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 (HCC) 是第五大常见癌症，全球第三大癌症死亡原因。所有肝脏常规治疗癌症充满副作用且疗效有限。因此，重要的是识别针对 HCC 生长的潜在分子事件的新药通过阻止细胞分裂和选择性诱导肿瘤来干扰 HCC 发展细胞凋亡。近年来，一种特殊的基因因其 Forkhead Box M1 (FoxM1) 在包括 HCC 在内的许多癌症中发挥着重要作用。 FoxM1 是一种转录因子，可调节许多基因的表达，这些基因参与细胞周期调节。有趣的是，我们发现 FoxM1 对于小鼠 HCC 的发展，表明 FoxM1 的抑制可能是治疗 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 Siomycin A 和 thiostrepton 作为有效的抑制剂福克斯M1。该提案的目的是研究作用的分子机制 Siomycin A/thiostrepton 并在小鼠肝脏模型中测试其体内功效癌症。在第一个具体目标中，我们将确定西霉素 A/硫链丝菌素如何抑制 FoxM1 的转录活性。接下来，我们将检验以下假设： FoxM1 的下调是导致 Siomycin A/thiostrepton 诱导的关键事件细胞凋亡。评估 Siomycin A/thiostrepton 作为抗癌药物的功效 vivo，我们将使用3种对噻唑类抗生素敏感的人肝癌细胞系体外诱导无胸腺小鼠异种移植肿瘤。西霉素的作用 A/硫链丝菌素治疗对 FoxM1 表达和异种移植肿瘤生长的影响在这些小鼠中进行了检查。此外，为了测试噻唑的抗癌特性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-26 FoxM1b TG 小鼠模型侵袭性转移性肝癌。我们将测试西霉素A/硫链丝菌素是否可以抑制这些小鼠的 HCC 生长和转移。另外，我们会测试是否小代表脱氢哌啶核心的硫链丝菌肽片段也抑制 FoxM1 和对肝癌具有抗癌特性。这些数据不仅可以帮助开发抗肝癌的新药，也将有助于更好地了解 HCC 的病因学。如果噻唑类抗生素毒性低，导致肝肿瘤在小鼠的回归中，我们将得出结论，这些化合物可能具有潜在的进一步针对肝癌的临床开发。人类肝细胞癌 (HCC) 是第五大常见癌症，第三大常见癌症全球癌症死亡的主要原因。所有肝癌的常规治疗方法都是充满副作用且效率有限。因此，识别新颖性很重要针对 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 对于肿瘤的发育至关重要 HCC，表明抑制 FoxM1 可能是一种有前途的治疗策略肝癌。本实验室鉴定出噻唑类抗生素西霉素A和硫链丝菌素作为 FoxM1 的有效抑制剂和肝癌细胞凋亡的诱导剂。目标是该提案旨在研究 Siomycin 的分子作用机制 A/硫链丝菌肽并在肝癌小鼠模型中测试其体内功效。噻唑抗生素可能是治疗 HCC 的有希望的药物，因为它们会诱导细胞死亡癌症，但不存在于正常细胞中。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进一步临床开发。