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.

人肝细胞癌（HCC）是第五大癌症，是全球癌症死亡的第三大主要原因。肝脏的所有常规治疗癌症充满副作用和有限的效率。因此，重要的是确定针对HCC生长的潜在分子事件的新型药物通过阻断细胞分裂并有选择地诱导肿瘤来干扰HCC的发育细胞凋亡。近年来由于其引起关注的一个特定基因包括HCC在内的许多癌症中的重要性是Forkhead Box M1（FOXM1）。 FOXM1是调节许多基因表达的转录因子参与细胞周期调节。有趣的是，发现FOXM1对于小鼠HCC的发展，表明抑制FOXM1可能是治疗HCC的有前途的策略。在我们的初步研究中，我们确定了抗生素噻唑化合物化合物siomycin A和硫代蛋白酶作为有效的抑制剂 FOXM1。该提议的目的是研究神经素A/硫代蛋白酶并在肝脏模型中测试其在体内功效癌症。在第一个特定目的中，我们将确定siomycin a/thiostrepton如何抑制 FOXM1的转录活性。接下来，我们将检验以下假设 FOXM1的下调是一个关键事件，可导致Siomycin a/thiostrepton诱导凋亡。评估神霉素A/硫代蛋白酶作为抗癌药的疗效体内，我们将使用3种对噻唑抗生素敏感的人肝癌细胞系体外诱导无胸腺小鼠的异种移植肿瘤。神霉素的作用 A/Thiostrepton治疗FOXM1表达和异种移植肿瘤的生长将是在这些小鼠中检查。此外，要测试噻唑的抗癌特性抗生素我们将使用二乙基硝基胺（DEN）/苯巴比妥（PB）肝肿瘤雄性小鼠的诱导方案和新的ARF - / - ROSA-26 FOXM1B TG小鼠模型的模型侵略性转移性肝癌。我们将测试Siomycin A/Thiostrepton是否可以抑制这些小鼠的HCC生长和转移。此外，我们将测试是否小代表脱氢吡啶核心的硫代膜的片段也抑制FOXM1和展示针对肝癌的抗癌特性。这些数据不仅有助于开发针对肝癌的新药，但也将有助于更好地了解 HCC病因。如果噻唑抗生素的毒性低并导致肝肿瘤小鼠的回归，我们将得出结论，这些化合物可能有潜力进一步针对肝癌的临床发育。人肝细胞癌（HCC）是第五大癌症，第三个全球癌症死亡的主要原因。所有有关肝癌的常规治疗方法都是充满副作用和有限的效率。因此，重要的是要识别小说针对HCC生长的潜在分子事件并干扰HCC的药物发展。结果表明，癌基因FOXM1对于开发的开发至关重要 HCC，表明抑制FOXM1可能是治疗的有前途的策略 HCC。在我们的实验室中鉴定出硫唑抗生素A和硫代作为FOXM1的有效抑制剂和肝癌细胞凋亡的诱导剂。目标该建议是研究二霉素作用的分子机制 a/thiostrepton并测试其在肝癌小鼠模型中体内功效。噻唑抗生素可能是针对HCC的有希望的药物，因为它们会诱导细胞死亡癌症，但不在正常细胞中。提案的完成将使我们能够确定是否噻唑抗生素适合进一步的临床发育。