Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia

Yu Chou Tseng, Samuel K. Kulp, I. Lu Lai, En Chi Hsu, Wei A. He, David E. Frankhouser, Pearlly S. Yan, Xiaokui Mo, Mark Bloomston, Gregory B. Lesinski, Guido Marcucci, Denis C. Guttridge, Tanios Bekaii-Saab, Ching Shih Chen

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)djv274
JournalJournal of the National Cancer Institute
Volume107
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Cachexia
Histone Deacetylase Inhibitors
Lewis Lung Carcinoma
Muscles
Neoplasms
MEF2 Transcription Factors
Cytokines
Therapeutics
Leukemia Inhibitory Factor
Ubiquitin-Protein Ligases
Metabolomics
Survival
Metabolome
Muscle Strength
Glycolysis
Lipase
Glycogen
Transcriptome
Proteolysis
Adipose Tissue

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia. / Tseng, Yu Chou; Kulp, Samuel K.; Lai, I. Lu; Hsu, En Chi; He, Wei A.; Frankhouser, David E.; Yan, Pearlly S.; Mo, Xiaokui; Bloomston, Mark; Lesinski, Gregory B.; Marcucci, Guido; Guttridge, Denis C.; Bekaii-Saab, Tanios; Chen, Ching Shih.

In: Journal of the National Cancer Institute, Vol. 107, No. 12, 01.12.2015, p. djv274.

Research output: Contribution to journalArticle

Tseng, YC, Kulp, SK, Lai, IL, Hsu, EC, He, WA, Frankhouser, DE, Yan, PS, Mo, X, Bloomston, M, Lesinski, GB, Marcucci, G, Guttridge, DC, Bekaii-Saab, T & Chen, CS 2015, 'Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia', Journal of the National Cancer Institute, vol. 107, no. 12, pp. djv274. https://doi.org/10.1093/jnci/djv274
Tseng, Yu Chou ; Kulp, Samuel K. ; Lai, I. Lu ; Hsu, En Chi ; He, Wei A. ; Frankhouser, David E. ; Yan, Pearlly S. ; Mo, Xiaokui ; Bloomston, Mark ; Lesinski, Gregory B. ; Marcucci, Guido ; Guttridge, Denis C. ; Bekaii-Saab, Tanios ; Chen, Ching Shih. / Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the Treatment of Cancer-Induced Cachexia. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 12. pp. djv274.
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AU - Hsu, En Chi

AU - He, Wei A.

AU - Frankhouser, David E.

AU - Yan, Pearlly S.

AU - Mo, Xiaokui

AU - Bloomston, Mark

AU - Lesinski, Gregory B.

AU - Marcucci, Guido

AU - Guttridge, Denis C.

AU - Bekaii-Saab, Tanios

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N2 - 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.

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