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

• Published in: Carcinogenesis (New York) 2013-01, Vol.34 (1), p.199-210
• Main Authors: Tran, Kim, Risingsong, Renee, Royce, Darlene B, Williams, Charlotte R, Sporn, Michael B, Pioli, Patricia A, Gediya, Lalji K, Njar, Vincent C, Liby, Karen T
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation; Disease Models, Animal; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - administration & dosage; Hydroxamic Acids - pharmacology; Mammary Neoplasms, Experimental - prevention & control; Mice; Original Manuscript; Triterpenes - administration & dosage; Triterpenes - pharmacology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgs319

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.