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.