The combination of the histone deacetylase inhibitor vorinostat and synthetic triterpenoids reduces tumorigenesis in mouse models of cancer
Menée in vitro et à l'aide de modèles murins de tumeur mammaire, cette étude montre que le vorinostat, un inhibiteur de l'histone désacétylase, peut, combiné à des triterpénoïdes synthétiques, réduire la tumorigenèse
Novel drugs and drug combinations are needed for the chemoprevention 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 cells and in primary mouse peritoneal macrophages. Additionally, SAHA enhanced the ability of synthetic triterpenoids to delay formation of ER-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 four (p < 0.001) and two (p < 0.05) weeks, respectively, compared to the control group in the time required to reach 50% tumor incidence. The combination of a triterpenoid with SAHA was significantly more potent than the individual drugs, 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 M-CSF in primary PyMT tumor cells. In addition SAHA and the synthetic triterpenoids cooperated to suppress secreted levels of the pro-angiogenic factor MMP-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.
http://carcin.oxfordjournals.org/content/early/2012/10/05/carcin.bgs319.abstract