RRC ID |
61251
|
著者 |
Uchihara Y, Ueda F, Tago K, Nakazawa Y, Ohe T, Mashino T, Yokota S, Kasahara T, Tamura H, Funakoshi-Tago M.
|
タイトル |
Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK.
|
ジャーナル |
PLoS One
|
Abstract |
Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although α-tocopherol suppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with α-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with α-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of α-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the α-tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E.
|
巻・号 |
12(8)
|
ページ |
e0183003
|
公開日 |
2017-1-1
|
DOI |
10.1371/journal.pone.0183003
|
PII |
PONE-D-17-18883
|
PMID |
28806414
|
PMC |
PMC5555621
|
MeSH |
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Crizotinib
Female
Humans
Lymphoma, Large-Cell, Anaplastic / metabolism
Mice, Nude
Phosphorylation / drug effects
Protein-Tyrosine Kinases / metabolism*
Pyrazoles / pharmacology*
Pyridines / pharmacology*
Reactive Oxygen Species / metabolism
Subcellular Fractions / metabolism
alpha-Tocopherol / pharmacology*
|
IF |
2.74
|
リソース情報 |
ヒト・動物細胞 |
Ba/F3(RCB0805) |