The unexpected anti-cancer potential of a common asthma medication reveals a new vulnerability in one of the most treatment-resistant cancers.
Imagine a drug prescribed for asthma suddenly revealing a hidden talent—the ability to fight cancer. This isn't science fiction. Zafirlukast, a medication used for years to control asthma symptoms, is now demonstrating remarkable capabilities against clear cell renal cell carcinoma (ccRCC), the most common and deadly form of kidney cancer. The discovery of its cancer-fighting potential emerged from a fascinating connection between two seemingly unrelated biological processes: inflammation and cancer growth.
Kidney cancer represents a significant health burden worldwide, ranking among the top ten most common cancers. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 70-80% of all kidney cancer cases and is responsible for the majority of kidney cancer-related deaths 6 8 .
of kidney cancer cases are ccRCC
median survival for metastatic ccRCC
key tumor suppressor lost in ccRCC
What makes ccRCC particularly challenging to treat is its unique biology. Unlike many other cancers, ccRCC is generally resistant to conventional chemotherapy and radiotherapy. For patients with metastatic ccRCC, the median survival is approximately 13 months, highlighting the urgent need for more effective treatments 2 .
The root of ccRCC's stubbornness lies in its genetic origins. In the majority of cases, the disease begins with the loss of a critical tumor suppressor gene called Von Hippel-Lindau (VHL). Under normal conditions, the VHL protein acts as a quality control manager, ensuring that specific proteins called hypoxia-inducible factors (HIFs) are properly disposed of when oxygen levels are normal 6 7 .
When VHL is missing, HIF-α subunits—particularly HIF-2α—accumulate uncontrollably, activating hundreds of genes that promote tumor growth, blood vessel formation, and metastasis. This happens regardless of oxygen availability, essentially putting cancer cells in a permanent state of "false hypoxia" that drives aggressive tumor behavior 6 7 8 .
| Feature | Description | Clinical Significance |
|---|---|---|
| Prevalence | 70-80% of all kidney cancers | Most common kidney cancer subtype |
| Cell of Origin | Proximal convoluted tubule | Understanding cancer beginnings |
| Genetic Driver | VHL loss/mutation (in ~95% cases) | Primary molecular event |
| Key Molecular Consequence | HIF-2α stabilization and accumulation | Drives tumor progression |
| Typical Treatment Resistance | Resistant to conventional chemotherapy/radiotherapy | Need for targeted therapies |
| 5-year Survival for Metastatic Disease | Approximately 10% | Highlights urgent need for better treatments |
Zafirlukast belongs to a class of drugs known as cysteinyl leukotriene receptor antagonists (LTRAs), commonly prescribed for managing asthma and allergic rhinitis. These medications work by blocking inflammatory molecules called leukotrienes 2 .
Long-term studies revealed that patients using LTRAs for asthma management showed a significantly decreased risk of developing several cancer types 2 . This observation sparked scientific curiosity about the potential anti-cancer properties of these drugs.
Subsequent research confirmed that zafirlukast and other leukotriene receptor antagonists could indeed inhibit tumor growth in various cancers, including glioblastoma, lung, prostate, colon, and triple-negative breast cancer 2 . But the mechanisms behind these effects remained largely unexplored until researchers turned their attention to kidney cancer.
A pivotal 2022 study published in the International Journal of Molecular Sciences uncovered exactly how zafirlukast targets kidney cancer cells with remarkable precision 1 2 3 . The researchers designed a series of elegant experiments using the 786-O ccRCC cell line, which naturally lacks functional VHL, mimicking the genetic setup of human ccRCC tumors.
The investigation began by exposing both VHL-deficient cancer cells and normal kidney cells with functional VHL to increasing concentrations of zafirlukast. The results were striking: zafirlukast selectively induced cell death in cancer cells while sparing normal kidney cells 2 .
To confirm VHL's role, researchers reintroduced functional VHL back into the cancer cells. The outcome was dramatic—cells with restored VHL became completely resistant to zafirlukast-induced death. This confirmed that the drug specifically targets the VHL-deficient environment of ccRCC cells 2 .
