title: The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer.
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.
authors.affiliation: Department of Pharmacology or Medicine,  Dartmouth Medical School, Hanover, NH 03755,  USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Tran
authors.forename: Renee
authors.initials: R
authors.lastname: Risingsong
authors.forename: Darlene B
authors.initials: DB
authors.lastname: Royce
authors.forename: Charlotte R
authors.initials: CR
authors.lastname: Williams
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pioli
authors.forename: Lalji K
authors.initials: LK
authors.lastname: Gediya
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Njar
authors.forename: Karen T
authors.initials: KT
authors.lastname: Liby
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D051379:Mice; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014315:Triterpenes; D000077337:Vorinostat