EFFECT OF ALCOHOL ON HEPATOCELLULAR CARCINOMA PROGRESSION IN VIVO

描述(申请人提供)：在美国和全球，肝细胞癌(HCC)的发病率正在急剧上升，每年造成超过60万人死亡。无论是化学或病毒诱导的肝硬变，都是肝细胞癌发生的主要易感因素。长期饮酒已被确定为患者发展为肝硬变和进展为肝细胞癌的重要危险因素，这既是其自身的原因，也是病毒或化学侮辱后的协同因素。我们对酒精摄入后影响细胞和生化途径的了解的进展已经证实，乙醇代谢(以及相关的活性氧物种(ROS)的产生/氧化应激)是介导酒精对肝脏和其他器官有害影响的主要因素。这些发现导致了建议使用全身性抗氧化剂来抑制包括肝癌在内的几种肝病的发展和进展。这些研究导致了S-腺苷蛋氨酸(SAME)作为一种潜在的治疗剂的出现。虽然在啮齿动物模型中是有效的，但它在人类临床试验中的有效性越来越受到关注。几千年来，天然抗氧化剂一直被用于治疗肝病。尽管它们在非处方药中可用，但人们对它们的有效性和作用机制知之甚少。我们实验室以前的研究表明，G-蛋白在体外肝细胞癌的有丝分裂过程中起着中心作用。此外，酒精处理增强了这些促有丝分裂途径。虽然相当多的研究已经确定了慢性饮酒背景下肝细胞转化过程中的重要事件，但对于酒精对易于形成肿瘤的肝脏中肝细胞癌进展速度的影响知之甚少。目前的建议假设长期饮酒会增加病灶发展和肝细胞癌进展的比率和发生率。为了验证这一假说，将使用慢性饮酒动物体内进行性病灶发展和肝癌进展的小鼠模型进行研究。此外，这项建议还将阐述水飞蓟宾(一种从水飞蓟植物中提取的常用黄烷类化合物)在没有和存在长期酒精摄入的情况下，在临床相关的肝癌模型中抑制肿瘤进展速度的机制效应。具体地说，这些研究将集中于确定特定的、促有丝分裂的信号级联在体外酒精处理影响的肝癌增殖中所起的重要作用。鉴于酒精在社会上的广泛使用和滥用，以及对现有治疗药物治疗肝癌疗效的担忧，我们认为探索替代方法是当务之急。虽然广泛使用，并传闻有效，但对植物来源的抗氧化剂在肝病治疗中的作用机制知之甚少。

DESCRIPTION (provided by applicant): The incidence of hepatocellular carcinoma (HCC) is increasing dramatically in the US and globally, and accounts for more than 600,000 deaths/year. Cirrhosis of the liver, whether chemically or virally induced, is the major predisposing factor to the development of HCC. Chronic alcohol consumption has been identified as a significant risk factor in patients developing cirrhosis and progression to HCC, both in its own right and as a synergistic factor following viral or chemical insult. Advances in our understanding of the cellular and biochemical pathways affected following alcohol ingestion have identified ethanol metabolism (and associated reactive oxygen species (ROS) generation/oxidative stress) as a major factor in mediating the deleterious effects of alcohol in the liver and other organs. These findings have led to the proposed use of systemic antioxidants to inhibit the development and progression of several hepatic diseases including HCC. These studies have led to the emergence of S-adenosyl methionine (SAMe) as a potential therapeutic agent. While efficacious in rodent models, there is increasing concern regarding its effectiveness in human clinical trials. For several millennia natural antioxidants have been used in the treatment of liver disease. Despite their over-the-counter availability relatively little is known about their efficacy and mechanisms of action. Previous studies by our laboratory demonstrate a central role for G-proteins in mediating mitogenesis in HCC in vitro. Furthermore, treatment with alcohol enhances these pro-mitogenic pathways. While considerable research has identified important events during hepatic cell transformation in the setting of chronic alcohol consumption, relatively little is known about the effects of alcohol on the rate of HCC progression in livers predisposed to tumor formation. The current proposal hypothesizes that chronic alcohol consumption increases the rate and incidence of foci development and HCC progression. To test this hypothesis studies will be performed using in vivo murine models of progressive foci development and HCC progression in animals undergoing chronic alcohol consumption. In addition this proposal will address the mechanistic effects by which silibinin, a commonly used flavanoid derived from the milk thistle plant, acts to inhibit the rate of tumor progression in a clinically relevant model of HCC in the absence and presence of chronic alcohol intake. Specifically, these studies will focus on identifying the role of specific, pro-mitogenic signaling cascades demonstrated to be important in HCC proliferation that are affected by alcohol treatment in vitro. Given the widespread use and abuse of alcohol in society, and concerns regarding the efficacy of current therapeutic agents for the treatment of HCC, we believe it is imperative to explore alternative approaches. While widely available, and anecdotally effective, little is understood about the mechanisms of action of plant- derived antioxidants in the treatment of hepatic disease.