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Mechanism of SHeA2 Action in Ovarian Cancer

SHeA2 在卵巢癌中的作用机制

基本信息

批准号：
7609055
负责人：
DORIS Mangiaracina BENBROOK
金额：
$ 27.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7609055
关键词：
Adherent Culture Animal Model Apoptosis Basic Science Biological Markers Blood capillaries Cancer cell line Cancerous Capillary Endothelial Cell Cells Clinical Trials Design Development Differentiation and Growth Endothelial Cells Epithelial Cells Exhibits Free Radicals Galactosamine Gene Expression Generations Genes Glycoproteins Growth Hepatic Human In Vitro Inorganic Sulfates Malignant Neoplasms Malignant neoplasm of ovary Metabolic Metabolism Mitochondria Molecular NF-kappa B National Cancer Institute Normal Cell Nuclear Outcome Ovarian Pathway interactions Pattern Platelet Factor 4 Prevention Proteins Rapid Access to Intervention Development Reactive Oxygen Species Regulation Research Research Personnel Resistance Retinoid Receptor Retinoids Role SHetA2 Sulfatases Surface Testing Therapeutic Thymidine Phosphorylase Tissue-Specific Gene Expression Toxic effect UDP-Glucose 4-Epimerase Unspecified or Sulfate Ion Sulfates Xenograft procedure cancer cell cancer diagnosis capillary improved in vivo mitochondrial membrane novel pre-clinical programs skin irritation thrombospondin 4 treatment strategy

项目摘要

DESCRIPTION (provided by applicant): SHetA2 is a novel anti-cancer compound that regulates growth and differentiation similar to retinoids, but does not directly activate RARs or RXRs. SHetA2 inhibited the growth of ovarian cancer xenografts without evidence of toxicity. Additional animal models have demonstrated that SHetA2 does not induce teratogenicity or skin irritation. Thus, SHetA2 exhibits an improved therapeutic ratio over retinoids capable of activating the retinoid receptors. Because SHetA2 is currently in pre-clinical development through the Rapid Access to Intervention and Development (RAID) program of the National Cancer Institute (NCI), additional basic science research, which is not supported by RAID, is needed to understand the mechanism of action of this compound before it is tested in humans. The hypothesis is that SHetA2 directly interacts with the mitochondria resulting in generation of reactive oxygen species, mitochondrial membrane depolarization, and inhibition of NF-kappaB activity and expression of thymidine phosphorylase and thrombospondin-4 gene expression. In endothelial cells this pathway inhibits the development of capillaries. The hyperactive metabolic state of ovarian cancer cells, increases the sensitivity of their mitochondria to the SHetA2 perturbations with the ultimate outcome being the induction of the intrinsic pathway to apoptosis. The more stable mitochondrial state of normal cells makes them more resistant to SHetA2-induced apoptosis. SHetA2 induces glandular differentiation through activation of hepatic nuclear factor-4, which regulates genes involved in glycoprotein metabolism, Galactosamine (N-acetyl)-6-sulfate sulfatase and UDP-galactose-4-epimerase and the TSP-4 glycoprotein. The specific aims are to decipher the SHetA2 molecular pathways of: 1) differential apoptosis in cancerous versus normal ovarian cells, 2) glandular differentiation and 3) inhibition of endothelial cell capillary formation. The results of these studies will provide mechanistic information on SHetA2 required for appropriate design of clinical trials and improved compounds, and scientific information on apoptosis and differentiation. The elucidation of the proteins involved in the SHetA2 pathwayswill provide potential biomarkers for ovarian cancer diagnosis, prevention and treatment strategies.

描述（由申请人提供）：SHetA2是一种新型抗癌化合物，类似于类维生素a调节生长和分化，但不直接激活RARs或RXRs。SHetA2抑制卵巢癌异种移植物的生长，无毒性证据。其他动物模型表明，SHetA2不会引起致畸性或皮肤刺激。因此，SHetA2表现出比激活类视黄酮受体的类视黄酮更好的治疗效果。由于SHetA2目前正通过美国国家癌症研究所（NCI）的快速干预和开发（RAID）项目进行临床前开发，因此在进行人体试验之前，还需要进行额外的基础科学研究，以了解该化合物的作用机制，而这些研究并没有得到RAID的支持。假设是SHetA2直接与线粒体相互作用，导致活性氧的产生，线粒体膜去极化，抑制NF-kappaB活性，胸苷磷酸化酶和血栓反应蛋白4基因的表达。在内皮细胞中，这一途径抑制毛细血管的发育。卵巢癌细胞过度活跃的代谢状态增加了线粒体对SHetA2扰动的敏感性，最终导致细胞凋亡的内在途径被诱导。正常细胞更稳定的线粒体状态使其更能抵抗sheta2诱导的细胞凋亡。SHetA2通过激活肝核因子-4诱导腺体分化，而核因子-4调节糖蛋白代谢相关基因、半乳糖胺（n -乙酰）-6-硫酸盐硫酸酯酶、udp -半乳糖-4- epimase和TSP-4糖蛋白。我们的具体目标是：1)卵巢癌细胞与正常卵巢细胞的差异凋亡；2)腺体分化；3)内皮细胞毛细血管形成的抑制。这些研究的结果将为适当设计临床试验和改进化合物提供有关SHetA2的机制信息，以及有关细胞凋亡和分化的科学信息。阐明参与SHetA2通路的蛋白将为卵巢癌的诊断、预防和治疗策略提供潜在的生物标志物。