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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent
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A naphthalimide-polyamine conjugate preferentially accumulates in hepatic carcinoma metastases as a lysosome-targeted antimetastatic agent

机译：萘酰亚胺 - 多胺缀合物优先积聚在肝癌转移中作为溶酶体靶向抗致锑剂

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摘要

Disseminated tumors lead to approximately 90% of cancer-associated deaths especially for hepatocellular carcinoma (HCC), indicating the imperative need of antimetastatic drugs and the ineffectiveness of current therapies. Recently polyamine derivatives have been identified as a promising prospect in dealing with metastatic tumors. Herein, a novel class of naphthalimide-polyamine conjugates 8a-8d, 13a-13c, 17 and 21 were synthesized and the mechanism was further determined. The polyamine conjugate 13b displayed remarkably elevated anti-tumor and anti-metastatic effects (76.01% and 75.02%) than the positive control amonafide (46.91% and 55.77%) at 5 mg/kg in vivo. The underlying molecular mechanism indicated that in addition to induce DNA damage by up-regulating p53 and gamma H2AX, 13b also targeted lysosome to modulate polyamine metabolism and function in a totally different way from that of amonafide. Furthermore, the HMGB1/p62/LC3II/LC3I and p53/SSAT/b-catenin pathways were mainly involved in the inhibition of 13b-induced HCC metastasis by targeting polyamine transporters (PTs) overexpressed in HCC. At last, 13b down-regulated the concentrations of Put, Spd and Spm by modulating polyamine metabolism key enzymes SSAT and PAO, which favored the suppression of fast growing tumor cells. Taken together, our study implies a promising strategy for naphthalimide conjugates to treat terminal cancer of HCC by targeting autophagy and tumor microenvironment with reduced toxicities and notable activities. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：播散性肿瘤导致约90%的癌症相关死亡，尤其是肝细胞癌（HCC），这表明抗转移药物的迫切需求和当前治疗的无效性。近年来，多胺衍生物被认为是治疗转移性肿瘤的一个很有前景的药物。在此，合成了一类新型萘酰亚胺多胺共轭物8a-8d、13a-13c、17和21，并进一步确定了其机理。在5 mg/kg的体内试验中，多胺结合物13b的抗肿瘤和抗转移效果（76.01%和75.02%）显著高于阳性对照阿莫那非（46.91%和55.77%）。潜在的分子机制表明，除了通过上调p53和γH2AX诱导DNA损伤外，13b还以溶酶体为靶点，以与阿莫那非完全不同的方式调节多胺代谢和功能。此外，HMGB1/p62/LC3II/LC3I和p53/SSAT/b-catenin通路主要通过靶向多胺转运体（PTs）在HCC中过度表达来抑制13b诱导的HCC转移。最后，13b通过调节多胺代谢关键酶SSAT和PAO来下调Put、Spd和Spm的浓度，有利于抑制快速生长的肿瘤细胞。综上所述，我们的研究表明，萘酰亚胺结合物通过靶向自噬和肿瘤微环境治疗晚期肝癌是一种很有前景的策略，其毒性降低，活性显著。（c）2021爱思唯尔马松SAS。版权所有。

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  • 作者

    Ma Jing; Li Linrong; Yue Kexin; Zhang Zhansheng; Su Shihao; Chen Yutong; Yu Lu; Zhang Pengfei; Ma Ruijuan; Li Yingguang; Ma Yinxia; Jia Huinan; Wang Chaojie; Wang Jiajia; Xie Songqiang;

  • 作者单位

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

    Henan Univ Key Lab Nat Med &

    Immunoengn Kaifeng 475004 Peoples R China;

    Henan Univ Henan Univ Joint Natl Lab Antibody Drug Engn Sch Basic Med Sci Kaifeng Peoples R;

    Henan Univ Sch Pharm Inst Innovat Drug Design &

    Evaluat N Jinming Ave Kaifeng 475004 Peoples R;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    Naphthalimide conjugates; Polyamine metabolism and function; Lysosome; Polyamine transporter; Hepatic carcinoma;

    机译：萘酰亚胺共轭物;多胺代谢和功能;溶酶体;多胺转运体;肝癌;

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