EFFECT OF ALCOHOL ON HEPATOCELLULAR CARCINOMA PROGRESSION IN VIVO

酒精对体内肝细胞癌进展的影响

• 批准号: 7470210
• 负责人: IAIN HUGH MCKILLOP
• 金额: $ 16.16万
• 依托单位: CAROLINAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-20 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470210
• 关键词: Accounting; Address; Adverse effects; Affect; Aflatoxins; Alcohol abuse; Alcohol consumption; Alcohols; Alternative Therapies; Animals; Antioxidants; Biochemical Pathway; Biological Availability; Blood; CYP2E1 gene; Cessation of life; Chemicals; Chronic; Cicatrix; Cirrhosis; Clinical Trials; Consumption; Controlled Study; Daily; Data; Development; Diethylnitrosamine; Disease; Effectiveness; Environment; Enzymes; Ethanol; Ethanol Metabolism; Event; Failure; Future; GTP-Binding Proteins; Generations; Gonadal Steroid Hormones; Growth; Healthcare; Hepatic; Hepatocyte; Histology; Human; Immune response; Immunoblotting; Immunohistochemistry; In Vitro; Incidence; Injection of therapeutic agent; Intake; Laboratories; Liver; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Measures; Mediating; Metabolism; Methionine; Milk Thistle; Modeling; Monitor; Mus; Nature; Neonatal; Operative Surgical Procedures; Organ; Oxidative Stress; Pathway interactions; Patients; Plants; Polymerase Chain Reaction; Predisposing Factor; Primary carcinoma of the liver cells; Range; Rate; Reactive Oxygen Species; Recording of previous events; Reporting; Research; Research Personnel; Rewards; Risk; Risk Factors; Rodent Model; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Societies; Stimulation of Cell Proliferation; System; Testing; Therapeutic Agents; Time; Tissues; Toxin; Translations; Viral; Week; alcohol abuse therapy; alcohol effect; aldehyde dehydrogenases; base; carcinogenesis; cell transformation; chronic alcohol ingestion; clinically relevant; day; dietary supplements; drinking water; enzyme activity; feeding; flavanoid; human disease; in vivo; interest; laser capture microdissection; male; mortality; novel; protective effect; silibinin; tumor; tumor progression

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.

描述（由申请人提供）：肝细胞癌 (HCC) 的发病率在美国和全球范围内急剧增加，每年导致超过 600,000 人死亡。肝硬化，无论是化学引起的还是病毒引起的，都是 HCC 发展的主要诱发因素。长期饮酒已被确定为患者发生肝硬化和进展为 HCC 的一个重要危险因素，无论是其本身还是病毒或化学损伤后的协同因素。我们对摄入酒精后受影响的细胞和生化途径的了解取得了进展，已经确定乙醇代谢（以及相关的活性氧（ROS）生成/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。这些发现导致建议使用全身抗氧化剂来抑制包括 HCC 在内的几种肝脏疾病的发生和进展。这些研究导致 S-腺苷甲硫氨酸 (SAMe) 作为潜在治疗剂的出现。虽然在啮齿动物模型中有效，但人们越来越关注其在人体临床试验中的有效性。几千年来，天然抗氧化剂一直被用于治疗肝脏疾病。尽管它们是非处方药，但对其功效和作用机制知之甚少。我们实验室之前的研究表明，G 蛋白在介导 HCC 体外有丝分裂发生中发挥着核心作用。此外，酒精治疗可以增强这些促有丝分裂途径。虽然大量研究已经确定了长期饮酒情况下肝细胞转化过程中的重要事件，但对于酒精对易形成肿瘤的肝脏中 HCC 进展速度的影响知之甚少。目前的提议假设，长期饮酒会增加病灶发展和 HCC 进展的速度和发生率。 为了检验这一假设，将使用长期饮酒动物体内进行性病灶发育和肝癌进展的小鼠模型进行研究。此外，该提案还将解决水飞蓟宾（一种源自水飞蓟植物的常用黄酮类化合物）在不存在或存在慢性酒精摄入的情况下在临床相关 HCC 模型中抑制肿瘤进展速率的机制效应。具体来说，这些研究将重点确定特定的促有丝分裂信号级联的作用，这些级联在体外受酒精治疗影响的 HCC 增殖中很重要。鉴于社会上酒精的广泛使用和滥用，以及对当前治疗 HCC 的药物疗效的担忧，我们认为必须探索替代方法。虽然植物来源的抗氧化剂被广泛使用，并且据说有效，但人们对植物源抗氧化剂治疗肝病的作用机制知之甚少。