PURPOSE: Histone deactylase inhibitors (HDACi) are a promising new class of 
anticancer therapeutics; however, little is known about HDACi activity in soft 
tissue sarcoma (STS), a heterogeneous cohort of mesenchymal origin malignancies. 
Consequently, we investigated the novel HDACi PCI-24781, alone/in combination 
with conventional chemotherapy, to determine its potential anti-STS-related 
effects and the underlying mechanisms involved.
EXPERIMENTAL DESIGN: Immunoblotting was used to evaluate the effects of 
PCI-24781 on histone and nonhistone protein acetylation and expression of 
potential downstream targets. Cell culture-based assays were utilized to assess 
the effects of PCI-24781 on STS cell growth, cell cycle progression, apoptosis, 
and chemosensitivity. Quantitative reverse transcription-PCR, chromatin 
immunoprecipitation, and reporter assays helped elucidate molecular mechanisms 
resulting in PCI-24781-induced Rad51 repression. The effect of PCI-24781, alone 
or with chemotherapy, on tumor and metastatic growth was tested in vivo using 
human STS xenograft models.
RESULTS: PCI-24781 exhibited significant anti-STS proliferative activity in 
vitro, inducing S phase depletion, G(2)/M cell cycle arrest, and increasing 
apoptosis. Superior effects were seen when combined with chemotherapy. A 
PCI-24781-induced reduction in Rad51, a major mediator of DNA double-strand 
break homologous recombination repair, was shown and may be a mechanism 
underlying PCI-24781 chemosensitization. We showed that PCI-24781 
transcriptionally represses Rad51 through an E2F binding-site on the Rad51 
proximal promoter. Although single-agent PCI-24781 had modest effects on STS 
growth and metastasis, marked inhibition was observed when combined with 
chemotherapy.
CONCLUSIONS: In light of these findings, this novel molecular-based combination 
may be applicable to multiple STS histologic subtypes, and potentially merits 
rigorous evaluation in human STS clinical trials.