Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK

作者：Uchihara Yuki; Ueda Fumihito; Tago Kenji; Nakazawa Yosuke; Ohe Tomoyuki; Mashino Tadahiko; Yokota Shigenobu; Kasahara Tadashi; Tamura Hiroomi; Funakoshi Tago Megumi^*

来源：PLos One, 2017, 12(8): e0183003.

DOI：10.1371/journal.pone.0183003

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 a-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although alpha-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 a-tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with a-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of a-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALKprovoked tumorigenesis in vivo. Furthermore, the a-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.

• 出版日期2017-8-14