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Evaluation of novel FoxM1 inhibitors against liver cancer

新型 FoxM1 抑制剂抗肝癌的评价

基本信息

批准号：
8232149
负责人：
ANDREI L GARTEL
金额：
$ 31.6万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8232149
关键词：
Ablation Adult Adverse effects Affect Alcohols Animal Model Animal Physical Conditioning Animals Antibiotics Antineoplastic Agents Apoptosis Apoptosis Promoter Attention Binding Boxing Breast Cancer Cell Cancer Etiology Cancer cell line Carcinoma Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Death Cell division Cells Cessation of life Clinical Complex DNA Binding Data Development Diethylnitrosamine Dose Down-Regulation Drug Delivery Systems Drug usage EP300 gene Etiology Evaluation Event Exhibits FDA approved Family Genes Genetic Goals Growth Hepatitis B Virus Hepatitis C virus Hepatocyte Human Human Development In Vitro Induction of Apoptosis Inhibition of Apoptosis Laboratories Lead Light Liver Liver Cirrhosis Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mediating Mitotic Modeling Molecular Molecular Mechanisms of Action Mus Neoplasm Metastasis Normal Cell Nude Mice Oncogenes Oncogenic Parasitic infection Peptides Pharmaceutical Preparations Phenobarbital Population Primary carcinoma of the liver cells Principal Investigator Property Protocols documentation Resistance Ribosomal RNA Rosa Testing Therapeutic Therapeutic Intervention Thiazoles Thiostrepton Tissues Toxic effect Translations Tumor Suppressor Proteins Viral Xenograft Model Xenograft procedure base cancer cell cell growth conventional therapy efficacy testing forkhead protein in vivo inhibitor/antagonist innovation killings liver xenograft male mouse model neoplastic cell novel overexpression programs research study siomycin A transcription factor tumor tumor growth tumor progression tumor xenograft

项目摘要

Human hepatocellular carcinoma (HCC) is the fifth most common cancer, and the third leading cause of cancer death worldwide. All conventional treatments for liver cancer are fraught with side effects and limited efficiency. Hence, it is important to identify novel drugs that target the underlying molecular events of HCC growth and interfere with HCC development by blocking cell division and selectively inducing tumor cell apoptosis. One particular gene that has gained attention in recent years due to its importance in a number of cancers including HCC is Forkhead Box M1 (FoxM1). FoxM1 is a transcription factor that regulates the expression of a number of genes that are involved in cell cycle regulation. Interestingly, it was found that FoxM1 is essential for the development of HCC in mice, suggesting that inhibition of FoxM1 might be a promising strategy for treating HCC. In our preliminary studies, we identified the antibiotic thiazole compounds Siomycin A and thiostrepton as potent inhibitors of FoxM1. The goal of this proposal is to investigate the molecular mechanisms of action of Siomycin A/thiostrepton and to test their efficacy in vivo in mouse models of liver cancer. In the first specific aim we will determine how Siomycin A/thiostrepton inhibit the transcriptional activity of FoxM1. Next, we will test the hypothesis that downregulation of FoxM1 is a key event that leads to Siomycin A/thiostrepton-induced apoptosis. To evaluate the efficacy of Siomycin A/thiostrepton as anticancer agents in vivo, we will use 3 human liver cancer cell lines that are sensitive to thiazole antibiotics in vitro to induce xenograft tumors in athymic mice. The effect of Siomycin A/thiostrepton treatment on FoxM1 expression and growth of xenograft tumors will be examined in these mice. Furthermore, to test the anticancer properties of the thiazole antibiotics we will use a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor induction protocol in male mice and a new ARF-/- Rosa-26 FoxM1b TG mouse model of aggressive metastatic liver cancer. We will test if Siomycin A/thiostrepton can inhibit HCC growth and metastasis in these mice. In addition, we will test whether the small fragment of thiostrepton representing the dehydropiperidine core also inhibits FoxM1 and exhibits anticancer properties against liver cancer. These data may not only help to develop new drugs against liver cancer, but also will help to better understand the etiology of HCC. If the thiazole antibiotics have low toxicity and lead to liver tumor regression in mice, we will conclude that these compounds may have a potential for further clinical development against liver cancer. Human hepatocellular carcinoma (HCC) is the fifth most common cancer, and the third leading cause of cancer death worldwide. All conventional treatments for liver cancer are fraught with side effects and limited efficiency. Hence, it is important to identify novel drugs that target the underlying molecular events of HCC growth and interfere with HCC development. It was shown that oncogene FoxM1 is essential for the development of HCC, suggesting that inhibition of FoxM1 might be a promising strategy for treating HCC. Thiazole antibiotics Siomycin A and thiostrepton were identified in our laboratory as potent inhibitors of FoxM1 and inducers of apoptosis in liver cancer cells. The goal of this proposal is to investigate the molecular mechanisms of action of Siomycin A/thiostrepton and to test their efficacy in vivo in mouse models of liver cancer. Thiazole antibiotics could be promising drugs against HCC because they induce cell death in cancer, but not in normal cells. Completion of our proposal will enable us to determine if thiazole antibiotics are suitable for further clinical development.

