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

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

Volume: 24 Issue: 15

Author(s): Mingdong Wang, Jizhong Yin, Qianyu Han, Bing Li*, Xue-Wei Zhao*Lei Xue*

Affiliation:

• Department of Respiratory and Critical Care Medicine, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, 1279 Sanmen Road, Shanghai, 200434, China

• Department of Thoracic Surgery, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, 1279 Sanmen Road, Shanghai, 200434, China

• Department of Thoracic Surgery, Changzheng Hospital, Naval Medical University, 415 Fengyang Road, Shanghai, 200003, China

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.

Cite this article as:

Wang Mingdong, Yin Jizhong, Han Qianyu, Li Bing*, Zhao Xue-Wei*, Xue Lei*, Arsenic Trioxide Suppresses Angiogenesis in Non-small Cell Lung Cancer via the Nrf2-IL-33 Signaling Pathway, Anti-Cancer Agents in Medicinal Chemistry 2024; 24 (15) . https://dx.doi.org/10.2174/0118715206288348240420174853