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The novel ALK inhibitor ZX‐29 induces apoptosis through inhibiting ALK and inducing ROS‐mediated endoplasmic reticulum stress in Karpas299 cells
Author(s) -
Zhou Xuejiao,
Zhang Xiaoning,
Wu Zhuzhu,
Xu Xiaobo,
Guo Ming,
Zhai Xin,
Zuo Daiying,
Wu Yingliang
Publication year - 2021
Publication title -
journal of biochemical and molecular toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.526
H-Index - 58
eISSN - 1099-0461
pISSN - 1095-6670
DOI - 10.1002/jbt.22666
Subject(s) - anaplastic lymphoma kinase , chemistry , apoptosis , endoplasmic reticulum , microbiology and biotechnology , unfolded protein response , anaplastic large cell lymphoma , ceritinib , cancer research , cell growth , biochemistry , lymphoma , biology , immunology , medicine , pleural effusion , malignant pleural effusion
It is a well‐known fact that 60%−85% of anaplastic large cell lymphoma (ALCL) is mainly driven by the anaplastic lymphoma kinase (ALK) fusion protein. Although ALK‐positive ALCL patients respond significantly to ALK inhibitors, the development of resistance is inevitable, which requires the development of new therapeutic strategies for ALK‐positive ALCL. Here, we investigated the anticancer activities of N ‐(2((5‐chloro‐2‐((2‐methoxy‐6‐(4‐methylpiperazin‐1‐yl)pyridin‐3yl)amino)pyrimidin‐4‐yl)amino)phenyl)methanesulfonamide (ZX‐29), a newly synthesized ALK inhibitor, against nucleophosmin−ALK‐positive cell line Karpas299. We demonstrated that ZX‐29 decreased Karpas299 cells growth and had better cytotoxicity than ceritinib, which was mediated through downregulating the expression of ALK and related proteins, inducing cell cycle arrest, and promoting cell apoptosis. Moreover, ZX‐29‐induced cell apoptosis by inducing endoplasmic reticulum stress (ERS). In addition, ZX‐29 increased the generation of reactive oxygen species (ROS), and cells pretreatment with N ‐acetyl‐ l ‐cysteine could attenuate ZX‐29‐induced cell apoptosis and ERS. Taken together, ZX‐29 inhibited Karpas299 cell proliferation and induced apoptosis through inhibiting ALK and its downstream protein expression and inducing ROS‐mediated ERS. Therefore, our results provide evidence for a novel antitumor candidate for the further investigation.