Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
Eur J Pharmacol. 2018 Apr 15;825:1-9. doi: 10.1016/j.ejphar.2018.02.012. Epub 2018 Feb 11.
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.
克唑替尼是一种间变性淋巴瘤激酶（ALK）抑制剂，对携带有 EML4-ALK 融合基因的非小细胞肺癌（NSCLC）患者具有显著的治疗益处。在本研究中，我们证明了α-生育酚（维生素 E 的主要成分之一）可独立于其抗氧化特性减弱克唑替尼的作用。α-生育酚可显著抑制 EML4-ALK 转化细胞中克唑替尼诱导的细胞凋亡。它还能有效减弱克唑替尼诱导的 EML4-ALK 及其下游分子 STAT3 和 ERK 的抑制作用，并抑制克唑替尼在焦点形成测定中对 EML4-ALK 介导的转化的抑制作用。另一方面，维生素 E 家族的其他成员，即β-生育酚、γ-生育酚、δ-生育酚和α-生育三烯酚，以及维生素 E 的水溶性类似物 Trolox，对 EML4-ALK 转化细胞中克唑替尼的抗肿瘤活性没有影响。总之，这些结果表明，当与含有α-生育酚（主要成分）的维生素 E 补充剂联合使用时，克唑替尼的抗肿瘤活性可能会减弱。
