Arsenic Trioxide Suppresses Angiogenesis in Non-small Cell Lung Cancer via the Nrf2-IL-33 Signaling Pathway.

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Anti-cancer agents in medicinal chemistry Pub Date : 2024-01-01 DOI:10.2174/0118715206288348240420174853

Mingdong Wang, Jizhong Yin, Qianyu Han, Bing Li, Xue-Wei Zhao, Lei Xue

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引用次数: 0

Abstract

Background: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis.

Objective: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway.

Methods: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR, and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO.

Results: High expression levels of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth.

Conclusion: Nrf2-IL-33 signaling is usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.

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三氧化二砷通过 Nrf2-IL-33 信号通路抑制非小细胞肺癌的血管生成

背景：非小细胞肺癌（NSCLC）是导致癌症相关死亡的主要原因之一，因此迫切需要寻找经济有效的抗 NSCLC 药物。我们的初步研究表明，三氧化二砷（ATO）能显著抑制 NSCLC 血管生成，发挥抗肿瘤作用。结合现有文献报道，Nrf2-IL-33通路正在成为NSCLC血管生成的一种新机制：本研究旨在阐明ATO是否能通过Nrf2-IL-33途径抑制NSCLC血管生成：方法：采用免疫组化方法评估 NSCLC 患者肿瘤组织中 Nrf2、IL-33 和 CD31 的表达。用 DETA-NONOate 作为一氧化氮（NO）供体来模拟肿瘤微环境中的高浓度 NO。利用 Western 印迹、定量实时 PCR 和酶联免疫吸附试验来评估 NCI-H1299 细胞系中 Nrf2 和 IL-33 的表达。通过植入 NCI-H1299 细胞建立裸鼠皮下异种移植模型，以评估 ATO 的抗肿瘤疗效：结果：在 NSCLC 患者的肿瘤样本中观察到 Nrf2 和 IL-33 的高表达水平，Nrf2 的表达与 NSCLC 的微血管密度呈正相关。在体外，NO（由 1mM DETA-NONOate 释放）促进了 NCI-H1299 细胞中 Nrf2-IL-33 信号通路的激活，而 ATO 逆转了这种激活。此外，Nrf2 缺乏和 ATO 处理都能显著减少 NO 诱导的 IL-33 表达。在体内，ATO和Nrf2抑制剂ML385都对血管生成肿瘤的生长有明显的抑制作用：结论：Nrf2-IL-33 信号通常在 NSCLC 中被激活，并与肿瘤血管生成呈正相关。ATO能有效破坏NSCLC中Nrf2-IL-33通路的激活，从而抑制血管生成，这表明它有可能作为一种抗血管生成药物用于治疗NSCLC。

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来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.