Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42.

Abstract

PURPOSE:

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC.

EXPERIMENTAL DESIGN:

The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). AsPC-1 subcutaneous xenograft and transgenic KPfl/flC (LSL-KrasG12D;Trp53flox/flox;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting.

RESULTS:

Growth suppression in AR-42-treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, AR-42 as a single agent preserved muscle size and increased grip strength in KPfl/flC mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone.

CONCLUSIONS:

These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer.

• Authors: Sally E Henderson, Li-Yun Ding, Xiaokui Mo, Tanios Bekaii-Saab, Samuel K Kulp, Ching-Shih Chen, Po-Hsien Huang
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 18 Issue 12 Pg. 765-774 (Dec 2016) ISSN: 1476-5586 [Electronic] United States
• PMID: 27889645 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• OSU-HDAC42 compound
• Phenylbutyrates
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Drug Synergism
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Kaplan-Meier Estimate
• Mice, Transgenic
• Muscle, Skeletal (drug effects, pathology)
• Pancreatic Neoplasms (complications, drug therapy, mortality, pathology)
• Phenylbutyrates (pharmacology)
• Tumor Burden (drug effects)
• Wasting Syndrome (drug therapy, etiology, pathology)
• Xenograft Model Antitumor Assays
• Gemcitabine