人类肝细胞癌是排名第五的常见癌症，而全球癌症死亡的第三大原因。所有传统的肝脏治疗方法癌症充满了副作用和有限的疗效。因此，重要的是要确定针对肝癌生长和潜在分子事件的新药通过阻断细胞分裂和选择性诱导肿瘤来干预肝癌的发展细胞凋亡。一种特殊的基因，近年来由于它的在包括肝癌在内的许多癌症中，重要的是Forkhead Box M1(FOXM1)。 FOXM1是一种转录因子，它调节许多基因的表达，这些基因参与细胞周期调控。有趣的是，人们发现FOXM1对于小鼠肝细胞癌的发生，提示抑制FOXM1可能是一种治疗肝癌的有希望的策略。在我们的初步研究中，我们发现抗生素噻唑类化合物西奥霉素A和硫代链菌素是一种有效的抑制药物 FOXM1。这项建议的目的是研究黄曲霉毒素的分子作用机制。西奥霉素A/硫代链球菌素及其在小鼠肝脏模型中的体内疗效癌症。在第一个具体目标中，我们将确定西奥霉素A/硫链霉菌如何抑制 FOXM1的转录活性。接下来，我们将检验这一假设 FOXM1的下调是导致西霉素A/硫链霉菌诱导的关键事件细胞凋亡。西奥霉素A/硫代链球菌素作为抗癌药物的疗效评价体内，我们将使用3个对噻唑类抗生素敏感的人肝癌细胞株在体外诱发裸鼠异种移植瘤。西红霉素的疗效观察 A/硫代链球菌素治疗对移植瘤FOXM1表达和生长的影响在这些小鼠身上进行了检查。此外，为了测试噻唑类化合物的抗癌性能抗生素我们将使用二乙基亚硝胺(DEN)/苯巴比妥(PB)肝肿瘤雄性小鼠的诱导方案和新的ARF-/-ROSA-26FoxM1b TG小鼠模型侵袭性转移性肝癌。我们将测试西奥霉素A/硫链霉菌是否能抑制肝癌在这些小鼠体内的生长和转移。此外，我们还将测试小的代表脱氢哌啶核的硫链霉菌素片段也抑制FOXM1和具有抗肝癌的抗癌特性。这些数据可能不仅有助于开发抗肝癌新药，也将有助于更好地了解肝细胞癌的病因。如果噻唑类抗生素毒性较低，会导致肝脏肿瘤在小鼠体内的退化，我们将得出结论，这些化合物可能有潜在的针对肝癌的进一步临床研究进展。人类肝细胞癌是第五大常见癌症，也是第三大常见癌症。是全球癌症死亡的主要原因。所有传统的肝癌治疗方法都是充满副作用和有限的效率。因此，识别小说是很重要的靶向肝癌生长的潜在分子事件并干扰肝癌的药物发展。研究表明，癌基因FOXM1在肿瘤的发生发展中起重要作用。提示抑制FOXM1可能是一种有前途的治疗策略肝细胞癌。噻唑类抗生素西奥霉素A和硫代链菌素在本实验室鉴定作为FOXM1的有效抑制剂和肝癌细胞的凋亡诱导剂。的目标是本研究旨在探讨西奥霉素的分子作用机制。并在小鼠肝癌模型上测试它们的体内疗效。噻唑抗生素可能是很有前途的抗肝癌药物，因为它们会诱导肝癌细胞死亡。癌症，但不是在正常细胞中。完成我们的提案将使我们能够确定是否噻唑类抗生素适合于进一步的临床开发。