Evaluation of novel FoxM1 inhibitors against liver cancer

新型 FoxM1 抑制剂抗肝癌的评价

• 批准号: 7618832
• 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/7618832
• 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; 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

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）是全球第五大癌症，也是癌症死亡的第三主要原因。所有用于肝癌的常规治疗都充满了副作用和有限的效率。因此，重要的是要鉴定出针对HCC生长的潜在分子事件的新型药物，并通过阻止细胞分裂并选择性地诱导肿瘤细胞凋亡来干扰HCC的发育。近年来由于其在包括HCC在内的许多癌症中的重要性而引起关注的一个特殊基因是Forkhead Box M1（FOXM1）。 FOXM1是一个转录因子，可调节细胞周期调节中许多基因的表达。有趣的是，发现FOXM1对于小鼠的HCC发展至关重要，这表明抑制FOXM1可能是治疗HCC的有前途的策略。在我们的初步研究中，我们确定抗生素噻唑化合物A siomycin A和硫代蛋白酶是FOXM1的有效抑制剂。该提案的目的是研究神经素A/硫代蛋白酶作用的分子机制，并测试其在肝癌小鼠模型中体内功效。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的下调是导致溶菌素A/硫代蛋白酶引起的细胞凋亡的关键事件。为了评估二霉素A/硫代蛋白酶作为体内抗癌剂的疗效，我们将使用3种对硫唑抗生素敏感的人肝癌细胞系在丘张小鼠中诱导异种移植肿瘤。在这些小鼠中，将检查神霉素A/硫代蛋白酶治疗对FOXM1表达和异种移植肿瘤生长的影响。此外，为了测试噻唑抗生素的抗癌特性，我们将使用雄性小鼠中的新ARF - /-ROSA-ROSA-26 FOXM1B FOXM1B TG TG小鼠模型的侵袭性转移性肝癌模型。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，我们还将测试代表脱氢二烷核的硫代膜的小片段是否还抑制FOXM1并表现出针对肝癌的抗癌特性。这些数据不仅可能有助于开发针对肝癌的新药，而且还将有助于更好地了解HCC的病因。如果噻唑抗生素的毒性低，导致小鼠肝肿瘤的消退，我们将得出结论，这些化合物可能具有进一步抗肝癌临床发育的潜力。 公共卫生相关性：人类肝细胞癌（HCC）是第五大常见的癌症，也是全球癌症死亡的第三主要原因。所有用于肝癌的常规治疗都充满了副作用和有限的效率。因此，重要的是要鉴定出针对HCC生长的潜在分子事件并干扰HCC发育的新型药物。结果表明，癌基因FOXM1对于HCC的发展至关重要，这表明FOXM1的抑制可能是治疗HCC的有前途的策略。噻唑抗生素siomycin A和硫代蛋白酶在我们的实验室中被鉴定为FOXM1的有效抑制剂，并且是肝癌细胞中凋亡的诱导剂。该提案的目的是研究神经素A/硫代蛋白酶作用的分子机制，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的有前途的药物，因为它们会诱导癌症的细胞死亡，但不能在正常细胞中诱导细胞死亡。我们的提案的完成将使我们能够确定噻唑抗生素是否适合进一步的临床开发。