Abstract 4717: The anti-leukemic efficacy of the histone deacetylase inhibitor phenylbutyrate (PB): Reversal of epigenetic inactivation of WNT signalling pathway by PB

Abstract

Abstract The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel antitumor agent. PB has shown anti-cancer efficacy in clinical trials and in in vitro and in vivo models. The anti-neoplastic effects have been linked to protein farnesylation inhibition and pro-apoptotic action in radiation-induced acute myeloid leukemia (AML) mice and malignant cells. Histone deacetylase (HDAC) is involved in epigenetic control of gene expression. The objective of the current study was to evaluate additional mechanisms i.e., epigenetic activity, of PB. A radiation late effects model was used to study PB epigenetic mechanisms. Mice were sub-lethally irradiated (3.5 Gy, 60Co) to induce leukemia. To test the anti-leukemia efficacy of PB and epigenetic mechanisms, mice were irradiated and then injected with PB (25 ug/kg) or saline daily 3 x weekly (2 weeks) for a total of 6 doses. Secreted Frizzled-related protein genes (SFRPs), which function in the Wnt signaling pathway, have been found to be down-regulated by promoter hypomethylation in human acute myeloid leukemia. Therefore, the methylation status of SFRP genes was analyzed in 20 samples obtained from radiation-induced AML mice. Aberrant CpG island methylation was observed in all four SFRP genes tested by methylation-specific PCR in AML mice. The frequencies of aberrant methylation among the irradiated mice samples were 55% for SFRP1, 30% for SFRP2, 15% for SFRP4, and 32% for SFRP5. In contrast, mice irradiated and treated with PB demonstrated aberration frequencies of 12% for SFRP1, 6% for SFRP2, 0% for SFRP4, and 4% for SFRP5 at 120 days post-radiation. At day 120 post-radiation, 50% of irradiated mice had developed leukemia while only 20% of mice treated with PB showed leukemia. The results demonstrate 1) that PB is an effective countermeasure against radiation-induced leukemia, 2) that epigenetic alterations are associated with radiation-induced leukemia and 3) that PB's efficacy may be associated with prevention of epigenetic disturbances involved in leukemogenesis. These studies do not reflect the opinion of the U.S. Government or the U.S. Department of Defense and are the scientific opinions of the author. This work was supported by DTRA Grant G1B2BJ, G2B2EM, AFRRI/USUHS RAB5AH, EU05-0089, and EU07-102. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4717. doi:1538-7445.AM2012-4717