Small-molecule inhibitor which reactivates p53 in human T-cell leukemia virus type 1-transformed cells.
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.
Jung
Kyung-Jin
KJ
Virus Tumor Biology Section, Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dasgupta
Arindam
A
Huang
Keven
K
Jeong
Soo-Jin
SJ
Pise-Masison
Cynthia
C
Gurova
Katerina V
KV
Brady
John N
JN
D000585:Aminacrine / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010957:Plasmids; D034741:RNA, Small Interfering / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000585:Aminacrine; D008156:Luciferases