Anti-adult T-cell leukemia effects of a novel synthetic retinoid, Am80 (Tamibarotene).
Clinical trials for treatment of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type I (HTLV-I) using all-trans-retinoic acid (ATRA) have shown satisfactory therapeutic responses, although efficacies were limited. Recently, many synthetic retinoids have been developed and among them, a novel synthetic retinoid, Am80 (Tamibarotene) is an RARalpha- and RARbeta-specific retinoid expected to overcome ATRA resistance. The present study examined the inhibitory effects of Am80 on HTLV-I-infected T-cell lines and ATL cells. Am80 had negligible growth inhibition of peripheral blood mononuclear cells but marked growth inhibition of both HTLV-I-infected T-cell lines and ATL cells. Am80 arrested cells in the G1 phase of the cell cycle and induced apoptosis in HTLV-I-infected T-cell lines. It inhibited also the phosphorylation of IkappaBalpha and NF-kappaB-DNA binding, in conjunction with reduction of expression of proteins involved in the G1/S cell cycle transition and apoptosis. Am80 also inhibited the expression of JunD, resulting in suppression of AP-1-DNA binding. Furthermore, severe combined immunodeficient mice with tumors induced by subcutaneous inoculation of HTLV-I-infected T cells, responded to Am80 treatment with partial regression of tumors and no side-effects. These findings demonstrate that Am80 is a potential inhibitor of NF-kappaB and AP-1, and is a potentially useful therapeutic agent against ATL.
Nakazato
Tetsuro
T
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Okudaira
Taeko
T
Ishikawa
Chie
C
Nakama
Shinji
S
Sawada
Shigeki
S
Tomita
Mariko
M
Uchihara
Jun-nosuke
JN
Taira
Naoya
N
Masuda
Masato
M
Tanaka
Yuetsu
Y
Ohshiro
Kazuiku
K
Takasu
Nobuyuki
N
Mori
Naoki
N
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001565:Benzoates; D013764:Tetrahydronaphthalenes; C061133:tamibarotene
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