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¹ Division of Molecular Virology and Oncology, Graduate School of Medicine, ² Division of Endocrinology and Metabolism, ³ Division of Child Health and Welfare, and ⁴ Division of Immunology, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan and ⁵ Department of Internal Medicine, Naha Prefectural Hospital, Naha, Okinawa, Japan

Requests for reprints: Naoki Mori, Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81-98-895-1130; Fax: 81-98-895-1410. E-mail: n-mori{at}med.u-ryukyu.ac.jp

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-B 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. [Mol Cancer Ther 2006;5(3):704–12]

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Received 10/24/05; revised 12/13/05; accepted 1/12/06.