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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2462-2471.
Prepublished online as a Blood First Edition Paper on June 14, 2005; DOI 10.1182/blood-2004-09-3646.
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Submitted September 22, 2004
Accepted May 22, 2005
Dual targeting of transformed and untransformed HTLV-1-infected T-cells by DHMEQ, a potent and selective inhibitor of NF- B, as a strategy for chemoprevention and therapy of adult T cell leukemia
Mariko Watanabe, Takeo Ohsugi, Momoko Shoda, Takaomi Ishida, Shigemi Aizawa, Masae Maruyama-Nagai, Atae Utsunomiya, Shin Koga, Yasuaki Yamada, Shimeru Kamihira, Akihiko Okayama, Hiroshi Kikuchi, Kimiharu Uozumi, Kazunari Yamaguchi, Masaaki Higashihara, Kazuo Umezawa, Toshiki Watanabe, and Ryouichi Horie*
Department of Hematology, Faculty of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan
Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan
Department of Hematology and Transfusion Service, Wakayama Medical University, Kimiidera, Wakayama City, Japan
Department of Laboratory Medicine, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan
Department of Laboratory Medicine, Faculty of Medicine, Miyazaki University, Kiyotakemachi, Miyazaki, Japan
Blood Transfusion Service, Faculty of Medicine, Oita University, Oita, Japan
Department of Internal Medicine, Kagoshima University School of Medicine, Kagoshima, Japan
Department of Safety Research on Blood and Biologics, National Institute of Infectious Diseases, Tokyo, Japan
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan
Department of Hematology, Faculty of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan; Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
* Corresponding author; email: rhorie{at}med.kitasato-u.ac.jp.
Human T-cell leukemia virus type I (HTLV-1) causes adult T-cell leukemia (ATL), a fatal T-cell leukemia resistant to chemotherapy, after more than 50 years of clinical latency from transmission through breast feeding. Polyclonal expansion of virus infected T-cells predisposes them to transformation. Constitutive activation of nuclear factor  B (NF-B) in the leukemic cells is essential for their growth and survival. Blocking NF-B has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-B inhibitor DHMEQ and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-B activation in primary ATL cells and cell lines derived from them, and induced apoptotic cell death. NF-B inhibition down-regulated expression of genes involved in anti-apoptosis or cell cycle progression. DHMEQ protected SCID mice inoculated with HTLV-1-transformed cells from death. In addition, DHMEQ selectively targeted HTLV-1-infected cells in the peripheral blood of virus carriers in vitro, resulting in a decreased number of infected cells. We conclude that NF-B is a potential for treatment and prevention of ATL. As a potent NF-B inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.
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