NIK-333 inhibits growth of human T-cell leukemia virus type I-infected T-cell lines and adult T-cell leukemia cells in association with blockade of nuclear factor-kappaB signal pathway.
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.
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Taeko
T
Okudaira
Mariko
M
Tomita
Jun-Nosuke
JN
Uchihara
Takehiro
T
Matsuda
Chie
C
Ishikawa
Hirochika
H
Kawakami
Masato
M
Masuda
Yuetsu
Y
Tanaka
Kazuiku
K
Ohshiro
Nobuyuki
N
Takasu
Naoki
N
Mori
D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015490:HTLV-I Infections / Q000188:drug therapy* / Q000821:virology; D015368:Human T-lymphotropic virus 1; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000821:virology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D012176:Retinoids / Q000627:therapeutic use*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000821:virology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D012176:Retinoids; D051636:X-Linked Inhibitor of Apoptosis Protein; C487689:(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; D019938:Cyclin D1