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一种通过ATM-Chk2途径显示出强大抗肿瘤功效的硫代苯基哒嗪酮新型化合物IMB5043。

A new compound of thiophenylated pyridazinone IMB5043 showing potent antitumor efficacy through ATM-Chk2 pathway.

作者信息

Gong Jianhua, Zheng Yanbo, Wang Ying, Sheng Weijin, Li Yi, Liu Xiujun, Si Shuyi, Shao Rongguang, Zhen Yongsu

机构信息

Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

出版信息

PLoS One. 2018 Feb 2;13(2):e0191984. doi: 10.1371/journal.pone.0191984. eCollection 2018.

DOI:10.1371/journal.pone.0191984
PMID:29394294
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5796703/
Abstract

Through cell-based screening models, we have identified a new compound IMB5043, a thiophenylated pyridazinone, which exerted cytotoxicity against cancer cells. In the present study, we evaluated its antitumor efficacy and the possible mechanism. By MTT assay, IMB5043 inhibited the proliferation of various human cancer cells lines, especially hepatocarcinoma SMMC-7721 cells. IMB5043 blocked cell cycle with G2/M arrest, induced cell apoptosis, and inhibited the migration and invasion of SMMC-7721 cells. As verified by comet assay and γ-H2AX foci formation, IMB5043 caused DNA damage and activated ATM, Chk2 and p53 through phosphorylation. As shown by Gene microarray analysis, the differentially expressed genes in SMMC-7721 cells treated with IMB5043 were highly related to cell death and apoptosis. IMB5043 suppressed the growth of hepatocarcinoma SMMC-7721 xenograft in athymic mice. By histopathological examination, no lesions were found in bone marrow and various organs of the treated mice. Our findings reveal that IMB5043 as an active compound consisting of both pyridazinone and thiophene moieties exerts antitumor efficacy through activation of ATM-Chk2 pathway. IMB5043 may serve as a promising leading compound for the development of antitumor drugs.

摘要

通过基于细胞的筛选模型，我们鉴定出一种新的化合物IMB5043，即一种噻吩基化哒嗪酮，它对癌细胞具有细胞毒性。在本研究中，我们评估了其抗肿瘤疗效及可能的作用机制。通过MTT法检测，IMB5043抑制了多种人类癌细胞系的增殖，尤其是肝癌SMMC - 7721细胞。IMB5043使细胞周期阻滞于G2/M期，诱导细胞凋亡，并抑制SMMC - 7721细胞的迁移和侵袭。经彗星试验和γ-H2AX焦点形成验证，IMB5043导致DNA损伤，并通过磷酸化激活ATM、Chk2和p53。基因芯片分析显示，用IMB5043处理的SMMC - 7721细胞中差异表达的基因与细胞死亡和凋亡高度相关。IMB5043抑制了无胸腺小鼠体内肝癌SMMC - 7721异种移植瘤的生长。通过组织病理学检查，在处理过的小鼠的骨髓和各个器官中未发现病变。我们的研究结果表明，IMB5043作为一种同时含有哒嗪酮和噻吩部分的活性化合物，通过激活ATM - Chk2途径发挥抗肿瘤疗效。IMB5043可能作为一种有前景的先导化合物用于开发抗肿瘤药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/2c77f62d7aa8/pone.0191984.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/652b32b64af3/pone.0191984.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/653accc25ac4/pone.0191984.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/7d80957900af/pone.0191984.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/c04411a37716/pone.0191984.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/ee3270baef66/pone.0191984.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/161b4f3aaac0/pone.0191984.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/2c77f62d7aa8/pone.0191984.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/652b32b64af3/pone.0191984.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/653accc25ac4/pone.0191984.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/7d80957900af/pone.0191984.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/c04411a37716/pone.0191984.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/ee3270baef66/pone.0191984.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/161b4f3aaac0/pone.0191984.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ca64/5796703/2c77f62d7aa8/pone.0191984.g007.jpg

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