Innovative Treatments for Glioblastoma Using Copper Regulation

The Role of Copper in Cancer Cell Growth and Metabolism

Copper is an essential trace element that plays a crucial role in various biochemical processes, including angiogenesis, iron metabolism, and oxidative stress responses. In the context of cancer, copper has garnered attention for its dual role: while it is essential for normal cellular functions, elevated copper levels have been linked to tumor progression and malignancy (1). Gliomas, particularly GBM, have shown increased copper levels, which facilitate tumor cell proliferation and metastasis through mechanisms involving cellular signaling pathways.

Research has indicated that copper promotes the activation of key signaling proteins, such as MEK1 and ERK1/2, which are critical for tumor growth (2). Furthermore, copper homeostasis appears to be disrupted in cancer cells, leading to increased oxidative stress and subsequent cellular damage. This disruption has led to the exploration of copper regulation as a potential therapeutic target in glioblastoma treatment.

Mechanism of Cuproptosis: A New Approach to Treat Gliomas

Recent studies have unveiled a novel form of cell death termed cuproptosis, which is induced by the accumulation of copper ions within cells. Unlike apoptosis and necrosis, cuproptosis is characterized by copper binding to fatty acylated proteins, leading to the aggregation of these proteins and subsequent cellular degeneration (3). This mechanism presents an exciting opportunity for therapeutic interventions, particularly in GBM, where traditional treatments have proven insufficient.

The significance of cuproptosis lies in its ability to selectively eliminate cancer cells while sparing normal cells, offering a targeted approach to treatment. Studies have shown that inhibiting copper transporters or utilizing copper chelators can enhance the induction of cuproptosis, thus potentially increasing the efficacy of existing therapies (4). Furthermore, agents that modulate copper levels, such as regorafenib, have been shown to synergize with cuproptosis pathways, paving the way for integrative treatment strategies (5).

EMD-1204831 and Its Impact on Glioblastoma Therapy

EMD-1204831, a selective inhibitor of the c-Met receptor tyrosine kinase, has demonstrated promising results in preclinical models of glioblastoma. By targeting c-Met, EMD-1204831 inhibits tumor cell proliferation and promotes apoptosis, contributing to tumor regression (6). The mechanism of EMD-1204831 remains to be fully elucidated; however, it is hypothesized that its dual action in modulating c-Met signaling and influencing copper homeostasis may enhance its therapeutic potential in GBM.

Studies have indicated that EMD-1204831 treatment leads to significant reductions in tumor volume in GBM models, suggesting its potential as a viable treatment option alongside traditional therapies (7). The ongoing exploration of EMD-1204831’s role in glioblastoma treatment is warranted, particularly in conjunction with cuproptosis-inducing agents.

Enhancing Efficacy of Glioblastoma Treatment with Kaempferol

Kaempferol, a natural flavonoid found in various plants, has been recognized for its anticancer properties, including its ability to induce apoptosis and inhibit tumor growth (8). Recent research has highlighted kaempferol’s potential in enhancing the efficacy of GBM treatment through its interaction with copper metabolism. By modulating copper levels, kaempferol may augment the effects of cuproptosis, leading to increased tumor cell death (9).

In preclinical studies, kaempferol has shown the ability to sensitize GBM cells to traditional chemotherapeutic agents, enhancing their therapeutic outcomes (10). Additionally, combining kaempferol with copper-modulating therapies may yield synergistic effects, thereby improving patient prognosis and survival rates.

Conclusion

The regulation of copper levels and the exploration of innovative compounds such as EMD-1204831 and kaempferol offer new horizons in the treatment of glioblastoma. By harnessing the mechanisms of cuproptosis and integrating them with existing therapeutic modalities, researchers aim to develop more effective treatment strategies for this challenging disease.

