Suppression of Hepatoma Cell Growth by Celecoxib

塞来昔布抑制肝癌细胞生长

• 批准号: 6686300
• 负责人: KE-QIN HU
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686300
• 关键词: alpha fetoprotein; apoptosis; athymic mouse; cell growth regulation; cell line; cell proliferation; chemoprevention; dosage; enzyme activity; growth inhibitors; hepatocellular carcinoma; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; prostaglandin E; prostaglandin endoperoxide synthase; western blottings; xenotransplantation

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for approximately six percent of all human cancers and one million deaths annually. The rising incidence, limited treatment, and poor prognosis of HCC emphasize an urgent need to explore innovative strategies for effective chemoprevention of this disease. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Celecoxib, a selective COX-2 inhibitor, suppresses growth of colon cancer and other malignancies and has recently been approved by FDA for chemoprevention of colon cancer. Even though our previous in vitro studies have indicated a potent inhibitory effect of celecoxib on growth of human HCC cells, such effect has never been tested in vivo. In response to PAR 02-176, we propose to determine the in vivo effect and mechanisms of celecoxib on growth of human HCC xenografts in nude mice. Two different human HCC cell lines, COX-2 expressing HuH7 and COX-2 non-expressing PLC/PRF/5, will be subcutaneously inoculated into nude mice to create HCC xenografts. Either celecoxib or control vehicle will be administered to these mice by gavage feeding. This model will be used to investigate our two specific aims: (1) To determine the in vivo effects of celecoxib on growth of COX-2 expressing HuH7 and COX-2 non-expressing PLC/PRF/5 HCC xenografts. (2) To examine the in vivo mechanisms of celecoxib-induced growth inhibition of these HCC xenografts. The size of HCC xenografts and level of plasma alpha fetoprotein will be used as primary end points to assess the effect of celecoxib on growth of HCC xenografis. COX-2 catalytic activity, alteration of cell cycle progression and apoptosis will be tested for celecoxib-mediated mechanisms. The results of these experiments will provide important information on degree and mechanisms of celecoxibmediated growth inhibition of HCC xenografis in vivo, which is an essential step for future clinical trials to test celecoxib as a clinical agent for HCC chemoprevention.

描述（由申请人提供）： 肝细胞癌（HCC）是世界上最常见的恶性肿瘤之一，约占所有人类癌症的6%，每年有100万人死亡。肝癌的发病率不断上升，治疗有限，预后差，强调迫切需要探索有效的化学预防这种疾病的创新策略。环氧合酶-2（考克斯-2）的过表达与肝癌的发生有关。塞来昔布是一种选择性的考克斯-2抑制剂，可抑制结肠癌和其他恶性肿瘤的生长，最近已被FDA批准用于结肠癌的化学预防。尽管我们之前的体外研究表明塞来昔布对人HCC细胞生长具有强效抑制作用，但这种作用从未在体内进行过测试。针对PAR 02-176，我们建议确定塞来昔布对裸鼠人肝癌移植瘤生长的体内作用和机制。将两种不同的人HCC细胞系，表达HuH 7的考克斯-2和不表达PLC/PRF/5的考克斯-2皮下接种到裸鼠中以产生HCC异种移植物。塞来昔布或对照溶剂将通过灌胃给予这些小鼠。该模型将用于研究我们的两个具体目标：（1）确定塞来昔布对表达HuH 7的考克斯-2和不表达考克斯-2的PLC/PRF/5 HCC异种移植物生长的体内作用。(2)研究塞来昔布对这些肝癌异种移植瘤生长抑制的体内机制。HCC异种移植物的大小和血浆甲胎蛋白水平将被用作主要终点，以评估塞来昔布对HCC异种移植物生长的影响。将检测塞来昔布介导机制的考克斯-2催化活性、细胞周期进程改变和细胞凋亡。这些实验的结果将提供塞来昔布介导的肝癌异种移植物生长抑制的程度和机制的重要信息，这是未来临床试验的重要步骤，以测试塞来昔布作为肝癌化学预防的临床药物。