Vitamin D and Ovarian Cancer Prevention and Treatment

维生素 D 与卵巢癌的预防和治疗

• 批准号: 7103707
• 负责人: WENLONG BAI
• 金额: $ 25.17万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103707
• 关键词: BCL2 gene /protein; apoptosis; athymic mouse; calpain; cancer prevention; cell cycle; cell cycle proteins; cell growth regulation; chemoprevention; chromatin immunoprecipitation; disease /disorder model; drug screening /evaluation; growth factor receptors; laboratory rabbit; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; ovary neoplasms; tumor suppressor genes; vitamin D; vitamin D receptors; western blottings; women' s health; xenotransplantation

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death among gynecological malignancies and its poor response to current treatments necessitates the development of novel therapeutic or preventive strategies to fight against this deadly disease. Our studies showed that multiple ovarian cancer cell lines responded to 1,25VD for growth suppression. Mechanistic studies suggest that 1,25VD suppresses growth factor signaling, induces cell cycle arrest and promotes apoptosis. Multiple tumor suppressors and oncogenes were identified as being regulated by 1,25VD to mediate these tumor-suppressing activities. More importantly, both in vitro and in vivo studies suggested that synthetic 1.25VD analog EB1089 is a promising drug that can be used to prevent and treat ovarian cancer. Based on these findings, we propose that 1.25VD, through the transcriptional activity of the nuclear vitamin D receptor (VDR), exert a tumor suppressing pathway in ovarian cancer cells; by inducing the expression of tumor suppressors and inhibiting the expression of oncogenes, leading to cell cycle arrest at G1/S and G2/M checkpoints as well as apoptosis. We believe that less calcemic synthetic VD analogues are not only useful drugs for the primary prevention of ovarian cancer, but wiU also premise ovarian cancer patients a new method of treatment. The proposed studies are to substantiate this hypothesis by achieving the following three specific aims: Aim 1. To test the concept that 1,25VD arrests ovarian cancer cell cycle progression at G1/S checkpoint by inhibiting the cells' response to serum growth factors through the transcriptional down-regulation of the epidermal growth factor receptor; Aim 2:To test the concept that the G2/M arrest and apoptosis induced by 1.25VD in ovarian cancer cells are coupled through the induction of GADD45 and to define the steps downstream of GADD45 that mediates the two separale activities of 1,25VD with a focus on the role of p38, Bcl-2 and calpain; Aim 3. To integrate the information from the molecular studies and, using the mechanistic information, to guide our effort to advance EB1089 for clinical management of ovarian cancer. We believe our studies address an area of research that is under studied and may lead to the development of EB1089 as a novel therapeutic or chemo-preventive drug to treat ovarian cancer. In addition, our studies made many novel findings about the mechanism of 1,25VD action, which may have a much broad impact beyond ovarian cancer.

描述（由申请人提供）：卵巢癌是妇科恶性肿瘤中导致死亡的主要原因，其对当前治疗的反应较差，因此需要开发新的治疗或预防策略来对抗这种致命疾病。我们的研究表明，多种卵巢癌细胞系对 1,25VD 的生长抑制有反应。机制研究表明 1,25VD 抑制生长因子信号传导、诱导细胞周期停滞并促进细胞凋亡。多种肿瘤抑制因子和癌基因被确定为受 1,25VD 调节以介导这些肿瘤抑制活性。更重要的是，体外和体内研究表明，合成的1.25VD类似物EB1089是一种有前途的药物，可用于预防和治疗卵巢癌。基于这些发现，我们提出1.25VD通过核维生素D受体（VDR）的转录活性，在卵巢癌细胞中发挥肿瘤抑制途径；通过诱导肿瘤抑制因子的表达并抑制癌基因的表达，导致细胞周期停滞在 G1/S 和 G2/M 检查点以及细胞凋亡。我们相信，低钙血症的合成VD类似物不仅是卵巢癌一级预防的有用药物，而且还为卵巢癌患者提供了一种新的治疗方法。拟议的研究旨在通过实现以下三个具体目标来证实这一假设： 目标 1. 测试 1,25VD 通过抑制细胞对血清生长因子的反应，在 G1/S 检查点阻止卵巢癌细胞周期进展的概念。表皮生长因子受体的转录下调；目标 2：测试卵巢癌细胞中 1.25VD 诱导的 G2/M 期停滞和细胞凋亡通过 GADD45 的诱导而耦合的概念，并确定 GADD45 介导 1,25VD 的两种独立活性的下游步骤重点关注p38、Bcl-2和钙蛋白酶的作用；目标 3. 整合分子研究的信息，并利用机制信息，指导我们推进 EB1089 用于卵巢癌临床治疗的努力。我们相信我们的研究涉及一个正在研究的研究领域，并可能导致 EB1089 开发为治疗卵巢癌的新型治疗或化学预防药物。此外，我们的研究得出了许多关于 1,25VD 作用机制的新发现，这些发现可能对卵巢癌以外的癌症产生更广泛的影响。