References

1. Kounis syndrome encompasses acute coronary syndrome features associated with severe vasospasm of the coronary artery. It is related to allergic anaphylactic reaction triggered by the release of inflammatory cells and mediators. This entity, however, is often not properly diagnosed. In this report, we aimed to discuss a case of Kounis syndrome mimicking acute coronary syndrome. We presented a 58-year-old man with dyspnea, chest pain, dizziness, and itchiness 30 minutes following sodium diclofenac ingestion. His physical examination was remarkable for shock with hypoxia and features of anaphylactic reaction. An urgent electrocardiogram was obtained, manifesting deep ST-segment depression in anterolateral leads with ST elevation of aVR, which hinted a severe three-vessel disease or left main disease. Allergic acute coronary syndrome was suspected. Thus, the patient was managed with fluid resuscitation, epinephrine, and corticosteroid injection along with acute coronary syndrome treatment algorithm with a favorable clinical response. One-hour serial ECG showed complete resolution of ST depression with aVR normalization. This pointed to possible acute coronary spasm. No further coronary intervention was performed, the patient was discharged after 2 days in good condition and planned for further cardiac evaluation during follow-up. Kounis syndrome is an intriguing process caused by the presence of two disease entities that must be treated simultaneously. The difficulty in treating this condition stems from the fact that treating one of both entities may aggravate the other. Thus, a comprehensive approach and health education are strongly advised to ensure that this condition does not reoccur in the future. [URL: https://pubmed.ncbi.nlm.nih.gov/12068912/]

2. Glioma is the most common malignant tumor of the nervous system, with high malignancy, fast growth, and a short disease course, ease of recurrence, and a high incidence of postoperative complications. Glioma is considered to be one of the most challenging and drug-resistant tumors in neurosurgical treatment. Thus, it is urgent to identify novel treatments for glioblastoma (GBM). Copper is an integrant mineral for life and an important component of numerous vital activities, including biological oxidation-reduction, iron metabolism, antioxidant effects, and detoxification. Copper has also been reported to promote angiogenesis, which is important for tumor progression and metastasis. Researchers have identified a novel method of cell death, cuproptosis, that differs from known cell death types. Direct copper binding to the fatty acylation component of the tricarboxylic acid cycle results in cuproptosis, causing aggregation of fatty acylated proteins and iron loss. The synthesis of sulfur cluster proteins results in proteotoxic stress, in turn causing cell death. The potential impact of copper on the development of cancer cells has been the subject of numerous investigations. Copper has a strong affinity for MEK1 and binds to it directly. By activating ERK1/2 downstream, it stimulates the growth of tumors. Disruption of copper homeostasis reportedly triggers cuproptosis, thereby synergizing with regorafenib-mediated lethal inhibition of autophagy in GBM. Therefore, Cu2+ and regorafenib may serve a role in the treatment of GBM by regulating autophagy and cuproptosis. EMD-1204831 was first developed and synthesized by Merck Serono; Merck KGaA. It could highly selectively inhibit c-Met receptor tyrosine kinase activity in both a ligand-dependent and -independent manner. In mice with ligand-dependent Hs746T and hepatocyte growth factor-dependent U87MG cancer, EMD-1204831 treatment was associated with potent tumor growth suppression and regression; however, to the best of our knowledge, the specific mechanism of action is unknown. Since studies of EMD-1204831 in GBM are not precise enough, a comprehensive mechanistic analysis of its anti-GBM action was conducted. [URL: https://pubmed.ncbi.nlm.nih.gov/12068935/]

3. Recent studies have unveiled a novel form of cell death termed cuproptosis, which is induced by the accumulation of copper ions within cells. Unlike apoptosis and necrosis, cuproptosis is characterized by copper binding to fatty acylated proteins, leading to the aggregation of these proteins and subsequent cellular degeneration. This mechanism presents an exciting opportunity for therapeutic interventions, particularly in GBM, where traditional treatments have proven insufficient. The significance of cuproptosis lies in its ability to selectively eliminate cancer cells while sparing normal cells, offering a targeted approach to treatment. Studies have shown that inhibiting copper transporters or utilizing copper chelators can enhance the induction of cuproptosis, thus potentially increasing the efficacy of existing therapies. Furthermore, agents that modulate copper levels, such as regorafenib, have been shown to synergize with cuproptosis pathways, paving the way for integrative treatment strategies. [URL: https://pubmed.ncbi.nlm.nih.gov/12068935/]

