The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer.

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TitleThe combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer.
Publication TypeJournal Article
Year of Publication2013
AuthorsTran, K, Risingsong, R, Royce, DB, Williams, CR, Sporn, MB, Pioli, PA, Gediya, LK, Njar, VCO, Liby, KT
JournalCarcinogenesis
Volume34
Issue1
Pagination199-210
Date Published2013 Jan
ISSN1460-2180
KeywordsAnimals, Cell Proliferation, Disease Models, Animal, Drug Therapy, Combination, Enzyme-Linked Immunosorbent Assay, Histone Deacetylase Inhibitors, Hydroxamic Acids, Mammary Neoplasms, Experimental, Mice, Triterpenes
Abstract

Novel drugs and drug combinations are needed for the chemoprevention and treatment of cancer. We show that the histone deacetylase inhibitor vorinostat [suberoylanilide hydroxamic acid (SAHA)] and the methyl ester or ethyl amide derivatives of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me and CDDO-Ea, respectively) cooperated to inhibit the de novo synthesis of nitric oxide in RAW 264.7 macrophage-like cells and in primary mouse peritoneal macrophages. Additionally, SAHA enhanced the ability of synthetic triterpenoids to delay formation of estrogen receptor-negative mammary tumors in MMTV-polyoma middle T (PyMT) mice. CDDO-Me (50 mg/kg diet) and SAHA (250 mg/kg diet) each significantly delayed the initial development of tumors by 4 (P < 0.001) and 2 (P < 0.05) weeks, respectively, compared with the control group in the time required to reach 50% tumor incidence. CDDO-Ea (400 mg/kg diet), as a single agent, did not delay tumor development. The combination of either triterpenoid with SAHA was significantly more potent than the individual drugs for delaying tumor development, with a 7 week (P < 0.001) delay before 50% tumor incidence was reached. SAHA, alone and in combination with CDDO-Me, also significantly (P < 0.05) inhibited the infiltration of tumor-associated macrophages into the mammary glands of PyMT mice and levels of the chemokine macrophage colony-stimulating factor in primary PyMT tumor cells. In addition, SAHA and the synthetic triterpenoids cooperated to suppress secreted levels of the pro-angiogenic factor matrix metalloproteinase-9. Similar results were observed in mouse models of pancreatic and lung cancer. At concentrations that were anti-inflammatory, SAHA had no effect on histone acetylation. These studies suggest that both SAHA and triterpenoids effectively delay tumorigenesis, thereby demonstrating a promising, novel drug combination for chemoprevention.

DOI10.1093/carcin/bgs319
Alternate JournalCarcinogenesis
PubMed ID23042302
PubMed Central IDPMC3534195
Grant ListP30 CA023108 / CA / NCI NIH HHS / United States
R01 CA078814 / CA / NCI NIH HHS / United States
R01 CA129379 / CA / NCI NIH HHS / United States
R01 CA129379 / CA / NCI NIH HHS / United States
R01 CA78814 / CA / NCI NIH HHS / United States