Abstract | INTRODUCTION: HDAC isoform-specific inhibitors may improve the therapeutic window while limiting toxicities. Developing inhibitors against class I isoforms poses difficulties as they share high homology among their catalytic sites; however, HDAC8 is structurally unique compared to other class I isoforms. HDAC8 inhibitors are novel compounds and have affinity for class I HDAC isoforms demonstrating anti- cancer effects; little is known about their activity in malignant peripheral nerve sheath tumors ( MPNST). Recently, we demonstrated anti- MPNST efficacy of HDAC8i in human and murine-derived MPNST pre-clinical models; we now seek to consider the potential therapeutic inhibition of HDAC8 in MPNST. METHODS: Four Human MPNST cell lines, a murine-derived MPNST cell line, and two HDAC8 inhibitors ( PCI-34051, PCI-48012; Pharmacyclics, Inc. Sunnyvale, CA) were studied. Proliferation was determined using MTS and clonogenic assays. Effects on cell cycle were determined via PI FACS analysis; effects on apoptosis were determined using Annexin V-PI FACS analysis and cleaved caspase 3 expression. In vivo growth effects of HDAC8i were evaluated using MPNST xenograft models. 2D gel electrophoresis and mass spectrometry were used to identify potential HDAC8 deacetylation substrates. RESULTS: HDAC8i induced cell growth inhibition and marked S-phase cell cycle arrest in human and murine-derived MPNST cells. Relative to control, HDAC8i induced apoptosis in both human and murine-derived MPNST cells. HDAC8i exhibited significant effects on MPNST xenograft growth (p=0.001) and tumor weight (p=0.02). Four potential HDAC8 substrate targets were identified using a proteomic approach: PARK7, HMGB1, PGAM1, PRDX6. CONCLUSIONS:
MPNST is an aggressive sarcoma that is notoriously therapy-resistant, hence the urgent need for improved anti- MPNST therapies. HDAC8 inhibition may be useful for MPNST by improving efficacy while limiting toxicities as compared to pan-HDACis.
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Authors | Gonzalo Lopez, Kate Lynn J Bill, Hemant Kumar Bid, Danielle Braggio, Dylan Constantino, Bethany Prudner, Abeba Zewdu, Kara Batte, Dina Lev, Raphael E Pollock |
Journal | PloS one
(PLoS One)
Vol. 10
Issue 7
Pg. e0133302
( 2015)
ISSN: 1932-6203 [Electronic] United States |
PMID | 26200462
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Histone Deacetylase Inhibitors
- Neoplasm Proteins
- Repressor Proteins
- HDAC8 protein, human
- HDAC8 protein, mouse
- Histone Deacetylases
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Topics |
- Animals
- Apoptosis
- Cell Line, Tumor
- Female
- Histone Deacetylase Inhibitors
(pharmacology)
- Histone Deacetylases
(biosynthesis, genetics)
- Humans
- Mice
- Mice, SCID
- Neoplasm Proteins
(antagonists & inhibitors, biosynthesis, genetics)
- Neurilemmoma
(drug therapy, enzymology, genetics, pathology)
- Repressor Proteins
(antagonists & inhibitors, biosynthesis, genetics)
- Xenograft Model Antitumor Assays
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