Abstract
Abstract A36 Phenyl fatty acids like phenylacetate (PA) and phenylbutyrate (PB) have shown anti-cancer efficacy in clinical trials and in both in vitro and in vivo models. The mechanism of action of these agents is not fully understood however. In vitro studies have demonstrated that PB treatment induces apoptosis and growth rate effects in a time- and dose- dependent manner in the p21ras-expressing hematopoietic cells, Ras-DC and the human chronic myeloid leukemia blast crisis cells, (CML-BC) K562 cells. Both leukemia cell types are characterized by deregulated activity of the oncoprotein tyrosine kinase known as Bcr-Abl frequently observed in radiation-associated leukemias. Molecular studies are underway to characterize the effect of PB on Bcr-Abl expression in these leukemia cells since Bcr-Abl is a well known client protein for Hsp90. Furthermore, gene expression profile analysis of PB treatment of leukemia cells and human osteoblast cells (HOS) demonstrated that PB down-regulated Hsp90 suggesting that PB may affect molecular chaperoning. The anti-leukemic activity of PB was investigated using the cobalt radiation-induced neoplastic transformation model, HOS cells. HOS cells were exposed to a total of 2 Gy (60Co, 50 cGy/exposure) and transformed foci were formed within 35 days. Cellular incubation with PB either pre- or post-radiation significantly suppressed the radiation-induced transformation. Molecular studies also showed that PB induced acetylation of histones H3 and H4 and apoptosis in this cell model. A radiation leukemia rodent model is currently being employed to evaluate PB’s anti-leukemia efficacy. Although preliminary, these data suggest that PB involvement in both Hsp90 molecular chaperoning and inhibition of histone deacetylase is mechanistically related to its anti-leukemia efficacy. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A36.
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