Evaluation of novel FoxM1 inhibitors against liver cancer

新型 FoxM1 抑制剂抗肝癌的评价

• 批准号: 7464247
• 负责人: ANDREI L GARTEL
• 金额: $ 32.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464247
• 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 Cycle; Cell Cycle Regulation; Cell Death; Cell division; Cells; Cessation of life; Clinical; Complex; Cultured Cells; DNA Binding; Data; Development; Diethylnitrosamine; Disease regression; Dose; Down-Regulation; Drug Delivery Systems; Drug usage; EP300 gene; Etiology; Evaluation; Event; Exhibits; 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; Numbers; Oncogenes; Oncogenic; Parasitic infection; Peptides; Pharmaceutical Preparations; Phenobarbital; Population; Primary carcinoma of the liver cells; Principal Investigator; Property; Protein Overexpression; Protocols documentation; Public Health; Purpose; Resistance; Ribosomal RNA; Rosa; Testing; Therapeutic; Therapeutic Intervention; Thiazoles; Thiostrepton; Tissues; Toxic effect; Translations; Tumor Suppressor Proteins; United States Food and Drug Administration; Viral; Xenograft Model; Xenograft procedure; base; cancer cell; cell growth; in vivo; inhibitor/antagonist; innovation; killings; liver xenograft; male; mouse model; neoplastic cell; novel; programs; research study; siomycin A; transcription factor; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：人肝细胞癌（HCC）是全球第五大常见癌症，也是第三大癌症死亡原因。所有肝癌的常规治疗都充满了副作用和有限的效率。因此，重要的是要确定新的药物，靶向HCC生长的潜在分子事件，并通过阻断细胞分裂和选择性诱导肿瘤细胞凋亡来干扰HCC的发展。近年来，由于其在包括HCC在内的许多癌症中的重要性，一种特殊的基因受到了关注，这就是叉头盒M1（FoxM 1）。FoxM 1是一种转录因子，调节参与细胞周期调控的许多基因的表达。有趣的是，研究发现FoxM 1对小鼠HCC的发展至关重要，这表明FoxM 1的抑制可能是治疗HCC的一种有希望的策略。在我们的初步研究中，我们确定了抗生素噻唑化合物Siomycin A和硫链丝菌素作为FoxM 1的有效抑制剂。本提案的目的是研究Siomycin A/thiostrepton作用的分子机制，并在肝癌小鼠模型中测试其体内疗效。在第一个具体目标中，我们将确定Siomycin A/thiostrepton如何抑制FoxM 1的转录活性。接下来，我们将检验这一假设，即FoxM 1的下调是导致Siomycin A/thiostrepton诱导的细胞凋亡的关键事件。为了评价Siomycin A/thiostrepton作为体内抗癌剂的疗效，我们将使用3种对噻唑类抗生素敏感的体外人肝癌细胞系在无胸腺小鼠中诱导异种移植肿瘤。将在这些小鼠中检查Siomycin A/硫链丝菌素处理对FoxM 1表达和异种移植肿瘤生长的影响。此外，为了测试噻唑类抗生素的抗癌特性，我们将在雄性小鼠和侵袭性转移性肝癌的新ARF-/- Rosa-26 FoxM 1b TG小鼠模型中使用二乙基亚硝胺（DEN）/苯巴比妥（PB）肝肿瘤诱导方案。我们将测试Siomycin A/thiostrepton是否可以在这些小鼠中抑制HCC生长和转移。此外，我们将测试代表脱氢哌啶核心的硫链丝菌肽的小片段是否也抑制FoxM 1并对肝癌表现出抗癌特性。这些数据不仅有助于开发新的抗肝癌药物，而且有助于更好地了解HCC的病因。如果噻唑类抗生素具有低毒性并导致小鼠肝肿瘤消退，我们将得出结论，这些化合物可能具有进一步临床开发抗肝癌的潜力。 公共卫生相关性：人类肝细胞癌（HCC）是全球第五大常见癌症，也是第三大癌症死亡原因。所有肝癌的常规治疗都充满了副作用和有限的效率。因此，重要的是要确定新的药物靶向HCC生长的潜在分子事件和干扰HCC的发展。研究表明，癌基因FoxM 1在HCC的发生发展中是必不可少的，这表明抑制FoxM 1可能是治疗HCC的一种有希望的策略。噻唑类抗生素Siomycin A和硫链丝菌素在我们的实验室中被鉴定为FoxM 1的有效抑制剂和肝癌细胞凋亡的诱导剂。本提案的目的是研究Siomycin A/thiostrepton作用的分子机制，并在肝癌小鼠模型中测试其体内疗效。噻唑类抗生素可能是治疗肝癌的有希望的药物，因为它们诱导癌症细胞死亡，而不是正常细胞。完成我们的提案将使我们能够确定噻唑类抗生素是否适合进一步的临床开发。