Hypoxia-induced activity loss of a photo-responsive microtubule inhibitor azobenzene combretastatin A4
Hypoxia-induced activity loss of a photo-responsive microtubule inhibitor azobenzene combretastatin A4
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DOI：
10.1007/s11705-019-1864-6
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发表时间：
2020-10-01
影响因子：
4.5
通讯作者：
Wang, Zheng
中科院分区：
文献类型：
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作者：
An, Yang;Chen, Chao;Wang, Zheng
偶氮苯偶氮菌素A4(Azo-CA4)的构象依赖活性为减少化疗的副作用提供了一种独特的途径，这是由于其偶氮苯部分的光触发构象转变。然而，在低氧肿瘤微环境下，偶氮还原酶的高表达可以将偶氮苯还原为苯胺。推测偶氮CA4可能在低氧条件下降解，导致其抗肿瘤活性降低。本研究的目的是在体外HeLa细胞中验证这一假说。定量药物浓度分析显示了降解最终产物的比率-计量形成，证实了偶氮-CA4的生物还原。微管蛋白染色研究表明，在低氧条件下，偶氮CA4失去了关闭微管动力学的能力。此外，细胞周期分析表明，在低氧条件下，偶氮CA4诱导有丝分裂停止的能力丧失。因此，在低氧条件下，偶氮CA4的细胞毒性被削弱。相比之下，无论光照和氧气水平如何，作为阳性对照的comretasteatin A4保持了抑制微管蛋白聚合和分解细胞核的效力。这项工作强调了低氧肿瘤微环境对Azo-CA4抗肿瘤效力的影响，在设计翻译Azo-CA4递送系统的早期阶段应该考虑这一点。
The conformation-dependent activity of azobenzene combretastatin A4 (Azo-CA4) provides a unique approach to reduce the side-effects of chemotherapy, due to the light-triggered conformation transition of its azobenzene moiety. Under hypoxic tumor microenvironment, however, the high expression of azoreductase can reduce azobenzene to aniline. It was postulated that the Azo-CA4 might be degraded under hypoxia, resulting in the decrease of its anti-tumor activity. The aim of this study was to verify such hypothesis in HeLa cellsin vitro. The quantitative drug concentration analysis shows the ratio-metric formation of degradation end-products, confirming the bioreduction of Azo-CA4. The tubulin staining study indicates that Azo-CA4 loses the potency of switching off microtubule dynamics under hypoxia. Furthermore, the cell cycle analysis shows that the ability of Azo-CA4 to induce mitotic arrest is lost at low oxygen content. Therefore, the cytotoxicity of Azo-CA4 is compromised under hypoxia. In contrast, combretastatin A4 as a positive control maintains the potency to inhibit tubulin polymerization and break down the nuclei irrespective of light irradiation and oxygen level. This work highlights the influence of hypoxic tumor microenvironment on the anti-tumor potency of Azo-CA4, which should be considered during the early stage of designing translational Azo-CA4 delivery systems.