P21 transcriptional inhibitors as proapoptotic compounds

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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.