In a groundbreaking study published in the latest issue of Cell Death Discovery, researchers have uncovered a novel mechanism through which amlodipine, a well-known antihypertensive drug, exerts potent inhibitory effects on glioma stem cells (GSCs). The investigation reveals that amlodipine actively promotes the degradation of epidermal growth factor receptor (EGFR), a critical driver of tumor growth and survival in gliomas, thereby suppressing the downstream pro-survival signaling cascades that render these stem cells resilient to traditional therapies.
Gliomas represent one of the most aggressive and fatal types of brain tumors, characterized by rapid proliferation and resistance to conventional chemotherapy and radiotherapy. At the heart of this oncogenic persistence are glioma stem cells, a subpopulation responsible for tumor initiation, progression, and relapse. These cells display enhanced self-renewal capabilities and heightened resistance to apoptosis, often fueled by aberrant signaling pathways downstream of receptors like EGFR. The study sheds light on how amlodipine, widely used for its vascular effects, can be repurposed for targeted glioma therapy by dismantling these molecular circuits.
The researchers focused on investigating the molecular interplay between amlodipine and EGFR stability within glioma stem cells. They discovered that treatment with amlodipine led to a marked decrease in EGFR protein levels, which was attributable to accelerated receptor degradation rather than transcriptional suppression. This finding is pivotal as EGFR overexpression and mutations are frequently implicated in the malignant transformation and therapeutic resistance of gliomas. By promoting receptor turnover, amlodipine effectively blunts the cell’s ability to exploit EGFR signaling for survival and proliferation.
Further mechanistic insights revealed that amlodipine disrupts multiple downstream signaling pathways emanating from EGFR, including the PI3K/Akt and MAPK/ERK cascades. These pathways are well-established mediators of cell survival, growth, and metabolic regulation, and their inhibition precipitates increased apoptotic activity within the GSC population. Consequently, treated glioma stem cells exhibited reduced viability and diminished capacity to form tumor-spheres, which serve as a functional hallmark of stem-like tumor properties.
An intriguing aspect of this research is the repositioning of amlodipine, a calcium channel blocker traditionally prescribed for hypertension and cardiovascular diseases, as an anti-cancer agent. Unlike classical chemotherapeutics, which often cause systemic toxicity, amlodipine’s established pharmacological profile and safety in humans make it a prime candidate for rapid clinical translation. This study pioneers a paradigm shift in glioma treatment strategies, emphasizing drug repurposing as a feasible and cost-effective avenue to tackle refractory cancers.
To validate these in vitro findings, the study incorporated in vivo experiments using glioma xenograft models in mice. Treatment with amlodipine significantly impeded tumor growth and prolonged survival rates, corroborating its therapeutic potential. Histological analysis of the tumors confirmed reduced EGFR expression and suppressed downstream signaling activity, reinforcing the mechanistic conclusions drawn from cellular assays. These preclinical data build a compelling case for advancing amlodipine into clinical trials focused on glioma patients.
Moreover, the molecular specificity of amlodipine’s action was explored by examining its impact on non-tumorigenic neural stem cells, which showed minimal sensitivity to the drug. This selective targeting minimizes the risk of adverse neurological effects, a crucial consideration in brain tumor therapies where damage to normal brain tissue must be avoided. The differential response underscores a therapeutic window whereby amlodipine preferentially attacks malignant stem cells without compromising healthy neural populations.
The investigation also delved into the dynamics of EGFR downregulation, demonstrating that amlodipine induces receptor internalization followed by lysosomal degradation. This process effectively removes EGFR from the cell surface, cutting off oncogenic signaling at its source. The ability to promote receptor trafficking toward degradation mechanisms represents a novel and effective approach to modulating receptor tyrosine kinase activity, which could have broader implications beyond gliomas.
Interestingly, the study indicates that the efficacy of amlodipine may be enhanced when combined with other targeted therapies that inhibit parallel or compensatory signaling pathways. This combinatorial strategy could overcome potential resistance mechanisms and maximize therapeutic outcomes. The integration of amlodipine into multi-modal treatment regimens heralds a new direction in personalized medicine for glioma patients, tailoring interventions based on tumor-specific molecular profiles.
Additionally, the research team utilized advanced proteomic analyses to chart the extensive network of protein interactions modulated by amlodipine treatment. Changes in phosphorylation states and expression levels of key survival proteins reinforced the drug’s comprehensive impact on glioma stem cell biology. Such granular insights provide a robust framework for deciphering the complexities of treatment responses and identifying biomarkers predictive of treatment efficacy.
In the broader context of cancer therapeutics, this study exemplifies the importance of revisiting existing medications under new scientific lenses. The repositioning of amlodipine offers an exemplary model, illustrating how pharmacological agents originally designed for unrelated diseases can unveil unexpected anti-cancer properties through meticulous molecular research. This approach not only expedites the drug development pipeline but also mitigates risks associated with novel drug discovery.
Looking ahead, Li et al. emphasize the necessity of clinical investigations to assess amlodipine’s efficacy and safety in glioma patients. They advocate for well-designed phase I/II trials to determine optimal dosing schedules, pharmacodynamics, and potential synergistic combinations. The translational trajectory outlined by this study promises to fast-track a novel therapeutic avenue, offering hope against one of the most challenging neuro-oncological diseases.
In conclusion, this pioneering research unearths a compelling new role for amlodipine as a disruptor of EGFR-dependent pro-survival pathways in glioma stem cells. By facilitating EGFR degradation and curbing downstream oncogenic signaling, amlodipine impairs glioma stemness and tumorigenesis. With its favorable safety profile and demonstrated in vivo efficacy, amlodipine stands poised to revolutionize glioma treatment paradigms and improve patient prognoses in this devastating disease.
Subject of Research: Investigation of the inhibitory effects of amlodipine on glioma stem cells through targeting EGFR degradation and downstream signaling pathways.
Article Title: Amlodipine exerts inhibitory effects against glioma stem cells through degrading EGFR and down-regulating its downstream pro-survival pathways.
Article References:
Li, Z., Zhang, X., Wen, P. et al. Amlodipine exerts inhibitory effects against glioma stem cells through degrading EGFR and down-regulating its downstream pro-survival pathways. Cell Death Discov. 11, 492 (2025). https://doi.org/10.1038/s41420-025-02784-3
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02784-3
Tags: Amlodipine and glioma stem cellsantihypertensive drugs in cancer therapycancer stem cell resilienceEGFR degradation in gliomasglioma aggressiveness and stemnessglioma treatment resistance mechanismsmolecular mechanisms of glioma stem cellsnovel therapeutic approaches for glioblastomarepurposing amlodipine for cancersignaling pathways in gliomastargeted therapy for brain tumorstumor growth inhibition strategies
