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


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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.

About the authors

Mingdong Wang

Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University

Email: info@benthamscience.net

Jizhong Yin

Department of Respiratory and Critical Care Medicine, Changzheng Hospital, Naval Medical University

Email: info@benthamscience.net

Qianyu Han

Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University

Email: info@benthamscience.net

Bing Li

Department of Respiratory and Critical Care Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University

Author for correspondence.
Email: info@benthamscience.net

Xue-Wei Zhao

Department of Thoracic Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University

Author for correspondence.
Email: info@benthamscience.net

Lei Xue

Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University

Author for correspondence.
Email: info@benthamscience.net

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