Suppr超能文献

一种基于吉西他滨的缀合物,通过在缺氧条件下抑制 HIF-1α 的表达来增强抗肿瘤疗效。

A gemcitabine-based conjugate with enhanced antitumor efficacy by suppressing HIF-1α expression under hypoxia.

机构信息

Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Institute of Nanjing Junruo Biomedicine, Nanjing 211100, China.

Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China.

出版信息

Bioorg Med Chem. 2021 Jul 1;41:116214. doi: 10.1016/j.bmc.2021.116214. Epub 2021 May 11.

Abstract

Hypoxia is one of the unique features of tumor physiology. Hypoxia inducible factor (HIF-1α), as a major transcription factor in response to hypoxia, has been considered as a promising tumor-specific target for anticancer therapy. The formation of a hypoxic microenvironment in tumors can decrease the curative effect of cytotoxic chemotherapeutic drugs. To promote the antitumor efficacy of chemotherapy by suppressing hypoxia, we designed and prepared a novel gemcitabine-based drug conjugate (GEM-5) containing a HIF-1α inhibitor (YC-1). As expected, GEM-5 showed excellent antiproliferative activity (IC = 0.03 μΜ under hypoxia) and remarkably induced the apoptosis of A2780 cells in vitro. Additionally, western blot analysis demonstrated that GEM-5 significantly down-regulated the expression of HIF-1α and up-regulated the expression of tumor suppressor p53. More importantly, GEM-5 effectively inhibited tumor growth in the A2780 xenograft mouse model and significantly ameliorated tumor hypoxia in vivo. This novel, simple, and effective strategy for overcoming tumor hypoxia and enhancing the antitumor effect of chemotherapeutic drugs has great potential in cancer therapy.

摘要

缺氧是肿瘤生理学的一个独特特征。缺氧诱导因子 (HIF-1α) 作为对缺氧反应的主要转录因子,已被认为是一种有前途的抗肿瘤治疗的肿瘤特异性靶点。肿瘤中缺氧微环境的形成会降低细胞毒性化疗药物的疗效。为了通过抑制缺氧来提高化疗的抗肿瘤疗效,我们设计并制备了一种新型基于吉西他滨的药物偶联物 (GEM-5),其中含有 HIF-1α 抑制剂 (YC-1)。正如预期的那样,GEM-5 在缺氧条件下表现出优异的增殖抑制活性 (IC = 0.03 μΜ),并显著诱导 A2780 细胞体外凋亡。此外,Western blot 分析表明,GEM-5 显著下调 HIF-1α 的表达,上调肿瘤抑制因子 p53 的表达。更重要的是,GEM-5 有效地抑制了 A2780 异种移植小鼠模型中的肿瘤生长,并显著改善了体内肿瘤缺氧。这种克服肿瘤缺氧和增强化疗药物抗肿瘤作用的新型、简单、有效的策略在癌症治疗中有很大的潜力。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验