Dual targeting of transformed and untransformed HTLV-1-infected T cells by DHMEQ, a potent and selective inhibitor of NF-kappaB, as a strategy for chemoprevention and therapy of adult T-cell leukemia

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....

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Bibliographic Details
Published in:Blood 2005-10, Vol.106 (7), p.2462
Main Authors: Watanabe, Mariko, Ohsugi, Takeo, Shoda, Momoko, Ishida, Takaomi, Aizawa, Shigemi, Maruyama-Nagai, Masae, Utsunomiya, Atae, Koga, Shin, Yamada, Yasuaki, Kamihira, Shimeru, Okayama, Akihiko, Kikuchi, Hiroshi, Uozumi, Kimiharu, Yamaguchi, Kazunari, Higashihara, Masaaki, Umezawa, Kazuo, Watanabe, Toshiki, Horie, Ryouichi
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Benzamides - pharmacology
Caspases - metabolism
Cell Cycle
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Proliferation
Cyclohexanones - pharmacology
Dose-Response Relationship, Drug
Down-Regulation
Gene Expression Regulation, Neoplastic
Genes, Reporter
Human T-lymphotropic virus 1 - metabolism
Humans
Immunoblotting
Immunohistochemistry
Jurkat Cells
K562 Cells
Leukemia, T-Cell - drug therapy
Leukemia, T-Cell - prevention & control
Leukemia, T-Cell - virology
Leukemia-Lymphoma, Adult T-Cell - drug therapy
Leukemia-Lymphoma, Adult T-Cell - virology
Leukocytes, Mononuclear - cytology
Leukocytes, Mononuclear - metabolism
Male
Mice
Mice, SCID
Microscopy, Fluorescence
Molecular Weight
NF-kappa B - antagonists & inhibitors
NF-kappa B - metabolism
Proviruses
Reverse Transcriptase Polymerase Chain Reaction
T-Lymphocytes - virology
Time Factors
Tumor Suppressor Protein p53 - metabolism
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Description
Summary: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-kappaB (NF-kappaB) in the leukemic cells is essential for their growth and survival. Blocking NF-kappaB has been shown to be a potential strategy to treat ATL. We tested this approach using a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), and also examined its application to chemoprevention by selective purging of the HTLV-1-infected cells. DHMEQ inhibited NF-kappaB activation in primary ATL cells and cell lines derived from them and induced apoptotic cell death. NF-kappaB inhibition down-regulated expression of genes involved in antiapoptosis or cell-cycle progression. DHMEQ protected severe combined immunodeficiency (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-kappaB is a potential molecular target for treatment and prevention of ATL. As a potent NF-kappaB inhibitor, DHMEQ is a promising compound allowing the translation of this strategy into clinical medicine.
ISSN:0006-4971
1528-0020