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. 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.
Watanabe
Mariko
M
Department of Hematology, Faculty of Medicine, Kitasato University, Sagamihara, Kanagawa, Japan.
Ohsugi
Takeo
T
Shoda
Momoko
M
Ishida
Takaomi
T
Aizawa
Shigemi
S
Maruyama-Nagai
Masae
M
Utsunomiya
Atae
A
Koga
Shin
S
Yamada
Yasuaki
Y
Kamihira
Shimeru
S
Okayama
Akihiko
A
Kikuchi
Hiroshi
H
Uozumi
Kimiharu
K
Yamaguchi
Kazunari
K
Higashihara
Masaaki
M
Umezawa
Kazuo
K
Watanabe
Toshiki
T
Horie
Ryouichi
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003512:Cyclohexanones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D019169:Jurkat Cells; D020014:K562 Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000517:prevention & control* / Q000821:virology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008970:Molecular Weight; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011533:Proviruses; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000821:virology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C464444:dehydroxymethylepoxyquinomicin; D020169:Caspases