Evaluation of novel FoxM1 inhibitors against liver cancer

人肝细胞癌（HCC）是第五常见的癌症，并且 是全球癌症死亡的第三大原因。所有肝脏的常规治疗 癌症充满了副作用和有限的效率。因此， 鉴定靶向HCC生长的潜在分子事件的新药， 通过阻断细胞分裂和选择性诱导肿瘤来干预HCC发展 细胞凋亡近年来，一种特殊的基因由于其 叉头盒M1（FoxM 1）在包括HCC在内的许多癌症中具有重要性。 FoxM 1是一种转录因子，调节许多基因的表达， 参与细胞周期调控。有趣的是，研究发现FoxM 1对于 小鼠肝癌的发展，这表明FoxM 1的抑制可能是一种治疗肝癌的方法。 有希望的治疗HCC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和硫链丝菌素作为有效的 FoxM1。该提案的目标是研究药物作用的分子机制， Siomycin A/硫链丝菌素，并在小鼠肝脏模型中测试它们的体内功效 癌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，我们将测试假设， FoxM 1的下调是导致Siomycin A/thiostrepton诱导的细胞凋亡的关键事件。 凋亡评价Siomycin A/thiostrepton作为抗癌药物在 体内，我们将使用3种对噻唑类抗生素敏感的人肝癌细胞系， 以在无胸腺小鼠中诱导异种移植肿瘤。Siomycin的作用 A/硫链丝菌素治疗对异种移植肿瘤的FoxM 1表达和生长的影响将在下文中描述。 在这些老鼠身上做了检查。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 雄性小鼠中的诱导方案和新的ARF-/- Rosa-26 FoxM 1b TG小鼠模型， 侵袭性转移性肝癌。我们将测试Siomycin A/thiostrepton是否能抑制 这些小鼠中的HCC生长和转移。此外，我们将测试是否小 代表脱氢哌啶核心的硫链丝菌素片段也抑制FoxM 1和 对肝癌具有抗癌特性。这些数据不仅有助于 开发针对肝癌的新药，也将有助于更好地了解 HCC的病因。如果噻唑类抗生素毒性较低， 回归小鼠，我们将得出结论，这些化合物可能有潜力， 进一步的临床开发针对肝癌。人肝细胞癌（HCC）是第五大最常见的癌症，并且是第三大最常见的癌症。 是全球癌症死亡的主要原因。肝癌的所有常规治疗都是 充满副作用且效率有限。因此，重要的是要确定新的 靶向HCC生长的潜在分子事件并干扰HCC的药物 发展研究表明，癌基因FoxM 1对肿瘤的发生至关重要。 这表明FoxM 1的抑制可能是治疗HCC的有希望的策略。 HCC。噻唑类抗生素Siomycin A和硫链丝菌酮是本实验室鉴定的 作为FoxM 1的有效抑制剂和肝癌细胞凋亡的诱导剂。的目标 本研究旨在探讨硅霉素的分子作用机制 A/硫链丝菌素，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，因为它们诱导细胞死亡， 癌症，但不是在正常细胞中。完成我们的建议书将使我们能够确定， 噻唑类抗生素适合于进一步的临床开发。

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.