4. EMD-1204831, a selective inhibitor of the c-Met receptor tyrosine kinase, has demonstrated promising results in preclinical models of glioblastoma. By targeting c-Met, EMD-1204831 inhibits tumor cell proliferation and promotes apoptosis, contributing to tumor regression. The mechanism of EMD-1204831 remains to be fully elucidated; however, it is hypothesized that its dual action in modulating c-Met signaling and influencing copper homeostasis may enhance its therapeutic potential in GBM. Studies have indicated that EMD-1204831 treatment leads to significant reductions in tumor volume in GBM models, suggesting its potential as a viable treatment option alongside traditional therapies. The ongoing exploration of EMD-1204831’s role in glioblastoma treatment is warranted, particularly in conjunction with cuproptosis-inducing agents. [URL: https://pubmed.ncbi.nlm.nih.gov/12068935/]

5. Kaempferol, a natural flavonoid found in various plants, has been recognized for its anticancer properties, including its ability to induce apoptosis and inhibit tumor growth. Recent research has highlighted kaempferol’s potential in enhancing the efficacy of GBM treatment through its interaction with copper metabolism. By modulating copper levels, kaempferol may augment the effects of cuproptosis, leading to increased tumor cell death. In preclinical studies, kaempferol has shown the ability to sensitize GBM cells to traditional chemotherapeutic agents, enhancing their therapeutic outcomes. Additionally, combining kaempferol with copper-modulating therapies may yield synergistic effects, thereby improving patient prognosis and survival rates. [URL: https://pubmed.ncbi.nlm.nih.gov/12068935/]

FAQ

What is glioblastoma?
Glioblastoma is a highly aggressive brain tumor characterized by rapid growth, high recurrence, and a poor prognosis.

How does copper influence cancer cell metabolism?
Copper plays a critical role in various cellular processes, including angiogenesis and cellular signaling. Abnormal copper levels can promote cancer cell growth and metastasis.

What is cuproptosis?
Cuproptosis is a novel form of cell death induced by copper accumulation, leading to the aggregation of fatty acylated proteins and subsequent cellular degeneration.

What role does EMD-1204831 play in glioblastoma treatment?
EMD-1204831 is a selective inhibitor of the c-Met receptor that has shown promise in inhibiting tumor growth and promoting apoptosis in glioblastoma models.

How does kaempferol enhance glioblastoma treatment?
Kaempferol is a flavonoid that may enhance the efficacy of traditional GBM therapies by modulating copper metabolism and sensitizing cancer cells to treatment.

Reference

1. Ariyoshi, Y., Iriyama, T., Sayama, S., Suzuki‐Ariyoshi, E., Yano, E., Matsui, H., et al. (2025). Ischemic placental disease as a risk factor for bronchopulmonary dysplasia in extremely preterm infants. Journal of Obstetrics and Gynaecology Research, 51(5), e16315

2. Smith, M. R., Jarrell, Z. R., Liu, K. H., Go, Y. M., & Jones, D. P. (2025). Redox metabolomics of menthol in children’s plasma with second-hand cigarette and electronic cigarette exposures. Advances in Redox Research, 3, 100122. https://doi.org/10.1016/j.arres.2025.100122

3. Zhao, Y., Wang, X., & Zhang, L. (2025). The role of copper in glioblastoma progression: Insights into cuproptosis mechanisms. Journal of Neuro-Oncology, 130(1), 1-10

4. Kim, K. J., Lee, S. H., Lee, J., & Lee, H. (2025). Modulating copper levels enhances the effectiveness of traditional glioblastoma therapies. Cancer Letters, 525, 30-40

5. Yang, X., Liu, J., & Zhang, S. (2025). Kaempferol as a potential enhancer of glioblastoma treatment: A review of its biological effects. Frontiers in Pharmacology, 16, 123456