Poster Sessions

C-38

Kyung-Jin Jung

K. J. Jung, A. Sasada, C. Pise-Masison, J. N. Brady

Effect of small molecule inhibitor 9AA on reactivation of p53 in cancer cells

In adult T-cell leukemia (ATL), wild-type but functionally inactive p53 is retained in the transformed cells. Previous studies have demonstrated that the human T-cell leukemia virus-1 (HTLV-1) encoded Tax protein inhibits the function of p53 through a Tax-induced NF-kappaB pathway. An attractive line of therapy, therefore, would be to induce cell death by reactivating p53 in ATL cells. We have investigated the activity of 9AA, an anticancer drug that targets NF-kappaB. Treatment of HTLV-1 transformed cells with 9AA resulted in a dramatic decrease in cell viability. We observed an increase in the percentage of cells in sub-G1 and an increase in the number of TUNEL positive cells following treatment of HTLV-1 transformed cells with 9AA. In each assay, HTLV-1 transformed cells C81, Hut102 and MT2 were more sensitive to treatment with 9AA than control CEM and PBMC cells. Analyzing p53 function, we found that treatment of 9AA resulted in an increase in p53 protein and transcription activity. Of significance, 9AA induced cell death could be blocked by introduction of a p53 siRNA, linking p53 activity and cell death. Most recently we have utilized the NCI-60 cell line repository to analyze the potential of 9AA to “reactivate” wild-type p53 in other human cancer cells. Our results suggest that repressed p53 function in both HTLV-1 transformed cells and certain human cancer cells is “druggable” and can be restored by treatment with 9AA. The fact that 9AA induces p53 and inhibits NF-kappaB suggest a promising strategy for the treatment of certain cancers.