title: Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, 1925 Coffey Rd., Columbus, OH, 43210, USA. Electronic address: Henderson.451@osu.edu.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Henderson
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan 701, Taiwan. Electronic address: pinpingding@gmail.com.
authors.forename: Li-Yun
authors.initials: LY
authors.lastname: Ding
authors.affiliation: Center for Biostatistics, The Ohio State University, 1800 Cannon Drive, Columbus, OH, 43210, USA. Electronic address: Xiaokui.Mo@osumc.edu.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ, 85054, USA. Electronic address: Bekaii-Saab.Tanios@mayo.edu.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, 500 West 12th Ave, Columbus, OH, 43210, USA. Electronic address: kulp.1@osu.edu.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, 500 West 12th Ave, Columbus, OH, 43210, USA; Institute of Biological Chemistry, Academia Sinica, 128, Academia Road Sec. 2, Taipei City, 115, Taiwan. Electronic address: chen.844@osu.edu.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, 1 University Rd., Tainan 701, Taiwan. Electronic address: phhuang@mail.ncku.edu.tw.
authors.forename: Po-Hsien
authors.initials: PH
authors.lastname: Huang
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D019282:Wasting Syndrome / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D003841:Deoxycytidine; D000093542:Gemcitabine