Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir.
Adult T-cell leukemia (ATL), an aggressive malignancy of CD4+ T cells associated with human T-cell leukemia virus type I (HTLV-I) infection, carries a very poor prognosis because of the resistance of leukemic cells to any conventional regimen, including chemotherapy. We examined the effect of ritonavir, an HIV protease inhibitor, on HTLV-I-infected T-cell lines and primary ATL cells and found that it induced apoptosis and inhibited transcriptional activation of NF-kappaB in these cells. Furthermore, ritonavir inhibited expression of Bcl-xL, survivin, c-Myc, and cyclin D2, the targets of NF-kappaB. In nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammacnull (NOG) mice, ritonavir very efficiently prevented tumor growth and leukemic infiltration in various organs of NOG mice at the same dose used for treatment of patients with AIDS. Our data indicate that ritonavir has potent anti-NF-kappaB and antitumor effects and might be clinically applicable for treatment of ATL. These results would provide a new concept and novel platform for new drug development of leukemia and solid cancer as well.
Dewan
M Zahidunnabi
MZ
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Uchihara
Jun-nosuke
JN
Terashima
Kazuo
K
Honda
Mitsuo
M
Sata
Tetsutaro
T
Ito
Mamoru
M
Fujii
Nobutaka
N
Uozumi
Kimiharu
K
Tsukasaki
Kunihiro
K
Tomonaga
Masao
M
Kubuki
Yoko
Y
Okayama
Akihiko
A
Toi
Masakazu
M
Mori
Naoki
N
Yamamoto
Naoki
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D000077022:Survivin; D014158:Transcription, Genetic / Q000187:drug effects*; D051020:bcl-X Protein / Q000378:metabolism
C107489:BIRC5 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D017320:HIV Protease Inhibitors; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D000077022:Survivin; D051020:bcl-X Protein; D019438:Ritonavir