Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42
| Autor: | Samuel K. Kulp, Xiaokui Mo, Li Yun Ding, Sally E. Henderson, Po Hsien Huang, Ching-Shih Chen, Tanios Bekaii-Saab |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Cancer Research medicine.medical_specialty Original article medicine.drug_class Cell Survival Mice Transgenic Kaplan-Meier Estimate Biology Deoxycytidine 03 medical and health sciences Histone H3 0302 clinical medicine In vivo Internal medicine Pancreatic cancer Cell Line Tumor medicine Animals Humans Muscle Skeletal Wasting Syndrome Histone deacetylase inhibitor Cell Cycle Drug Synergism medicine.disease Phenylbutyrates Xenograft Model Antitumor Assays Gemcitabine 3. Good health Tumor Burden Histone Deacetylase Inhibitors Pancreatic Neoplasms Disease Models Animal 030104 developmental biology Endocrinology Apoptosis 030220 oncology & carcinogenesis Cancer research Female Histone deacetylase medicine.drug |
| Zdroj: | Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | 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 KP fl/fl C (LSL-Kras G12D ;Trp53 flox/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 KP fl/fl C 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 KP fl/fl C 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. |
| Databáze: | OpenAIRE |
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