Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma.
OBJECTIVE
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.


METHODS
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.
Department of Cancer Biology, Sarcoma Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Gonzalo
G
Lopez
Juehui
J
Liu
Wenhong
W
Ren
Wei
W
Wei
Suizhao
S
Wang
Guy
G
Lahat
Quan-Sheng
QS
Zhu
William G
WG
Bornmann
David J
DJ
McConkey
Raphael E
RE
Pollock
Dina C
DC
Lev
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase / Q000187:drug effects; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D004317:Doxorubicin; D008156:Luciferases; D005092:Exonucleases; C113574:Rad1 protein, human; D006655:Histone Deacetylases; C512352:abexinostat; D002945:Cisplatin