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Updated: Sep 27, 2025
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells
Christopher Wolf1, Sonja Smith1, Sjoerd J L van Wijk1
1Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany.
Abstract:
Mutations in the Von Hippel-Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
Insights
Zafirlukast triggers a novel cell death pathway in clear cell renal cell carcinoma (ccRCC) that depends on Von Hippel-Lindau (VHL) and HIF-2α. This discovery offers potential new treatments for ccRCC, a cancer resistant to current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Clear cell renal cell carcinoma (ccRCC) is driven by Von Hippel-Lindau (VHL) gene mutations, leading to hypoxia-inducible factor (HIF) pathway activation.
- Despite advances, ccRCC remains resistant to conventional therapies, necessitating novel therapeutic strategies.
- Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are used for asthma and have shown potential in reducing cancer risk, but their mechanisms in cancer are unclear.
Purpose of the Study:
- To elucidate the mechanisms of zafirlukast-induced cell death in ccRCC cells.
- To investigate the roles of VHL, HIF-2α, oxidative stress, and proteasomal degradation in zafirlukast's anti-ccRCC effects.
Main Methods:
- Treatment of ccRCC cells with zafirlukast.
- Assessment of cell death pathways (non-apoptotic, non-necroptotic).
- Evaluation of the roles of VHL, HIF-2α, antioxidants, PARP-1 inhibitor (Olaparib), and proteasome inhibitor (MG-132).
Main Results:
- Zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells.
- This cell death is mitigated by antioxidants and Olaparib, and critically depends on HIF-2α.
- Proteasome inhibition with MG-132 sensitizes VHL wild-type cells to zafirlukast, and HIF-2α inhibition rescues cell death induced by both agents.
Conclusions:
- Zafirlukast triggers oxidative cell death in ccRCC cells through a pathway involving VHL, HIF-2α, and proteasomal degradation.
- These findings reveal a novel mechanism of action for zafirlukast with potential therapeutic implications for ccRCC treatment.
