P21 transcriptional inhibitors as proapoptotic compounds

描述(由申请人提供)： 放疗和化疗都是癌症治疗的重要方式。它 已经提出这些抗癌治疗通过以下方式消除肿瘤细胞 诱导细胞程序性死亡(细胞凋亡)。细胞周期蛋白依赖性激酶 抑制物p21(WAFL/Cipl)是在转录水平上被诱导的 参与癌症发展的信号通路，并通过一个 各种抗癌治疗。越来越多的证据表明，p21是一种 一般的细胞凋亡抑制因子。我们假设对p21的抑制 肿瘤细胞中的转录将增强其对辐射和 化疗是因为p21的转录诱导通常会使肿瘤 对这些治疗有抵抗力。我们提出了一种识别化学物质的策略 P21启动子的抑制剂，我们计划测试有效的化学抑制剂 P21转录与放化疗药物在肿瘤中的作用 不同来源和异种移植瘤细胞系的比较 P53依赖和非依赖的细胞凋亡对细胞杀伤的影响。一间牢房 与人类p21启动子控制下的细菌LacZ基因一致， 阿霉素通过P53依赖的机制高度诱导 将会建立起来。该细胞系将用于鉴定化学物质 筛选p21转录抑制剂的研究进展 可从Chembridge获得的化学DlVERSet(TM)库 公司。抑制p21启动子的化合物将在 含LacZ报告基因的ConA细胞株 AP53反应启动子，以确保它们不会损害 P53作为转录激活剂。最有效的抑制药物 不影响P53依赖的p21启动子的P53依赖激活 LacZ在ConA细胞中的激活将在体外和在 活着。这些化合物将代表p21启动子的抑制物，但不是 P53的抑制剂。这项研究的具体目的是识别化学物质 P21转录抑制物并联合检测 癌细胞系和异种移植瘤中的化疗药物。我们预计 这些化合物将使肿瘤细胞对抗癌治疗敏感， 验证p21表达作为治疗靶点的有效性。这项研究可能会改进 通过鉴定新的化合物来治疗癌症 将提高细胞死亡的效率促进抗癌药物的使用 癌症治疗。

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.