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Journal of Virology, September 2008, p. 8537-8547, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00690-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Small-Molecule Inhibitor Which Reactivates p53 in Human T-Cell Leukemia Virus Type 1-Transformed Cells{triangledown}

Kyung-Jin Jung,1 Arindam Dasgupta,1 Keven Huang,1 Soo-Jin Jeong,1 Cynthia Pise-Masison,1 Katerina V. Gurova,2 and John N. Brady1*

Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,1 Anti-Cancer Drug Discovery Lab, Cleveland Biolabs, Inc., Buffalo, New York 142032

Received 27 March 2008/ Accepted 4 June 2008

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of the aggressive and fatal disease adult T-cell leukemia. Previous studies have demonstrated that the HTLV-1-encoded Tax protein inhibits the function of tumor suppressor p53 through a Tax-induced NF-{kappa}B pathway. Given these attributes, we were interested in the activity of small-molecule inhibitor 9-aminoacridine (9AA), an anticancer drug that targets two important stress response pathways, NF-{kappa}B and p53. In the present study, we have examined the effects of 9AA on HTLV-1-transformed cells. Treatment of HTLV-1-transformed cells with 9AA resulted in a dramatic decrease in cell viability. Consistent with these results, we observed an increase in the percentage of cells in sub-G1 and an increase in the number of cells positive by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay following treatment of HTLV-1-transformed cells with 9AA. In each assay, HTLV-1-transformed cells C8166, Hut102, and MT2 were more sensitive to treatment with 9AA than control CEM and peripheral blood mononuclear cells. Analyzing p53 function, we demonstrate that treatment of HTLV-1-transformed cells with 9AA resulted in an increase in p53 protein and activation of p53 transcription activity. Of significance, 9AA-induced cell death could be blocked by introduction of a p53 small interfering RNA, linking p53 activity and cell death. These results suggest that Tax-repressed p53 function in HTLV-1-transformed cells is "druggable" and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-{kappa}B suggests a promising strategy for the treatment of HTLV-1-transformed cells.

* Corresponding author. Mailing address: Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Building 41, Room B201, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-0986. Fax: (301) 496-4951. E-mail: bradyj{at}exchange.nih.gov

{triangledown} Published ahead of print on 11 June 2008.

Journal of Virology, September 2008, p. 8537-8547, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00690-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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