title: Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia.
abstract: BACKGROUND
  Cancer cachexia is a debilitating condition that impacts patient morbidity, mortality, and quality of life and for which effective therapies are lacking. The anticachectic activity of the novel HDAC inhibitor AR-42 was investigated in murine models of cancer cachexia.
  
  
  METHODS
  The effects of AR-42 on classic features of cachexia were evaluated in the C-26 colon adenocarcinoma and Lewis lung carcinoma (LLC) models. Effects on survival in comparison with approved HDAC inhibitors (vorinostat, romidepsin) were determined. The muscle metabolome and transcriptome (by RNA-seq), as well as serum cytokine profile, were evaluated. Data were analyzed using mixed effects models, analysis of variance, or log-rank tests. All statistical tests were two-sided.
  
  
  RESULTS
  In the C-26 model, orally administered AR-42 preserved body weight (23.9±2.6 grams, AR-42-treated; 20.8±1.3 grams, vehicle-treated; P = .005), prolonged survival (P < .001), prevented reductions in muscle and adipose tissue mass, muscle fiber size, and muscle strength and restored intramuscular mRNA expression of the E3 ligases MuRF1 and Atrogin-1 to basal levels (n = 8). This anticachectic effect, confirmed in the LLC model, was not observed after treatment with vorinostat and romidepsin. AR-42 suppressed tumor-induced changes in inflammatory cytokine production and multiple procachexia drivers (IL-6, IL-6Rα, leukemia inhibitory factor, Foxo1, Atrogin-1, MuRF1, adipose triglyceride lipase, uncoupling protein 3, and myocyte enhancer factor 2c). Metabolomic analysis revealed cachexia-associated changes in glycolysis, glycogen synthesis, and protein degradation in muscle, which were restored by AR-42 to a state characteristic of tumor-free mice.
  
  
  CONCLUSIONS
  These findings support further investigation of AR-42 as part of a comprehensive therapeutic strategy for cancer cachexia.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Yu-Chou
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: I-Lu
authors.initials: IL
authors.lastname: Lai
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: En-Chi
authors.initials: EC
authors.lastname: Hsu
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Wei A
authors.initials: WA
authors.lastname: He
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: David E
authors.initials: DE
authors.lastname: Frankhouser
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Pearlly S
authors.initials: PS
authors.lastname: Yan
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC).
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC). Tanios.Saab@osumc.edu chen.844@osu.edu.
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (YCT, SKK, ILL, ECH, CSC), Department of Molecular Virology, Immunology, and Medical Genetics (WAH, DCG), Department of Surgery (MB), Department of Internal Medicine (GBL, GM, TBS), and Center for Biostatistics (XM), College of Medicine, and Genomics Shared Resource (DEF, PSY), The Comprehensive Cancer Center, The Ohio State University, Columbus, OH; Institute of Basic Medical Sciences, National Cheng-Kung University, Tainan, Taiwan (CSC); Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan (CSC). Tanios.Saab@osumc.edu chen.844@osu.edu.
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000150:complications; D000273:Adipose Tissue / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D018827:Carcinoma, Lewis Lung / Q000150:complications; D003110:Colonic Neoplasms / Q000150:complications; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000150:complications*; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D016019:Survival Analysis; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000071247:Uncoupling Protein 3; D015431:Weight Loss / Q000187:drug effects*; D000217:Acyltransferases
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D007473:Ion Channels; D053605:Leukemia Inhibitory Factor; D008049:Lipase; D064326:MEF2 Transcription Factors; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D010654:Phenylbutyrates; D019947:Receptors, Interleukin-6; D044843:SKP Cullin F-Box Protein Ligases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D000071247:Uncoupling Protein 3; C467200:Foxo1 protein, mouse; C507838:Lif protein, mouse; C529674:OSU-HDAC42 compound; C000604393:Ucp3 protein, mouse; C577686:interleukin-6, mouse; C486691:Fbxo32 protein, mouse; C499084:Trim63 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases