P21 transcriptional inhibitors as proapoptotic compounds

Summary

Principal Investigator: Andrei Gartel
Abstract: 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.
Funding Period: 2002-09-06 - 2005-08-31
more information: NIH RePORT

Top Publications

  1. pmc ARC synergizes with ABT-737 to induce apoptosis in human cancer cells
    Uppoor G Bhat
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Mol Cancer Ther 9:1688-96. 2010
  2. ncbi Lost in transcription: p21 repression, mechanisms, and consequences
    Andrei L Gartel
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Cancer Res 65:3980-5. 2005
  3. ncbi The conflicting roles of the cdk inhibitor p21(CIP1/WAF1) in apoptosis
    Andrei L Gartel
    Leuk Res 29:1237-8. 2005
  4. ncbi Multiple alternate p21 transcripts are regulated by p53 in human cells
    S K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, 60612, USA
    Oncogene 25:1812-5. 2006
  5. ncbi A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity
    Senthil K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, Illinois 60612, USA
    Cancer Res 66:3264-70. 2006
  6. ncbi CDK9 phosphorylates p53 on serine residues 33, 315 and 392
    Senthil K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Cell Cycle 5:519-21. 2006

Scientific Experts

  • Andrei Gartel
  • Senthil K Radhakrishnan
  • Uppoor G Bhat
  • S K Radhakrishnan
  • Bulbul Pandit
  • J Gierut

Detail Information

Publications6

  1. pmc ARC synergizes with ABT-737 to induce apoptosis in human cancer cells
    Uppoor G Bhat
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Mol Cancer Ther 9:1688-96. 2010
    ..These data suggest that the ABT-737/ARC combination, which simultaneously targets Bcl-2 and Mcl-1, may be efficient against human cancer...
  2. ncbi Lost in transcription: p21 repression, mechanisms, and consequences
    Andrei L Gartel
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Cancer Res 65:3980-5. 2005
    ..Further identification of factors that repress p21 is likely to contribute to the better understanding of its role in cancer...
  3. ncbi The conflicting roles of the cdk inhibitor p21(CIP1/WAF1) in apoptosis
    Andrei L Gartel
    Leuk Res 29:1237-8. 2005
  4. ncbi Multiple alternate p21 transcripts are regulated by p53 in human cells
    S K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, 60612, USA
    Oncogene 25:1812-5. 2006
    ..The existence of the alternate transcripts underscores the complexity of the human p21 genomic locus and opens up new avenues for further investigation...
  5. ncbi A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity
    Senthil K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, Illinois 60612, USA
    Cancer Res 66:3264-70. 2006
    ..Taken together, our data suggests that ARC may be an attractive candidate for anticancer drug development...
  6. ncbi CDK9 phosphorylates p53 on serine residues 33, 315 and 392
    Senthil K Radhakrishnan
    Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA
    Cell Cycle 5:519-21. 2006
    ..Specifically, Ser33 on the N-terminus and, Ser315 and Ser392 on the C-terminus of p53 were found to be phosphorylated. The precise biological role of this phosphorylation remains to be elucidated...