Further investigation revealed that the type of cell death induced by zafirlukast was unusual—it wasn't traditional apoptosis (programmed cell death) or necroptosis. Instead, the drug triggered oxidative cell death characterized by massive buildup of reactive oxygen species (ROS). When researchers added antioxidants, they successfully rescued the cells from zafirlukast-induced death, confirming the oxidative nature of the cell death 1 2 .
The final piece of the puzzle involved HIF-2α. By inhibiting HIF-2α, researchers could protect cancer cells from zafirlukast, demonstrating that HIF-2α is essential for the drug's mechanism 1 2 . Even more intriguingly, when they combined zafirlukast with proteasome inhibitors (which block protein degradation), they could sensitize even VHL-positive cells to the drug's effects 1 2 .
| Experimental Condition | Effect on Zafirlukast-Induced Cell Death | Scientific Significance |
|---|---|---|
| VHL-deficient cells | High cell death | Confirms selective targeting of cancer cells |
| VHL-restored cells | Resistant to cell death | Demonstrates VHL-dependence |
| Addition of antioxidants | Cell death prevented | Identifies oxidative cell death mechanism |
| HIF-2α inhibition | Cell death prevented | Establishes HIF-2α requirement |
| Proteasome inhibition + zafirlukast | Sensitized VHL-positive cells | Reveals potential combination strategy |
| Research Tool | Function/Application | Relevance to Study |
|---|---|---|
| 786-O cell line | VHL-mutated human ccRCC cells | Primary disease model for experiments |
| 293T cell line | Human embryonic kidney cells with wild-type VHL | Normal cell control |
| Olaparib | PARP-1 inhibitor | Demonstrates involvement of PARP-1 in cell death mechanism |
| MG-132 | Proteasome inhibitor | Sensitizes VHL wild-type cells to zafirlukast |
| HIF-2α inhibitors | Specifically blocks HIF-2α activity | Confirms HIF-2α dependence in zafirlukast-induced death |
| Propidium Iodide (PI) | Fluorescent DNA dye that excludes live cells | Measures cell death through flow cytometry |
| Antioxidants | Scavenge reactive oxygen species | Confirms oxidative cell death mechanism |
Loss of tumor suppressor gene creates vulnerability
Stabilized HIF-2α drives cancer progression
Zafirlukast induces ROS-mediated cell death
VHL-deficient ccRCC cells die while normal cells are spared
The discovery of zafirlukast's unique mechanism represents more than just academic interest—it opens up tangible therapeutic possibilities. The dependence on both VHL deficiency and HIF-2α creates a built-in safety mechanism that could potentially spare healthy cells, reducing side effects commonly associated with traditional chemotherapy 1 2 .
The dual dependence on VHL deficiency and HIF-2α creates a built-in safety mechanism that could potentially spare healthy cells.
Proteasome inhibition can sensitize VHL-positive cells to zafirlukast, suggesting potential combination therapies.
This research comes at a time when HIF-2α is already a validated drug target in ccRCC. The FDA has approved belzutifan, a HIF-2α inhibitor, for certain VHL-associated cancers, confirming the clinical relevance of this pathway 9 . Zafirlukast's different mechanism—inducing oxidative death specifically in HIF-2α-active cells rather than simply inhibiting it—adds a new strategic approach to targeting this crucial cancer pathway.
The finding that proteasome inhibition can sensitize VHL-positive cells to zafirlukast suggests potential combination therapies that could broaden the drug's applicability beyond VHL-deficient cancers 1 2 . This is particularly important given that some ccRCC cases without clear VHL mutations still exhibit similar molecular signatures.
The story of zafirlukast exemplifies how observing unexpected clinical correlations can lead to groundbreaking scientific discoveries. What began as an asthma medication has revealed a novel vulnerability in one of the most treatment-resistant cancers.
Zafirlukast represents not just a potential new treatment, but a completely different strategy for attacking kidney cancer—one that exploits the very genetic defects that make the cancer aggressive in the first place.
While more research is needed to translate these findings from laboratory models to human patients, the implications are profound. As research continues, the hope is that zafirlukast or drugs developed based on its mechanism could provide a more targeted, effective, and less toxic alternative for the thousands of patients diagnosed with this challenging disease each year. In the ongoing battle against cancer, sometimes the most powerful weapons come from the most unexpected places.