A major component of vitamin E, α-tocopherol inhibits the anti-tumor activity of crizotinib against cells transformed by EML4-ALK

• Published in: European journal of pharmacology 2018-04, Vol.825, p.1-9
• Main Authors: Uchihara, Yuki, Kidokoro, Takayuki, Tago, Kenji, Mashino, Tadahiko, Tamura, Hiroomi, Funakoshi-Tago, Megumi
• Format: Article
• Language: English
• Subjects: Crizotinib; EML4-ALK; NSCLC; Vitamin E; α-tocopherol
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2018.02.012

Crizotinib is an inhibitor of anaplastic lymphoma kinase (ALK) and is of significant therapeutic benefit to patients with non-small cell lung cancer (NSCLC) harboring the EML4-ALK fusion gene. In the present study, we demonstrated that α-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. α-Tocopherol significantly inhibited crizotinib-induced apoptosis in cells transformed by EML4-ALK. It also effectively attenuated the crizotinib-induced inhibition of EML4-ALK and its downstream molecules, STAT3 and ERK, and suppressed the inhibitory effects of crizotinib on EML4-ALK-mediated transformation in the focus formation assay. On the other hand, other members of the vitamin E family, namely, β-tocopherol, γ-tocopherol, δ-tocopherol, and α-tocotrienol, and a water-soluble analog of vitamin E, Trolox had no effects on the anti-tumor activity of crizotinib in cells transformed by EML4-ALK. Collectively, these results revealed the risk of the anti-tumor activity of crizotinib being attenuated when it is administrated in combination with vitamin E supplements containing α-tocopherol as a major component. [Display omitted] •α-tocopherol attenuates crizotinib-induced inhibition of EML4-ALK, STAT3 and ERK.•α-tocopherol inhibits crizotinib-induced apoptosis in cells transformed by EML4-ALK.•α-tocopherol functions independently of its anti-oxidant properties.