalapally V. Rao
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 59-68; DOI: https://doi.org/10.1124/jpet.113.208645

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Research ArticleDrug Discovery and Translational Medicine

Chemoprevention of Colon Carcinogenesis by an HDAC2-Selective Inhibitor

Durgadevi Ravillah, Altaf Mohammed, Li Qian, Misty Brewer, Yuting Zhang, Laura Biddick, Vernon E. Steele and Chinthalapally V. Rao
Journal of Pharmacology and Experimental Therapeutics January 1, 2014, 348 (1) 59-68; DOI: https://doi.org/10.1124/jpet.113.208645
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