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
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).
J Natl Cancer Inst. 2015 Oct 12;107(12):djv274. doi: 10.1093/jnci/djv274. Print 2015 Dec.
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.
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.
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.
These findings support further investigation of AR-42 as part of a comprehensive therapeutic strategy for cancer cachexia.
癌症恶病质是一种使人衰弱的病症，会影响患者的发病率、死亡率和生活质量，且目前缺乏有效的治疗方法。在癌症恶病质的小鼠模型中研究了新型组蛋白去乙酰化酶（HDAC）抑制剂AR - 42的抗恶病质活性。
在C - 26结肠腺癌和刘易斯肺癌（LLC）模型中评估AR - 42对恶病质经典特征的影响。确定与已批准的HDAC抑制剂（伏立诺他、罗米地辛）相比对生存的影响。评估肌肉代谢组和转录组（通过RNA测序）以及血清细胞因子谱。使用混合效应模型、方差分析或对数秩检验分析数据。所有统计检验均为双侧检验。
在C - 26模型中，口服AR - 42可维持体重（AR - 42治疗组为23.9±2.6克；载体治疗组为20.8±1.3克；P = 0.005），延长生存期（P < 0.001），防止肌肉和脂肪组织质量、肌纤维大小和肌肉力量的降低，并将E3连接酶MuRF1和Atrogin - 1的肌内mRNA表达恢复至基础水平（n = 8）。在LLC模型中证实的这种抗恶病质作用，在使用伏立诺他和罗米地辛治疗后未观察到。AR - 42抑制肿瘤诱导的炎症细胞因子产生变化以及多种恶病质驱动因子（IL - 6、IL - 6Rα、白血病抑制因子、Foxo1、Atrogin - 1、MuRF1、脂肪甘油三酯脂肪酶、解偶联蛋白3和肌细胞增强因子2c）。代谢组学分析揭示了恶病质相关的肌肉糖酵解、糖原合成和蛋白质降解变化，AR - 42将其恢复到无肿瘤小鼠的特征状态。
这些发现支持进一步研究将AR - 42作为癌症恶病质综合治疗策略的一部分。
