Aurora kinase inhibitor AZD1152 negatively affects the growth and survival of HTLV-1-infected T lymphocytes in vitro.
Aurora kinases play an essential role in regulating mitosis and cell division. Inhibition of Aurora kinases results in suppression of cell division, phosphorylation of histone H3 and induction of apoptosis in many cell types. These characteristics have prompted the testing of Aurora kinase inhibitors as chemotherapeutic agents. In our study, we report the in vitro activities of AZD1152, a selective inhibitor of Aurora B kinase in human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia (ATL), -infected T-cell lines. Overexpression of Aurora B was noted in HTLV-1-infected T-cell lines compared to HTLV-1-uninfected T-cell lines. AZD1152 reduced the viability of HTLV-1-infected T-cell lines within 24 hr but did not affect that of -uninfected T-cell lines. Although AZD1152 inhibited phosphorylation of histone H3 on Ser10 in both HTLV-1-infected and -uninfected T-cell lines, it induced polyploidy only in HTLV-1-uninfected T-cell lines. AZD1152 induced early apoptosis of HTLV-1-infected T-cells without induction of polyploidy. We have reported previously that a pan-Aurora kinase inhibitor induced apoptosis through inhibition of NF-kappaB signaling activity in HTLV-1-infected T-cell lines. In contrast, AZD1152 did not affect NF-kappaB activity in these cells. It induced p53 and p21 expression in HTLV-1-infected but not in HTLV-1-uninfected T-cell lines, suggesting that activation of p53-dependent postmitotic checkpoint might prevent polyploidy in HTLV-1-infected T-cells. Our results suggest that specific inhibition of Aurora B kinase is a potentially useful therapeutic strategy in the treatment of ATL and that further in vivo exploration is warranted.
Tomita
Mariko
M
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Tanaka
Yuetsu
Y
Mori
Naoki
N
D064107:Aurora Kinase B; D064127:Aurora Kinases; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D010755:Organophosphates / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology*; D014162:Transfection
C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010755:Organophosphates; D011799:Quinazolines; D034741:RNA, Small Interfering; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases