Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Eur J Pharmacol. 2014 Nov 15;743:1-10. doi: 10.1016/j.ejphar.2014.09.025. Epub 2014 Sep 23.
Cancer cachexia is a multifactorial, critical illness syndrome characterized by an ongoing loss of skeletal muscle and adipose tissue. The reductions in body weight and skeletal muscle mass are important prognostic indicators for cancer patients that are refractory to current therapies. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is produced in the stomach, stimulates food intake and growth hormone secretion, suppresses inflammation, and prevents muscle catabolism. We investigated the pharmacological potential of ghrelin in the treatment of cancer cachexia by using urethane-treated, bronchioalveolar epithelium-specific Pten-deficient mice that developed lung adenocarcinomas. Ghrelin or phosphate-buffered saline was given to mice daily for four weeks beginning at five months after urethane injection, which corresponded to the time point of lung adenocarcinoma formation. Ghrelin inhibited the inductions of C-reactive protein, tumor necrosis factor-α, interleukin-1β, and interleukin-6, mitigated the reduction of food intake and fat mass, and consequently ameliorated body weight loss in the mouse model of lung adenocarcinoma. We also demonstrated that skeletal muscle mass and muscle contraction force in both fast-twitch muscle and slow-twitch muscle were retained in ghrelin-treated mice in conjunction with an upregulation of local insulin-like growth factor 1/Akt signaling. In addition, ghrelin administration reduced the expressions of phosphorylated-p38 mitogen-activated protein kinase, phosphorylated-nuclear factor-kappa B, Forkhead box protein O1, muscle RING-finger protein-1, and F-Box protein 32 in the lysates of skeletal muscle in the tumor-bearing state. Our results indicate that ghrelin administration exerts a protective effect against cancer cachexia by ameliorating skeletal muscle wasting and regulating systemic inflammation.
癌症恶病质是一种多因素的危重病综合征，其特征是持续的骨骼肌和脂肪组织丧失。体重和骨骼肌质量的减少是癌症患者对当前治疗方法产生抗药性的重要预后指标。胃泌素是生长激素促分泌素受体的内源性配体，在胃中产生，刺激食欲和生长激素分泌，抑制炎症，并防止肌肉分解代谢。我们通过使用在五个月后接受乌头碱处理的、支气管肺泡上皮特异性 Pten 缺陷型小鼠来研究胃泌素在治疗癌症恶病质中的药理学潜力，这些小鼠发展为肺腺癌。从乌头碱注射后五个月开始，即肺腺癌形成的时间点，每天给小鼠给予胃泌素或磷酸盐缓冲盐水，持续四周。胃泌素抑制 C 反应蛋白、肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6 的诱导，减轻食物摄入和脂肪质量的减少，并因此改善了肺腺癌小鼠模型的体重减轻。我们还表明，与局部胰岛素样生长因子 1/Akt 信号转导上调相关，胃泌素治疗可保留快速抽搐肌肉和缓慢抽搐肌肉中的骨骼肌质量和肌肉收缩力。此外，胃泌素给药可减少肿瘤状态下骨骼肌裂解物中磷酸化 p38 丝裂原活化蛋白激酶、磷酸化核因子-κB、叉头框蛋白 O1、肌肉 RING 指蛋白-1 和 F 框蛋白 32 的表达。我们的结果表明，胃泌素给药通过改善骨骼肌消耗和调节全身炎症来发挥对癌症恶病质的保护作用。
