Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells
Graduate School of Biomedical Sciences; Virus Tumor Biology Section; Department of Molecular Genetics & Microbiology
Medical Subject Headings
Aminacrine; Anticarcinogenic Agents; Apoptosis; Cell Cycle; Cell Death; Cell Line, Transformed; Cell Survival; Cell Transformation, Viral; Dose-Response Relationship, Drug; G1 Phase; Genes, Reporter; Human T-lymphotropic virus 1; Humans; In Situ Nick-End Labeling; Luciferases; NF-kappa B; Plasmids; RNA, Small Interfering; Time Factors; Transcription, Genetic; Transfection; Tumor Suppressor Protein p53
Life Sciences | Medicine and Health Sciences
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-kappaB 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-kappaB 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-G(1) 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-kappaB suggests a promising strategy for the treatment of HTLV-1-transformed cells.
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Citation: J Virol. 2008 Sep;82(17):8537-47. Epub 2008 Jun 11. Link to article on publisher's site
DOI of Published Version
Journal of virology
Jung, Kyung-Jin; Dasgupta, Arindam; Huang, Keven; Jeong, Soo-Jin; Pise-Masison, Cynthia Ann; Gurova, Katerina V.; and Brady, John N., "Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells" (2008). GSBS Student Publications. 1518.