(2e-4e-6e-10e)-3-7-11-15-tetramethyl-2-4-6-10-14-hexadecapentaenoic-acid and HTLV-I-Infections

Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type I (HTLV-I) and remains incurable. NIK-333, a novel synthetic retinoid, prevents the recurrence of human hepatoma after surgical resection of primary tumors. We explored the effects of NIK-333 on HTLV-I-infected T-cell lines and ATL cells. NIK-333 inhibited cell proliferation, induced G1 arrest, and resulted in massive apoptosis in all tested HTLV-I-infected T-cell lines and ATL cells, whereas little effect was observed on normal peripheral blood mononuclear cells. NIK-333 treatment decreases the levels of cyclin D1, cyclin D2, cIAP2, and XIAP proteins. Further analysis showed that NIK-333 inactivated nuclear factor-kappaB in HTLV-I-infected T-cell lines. In animal studies, treatment with NIK-333 (100 mg/kg given orally every other day) produced partial inhibition of growth of tumors of a HTLV-I-infected T-cell line transplanted s.c. in severe combined immunodeficient mice. Our results indicate that NIK-333 is a potentially useful therapeutic agent for patients with ATL.

Topics: Animals; Apoptosis; Cell Line, Transformed; Cell Line, Tumor; Cyclin D1; Cyclin D2; Cyclins; Down-Regulation; Female; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Inhibitor of Apoptosis Proteins; Leukemia-Lymphoma, Adult T-Cell; Leukemia, T-Cell; Mice; Mice, Inbred Strains; NF-kappa B; Retinoids; Signal Transduction; T-Lymphocytes; X-Linked Inhibitor of Apoptosis Protein