Evaluation of novel FoxM1 inhibitors against liver cancer

新型 FoxM1 抑制剂抗肝癌的评价

• 批准号: 8036001
• 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
• 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/8036001
• 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; public health relevance; 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）：人类肝细胞癌（HCC）是第五大常见癌症，也是全球第三大癌症死亡原因。所有肝癌的传统治疗方法都充满副作用且疗效有限。因此，识别针对 HCC 生长的潜在分子事件并通过阻止细胞分裂和选择性诱导肿瘤细胞凋亡来干扰 HCC 发展的新药物非常重要。 Forkhead Box M1 (FoxM1) 是近年来因其在包括 HCC 在内的多种癌症中的重要性而受到关注的一个特殊基因。 FoxM1 是一种转录因子，可调节许多参与细胞周期调控的基因的表达。有趣的是，研究发现 FoxM1 对于小鼠 HCC 的发展至关重要，这表明抑制 FoxM1 可能是治疗 HCC 的一种有前景的策略。在我们的初步研究中，我们确定抗生素噻唑化合物 Siomycin A 和硫链丝菌素是 FoxM1 的有效抑制剂。本提案的目的是研究 Siomycin A/thiostrepton 的分子作用机制，并在肝癌小鼠模型中测试其体内功效。在第一个具体目标中，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 FoxM1 下调是导致 Siomycin A/thiostrepton 诱导细胞凋亡的关键事件这一假设。为了评估 Siomycin A/thiostrepton 作为体内抗癌药物的功效，我们将在体外使用对噻唑类抗生素敏感的 3 种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/thiostrepton 治疗对 FoxM1 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，我们将在雄性小鼠中使用二乙基亚硝胺 (DEN)/苯巴比妥 (PB) 肝肿瘤诱导方案和新的 ARF-/- Rosa-26 FoxM1b TG 侵袭性转移性肝癌小鼠模型。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，我们将测试代表脱氢哌啶核心的硫链丝菌肽小片段是否也能抑制FoxM1并表现出抗肝癌的特性。这些数据不仅可能有助于开发抗肝癌的新药，而且将有助于更好地了解HCC的病因。如果噻唑类抗生素具有低毒性并导致小鼠肝脏肿瘤消退，我们将得出结论，这些化合物可能具有进一步针对肝癌临床开发的潜力。 公共健康相关性：人类肝细胞癌 (HCC) 是第五大常见癌症，也是全球第三大癌症死亡原因。所有肝癌的传统治疗方法都充满副作用且疗效有限。因此，识别针对 HCC 生长的潜在分子事件并干扰 HCC 发展的新药物非常重要。结果表明，癌基因 FoxM1 对于 HCC 的发展至关重要，这表明抑制 FoxM1 可能是治疗 HCC 的一种有前景的策略。噻唑类抗生素 Siomycin A 和 thiostrepton 在我们的实验室被鉴定为 FoxM1 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 的分子作用机制，并在肝癌小鼠模型中测试其体内功效。噻唑类抗生素可能是治疗肝癌的有前途的药物，因为它们会诱导癌症细胞死亡，但不会诱导正常细胞死亡。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。