P21 transcriptional inhibitors as proapoptotic compounds

P21 转录抑制剂作为促凋亡化合物

• 批准号: 6466727
• 负责人: ANDREI L GARTEL
• 金额: $ 15.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-06 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6466727
• 关键词: antineoplastics; apoptosis; athymic mouse; bacterial genetics; breast neoplasms; cell line; cellular oncology; chemical registry /resource; colorectal neoplasms; computer program /software; doxorubicin; drug screening /evaluation; flow cytometry; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplastic cell; nonhuman therapy evaluation; northern blottings; oncoprotein p21; p53 gene /protein; paclitaxel; transcription factor; transcription termination; xenotransplantation

DESCRIPTION (provided by applicant): Both radiation and chemotherapy are important modes of cancer treatment. It has been suggested that these anticancer treatments eliminate tumor cells by inducing programmed cell death (apoptosis). The cyclin-dependent kinase inhibitor p21 (Wafl/Cipl) is induced at the transcriptional level both by signaling pathways that participate in the development of cancer, and by a variety of anticancer treatments. There is a mounting evidence that p21 is a general inhibitor of apoptosis. We hypothesize that suppression of p21 transcription in tumor cells will enhance their response to radiation and chemotherapy because transcriptional induction of p21 usually makes tumors resistant to these treatments. We propose a strategy to identify chemical inhibitors of p21 promoter and we plan to test potent chemical inhibitors of p21 transcription together with radiation and chemotherapeutic drugs in tumor cell lines of different origin and in xenograft tumors to evaluate their effect on cell killing via p53-dependent and -independent apoptosis. A cell line with the bacterial LacZ gene under control of the human p21 promoter, which will be highly inducible by adriamycin via a p53-dependent mechanism will be established. This cell line will be used for identifying chemical inhibitors of p21 transcription by screening of individual compounds of a chemical DlVERSet(TM) library that is commerically available from Chembridge Corporation. Compounds that repress the p21 promoter will be rescreened in a ConA cell line containing the lacZ reporter gene under the control of ap53-responsive promoter to ensure that they do not compromise the ability of p53 to act as a transcriptional activator. The most potent inhibitors of p53-dependent activation of the p21 promoter that do not affect p53-dependent activation of LacZ in ConA cells will be identified and tested in vitro and in vivo. These compounds will represent repressors of the p21 promoter, but not inhibitors of p53. The specific aims of the study are to identify chemical inhibitors of p21 transcription and to test them in combination with chemotherapeutic drugs in cancer cell lines and xenograft tumors. We expect that such compounds will sensitize tumor cells to anti-cancer therapy, validating p21 expression as a therapeutic target. This study may improve treatment of cancer by leading to the identification of new compounds that will increase the efficiency of cell death promoting anticancer drugs for cancer treatment.

描述（由申请人提供）： 放射线和化学疗法都是癌症治疗的重要模式。它 已经建议这些抗癌治疗消除了肿瘤细胞 诱导程序性细胞死亡（凋亡）。依赖细胞周期蛋白的激酶 抑制剂p21（WAFL/CIPL）在转录水平上均通过 参与癌症发展的信号通路，并通过 各种抗癌治疗。有一个越来越多的证据表明p21是 凋亡的一般抑制剂。我们假设抑制p21 肿瘤细胞中的转录将增强其对辐射的反应，并且 化学疗法是因为P21的转录诱导通常会导致肿瘤 对这些疗法有抵抗力。我们提出了一种识别化学的策略 p21启动子的抑制剂，我们计划测试 p21转录与肿瘤中的辐射和化学治疗药物一起 不同起源和异种移植肿瘤中的细胞系以评估其 通过p53依赖性和非依赖性细胞凋亡对细胞杀死的影响。一个单元 与人类p21启动子控制的细菌LACZ基因线 通过依赖p53的机制，阿霉素将高度诱导 将建立。该细胞系将用于识别化学 p21转录的抑制剂通过筛选A的单个化合物 化学dlverset（TM）库，可从Chembridge获得。 公司。压抑P21启动子的化合物将在 在控制下包含LACZ报告基因的CONA细胞系 AP53响应启动子，以确保它们不会损害 p53充当转录激活剂。最有效的抑制剂 p53依赖性激活p21启动子不影响p53 将在体外鉴定和测试CONA细胞中LACZ的激活 体内。这些化合物将代表p21启动子的阻遏物，但不能 p53的抑制剂。该研究的具体目的是识别化学 p21转录的抑制剂，并结合测试 癌细胞系和异种移植肿瘤中的化学治疗药物。我们期望 这样的化合物会使肿瘤细胞对抗癌疗法敏感， 将p21表达验证为治疗靶标。这项研究可能会有所改善 通过鉴定新化合物来治疗癌症 将提高细胞死亡促进抗癌药物的效率 癌症治疗。