Mechanism of SHeA2 Action in Ovarian Cancer

SHeA2 在卵巢癌中的作用机制

• 批准号: 6989215
• 负责人: DORIS Mangiaracina BENBROOK
• 金额: $ 24.45万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989215
• 关键词: angiogenesis inhibitors; antineoplastics; apoptosis; capillary; cell differentiation; cell growth regulation; clinical research; drug screening /evaluation; female; human tissue; laboratory mouse; mitochondria; neoplastic cell; ovary neoplasms; pharmacokinetics; retinoids; tissue /cell culture

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是一种新型的抗癌化合物，可调节类似于类似类维生素的生长和分化，但并未直接激活RARS或RXR。 sheta2抑制了卵巢癌异种移植物的生长，而没有毒性证据。其他动物模型表明，sheta2不会诱导致畸性或皮肤刺激。因此，Sheta2与能够激活类维生素类动物受体的类视角素相比表现出改善的治疗比率。由于SHETA2目前正在通过迅速获得国家癌症研究所（NCI）的干预和开发计划（RAID）计划（NCI）进行临床前开发，因此需要其他基础科学研究（不受RAID支持）才能理解该化合物在人类中进行测试之前的作用机理。假设是sheta2直接与线粒体相互作用，导致活性氧，线粒体膜去极化以及抑制NF-kappab活性以及胸苷磷酸酶和血栓福斯蛋白-4基因表达的表达。在内皮细胞中，该途径抑制了毛细血管的发展。卵巢癌细胞的多活跃代谢状态增加了线粒体对sheta2扰动的敏感性，最终结果是诱导了凋亡的内在途径。正常细胞的线粒体状态更稳定，使其对Sheta2诱导的凋亡具有更大的耐药性。 sheta2通过激活肝核因子-4诱导腺分化，该因子-4调节涉及糖蛋白代谢，半乳糖胺（N-乙酰基）-6-硫酸盐硫酸盐硫酸硫酸盐硫酸硫酸盐和UDP-galactose-4-4- epimerase和TSP-4糖蛋白的基因。具体的目的是破译：1）癌性与正常卵巢细胞的差凋亡的sheta2分子途径，2）腺体分化和3）抑制内皮细胞毛细血管形成。这些研究的结果将提供有关适当设计临床试验和改进化合物所需的Sheta2的机械信息，以及有关细胞凋亡和分化的科学信息。 Sheta2途径涉及的蛋白质的阐明将为卵巢癌诊断，预防和治疗策略提供潜在的生物标志物。