Metformin Shows Potential As An Angiogenic Supplemental Adjuvant For Glioblastoma Treatment

Medical News: Glioblastoma (GBM) stands as the most prevalent primary tumor in the adult central nervous system (CNS), classified as a grade IV malignancy by the World Health Organization (WHO). The prognosis for those diagnosed with GBM remains bleak, with an average survival time of approximately 15 months. This malignancy presents unique challenges, primarily due to its aggressive nature and resistance to conventional treatments. Among its many aggressive characteristics, aberrant angiogenesis - promoting tumor neovascularization - serves as a potential target for molecular treatments. Additionally, the presence of glioma stem cells (GSCs) within the tumor, which exhibit resistance to chemotherapy and radiation, further complicates treatment efforts.


Metformin Shows Potential As An Angiogenic Supplemental
Adjuvant For Glioblastoma Treatment

Current Challenges in GBM Treatment
Despite extensive research and various clinical trials, anti-angiogenic medications have not significantly improved overall survival (OS) in GBM patients. This lack of significant progress underscores the need to explore new treatment strategies. Recently, metformin, a drug primarily used as a first-line treatment for type 2 diabetes mellitus (T2DM), has garnered attention for its potential anti-tumoral properties in various cancers, including glioblastoma. This Medical News report explores metformin's mechanisms and evaluates its potential role as an anti-angiogenic agent in GBM treatment based on a study reviewed conducted by researchers from the Department of Neurosurgery, University of Florida-USA and the University of Illinois, Chicago-USA.
 
Mechanism of Action of Metformin in Cancer - Inhibition of Cellular Proliferation
Metformin, a member of the Biguanides family, has been repurposed based on its demonstrated ability to inhibit cancer cell growth. One primary mechanism involves the blockade of the LKB1/AMPK/mTOR/S6K1 pathway. By activating adenosine monophosphate-activated protein kinase (AMPK), metformin influences various cellular processes. AMPK activation leads to the inhibition of cellular proliferation by halting mitotic cell division, largely through the suppression of the cyclin D1 proto-oncogene. Cyclin D1 is crucial for the transition from the G1 to S phase of the cell cycle and is often overexpressed in cancers.
 
Induction of Apoptosis and Autophagy
Metformin's anti-cancer effects also involve promoting apoptosis (programmed cell death) and autophagy (cellular degradation). These processes are vital for eliminating cancer cells and reducing tumor growth. The activation of AMPK by metformin induces P53 phosphorylation and activation, promoting cell cycle arrest and apoptosis. Additionally, metformin inhibits the mammalian target of rapamycin (mTOR), a kinase associated with cancer progression and drug resistance. This inhibition is mediated both directly and indirectly through pathways such as REDD1 activation, which suppresses mTOR expression.

Targeting GSCs
Glioblastoma stem cells (GSCs) contribute si gnificantly to the aggressive nature and treatment resistance of GBM. Metformin exhibits selective toxicity towards GSCs, inhibiting their proliferation and promoting their death. This selective action is crucial, as GSCs are believed to play a pivotal role in tumor recurrence and resistance to conventional therapies. By targeting these cells, metformin could potentially reduce the likelihood of recurrence and enhance the overall effectiveness of GBM treatments.
 
Molecular Pathways
Metformin's impact on GSCs involves multiple molecular pathways. Activation of AMPK leads to the inhibition of FOXO3 transcription factor, which is essential for GSC differentiation. Additionally, metformin inhibits chloride intracellular channel-1 (CLIC1), a protein that promotes GSC survival, proliferation, and migration. These mechanisms collectively contribute to metformin's potential as a therapeutic agent in targeting GSCs and improving GBM treatment outcomes.
 
Clinical Evidence and Trials - Epidemiological Evidence
Several studies have hinted at the potential benefits of metformin in GBM treatment. Epidemiological data suggest a reduced cancer incidence and mortality rate in individuals treated with metformin. For instance, one past study observed longer progression-free survival among diabetic patients with primary GBM who received metformin treatment. Similarly, another study demonstrated improved overall and progression-free survival in patients with high-grade gliomas under metformin therapy, particularly in WHO grade III tumors.
 
Combination with Temozolomide
Temozolomide (TMZ) is a standard chemotherapeutic agent used in GBM treatment. Research indicates that combining metformin with TMZ may enhance therapeutic outcomes. This combination has shown promise in overcoming TMZ resistance, potentially through metformin's inhibition of the MGMT gene, which plays a crucial role in chemotherapy resistance. Preclinical studies have demonstrated the synergistic interaction between metformin and TMZ, resulting in enhanced cytotoxicity and improved treatment outcomes in GBM models.
 
Metformin and the Blood-Brain Barrier - Managing Brain Edema
Metformin's ability to cross the blood-brain barrier (BBB) allows it to exert effects directly within the CNS. This capability is particularly beneficial in managing brain edema, a common complication in GBM. Metformin reduces vasogenic edema by activating the AMPK pathway in BBB endothelial cells, leading to enhanced barrier tightness. This reduction in edema can alleviate symptoms and improve patient outcomes.
 
Enhancing Drug Penetration
While metformin's impact on the BBB can reduce edema, it may also affect the penetration of other therapeutic agents like TMZ. Careful monitoring of metformin and TMZ administration is necessary to optimize drug delivery and efficacy. Strategies such as timing TMZ delivery to achieve optimal brain concentrations before starting metformin or using metformin in a way that minimizes its impact on TMZ penetration are being explored.
 
In Vivo and Clinical Research - Animal Models
In vivo investigations in animal models, such as mice, have employed doses of 500 mg/kg/day to achieve effective plasma concentrations capable of inhibiting Akt. These levels result in substantial systemic exposure, corresponding to human doses of about 2000 mg/day. This dosage is within the tolerable range for humans, suggesting the feasibility of metformin's use in clinical settings.
 
Human Studies
In human studies, the maximal tolerable dosage of metformin is around 2000–2500 mg/day. Achieving intra-tumoral concentrations high enough to directly inhibit Akt may be challenging due to pharmacokinetic restrictions such as drug distribution and BBB permeability. However, higher dosages or combination strategies with other medications to enhance delivery to the tumor site are being explored.
 
Personalized Treatment Approaches - Genetic Markers
The variability in responses to metformin based on genetic differences, such as MGMT promoter methylation status, highlights the need for personalized treatment approaches. Understanding these genetic markers can help identify patient subgroups who are most likely to benefit from metformin-based therapies.
 
Future Research Directions
Future research should focus on optimizing dosing regimens and exploring metformin's efficacy in other aggressive cancers. Expanding the scope of clinical trials to include diverse patient populations and genetic profiles will be crucial in understanding metformin's full therapeutic potential.
 
Conclusion
Metformin's extensive anti-cancer properties, favorable safety profile, and potential to enhance the efficacy of existing treatments like TMZ make it a promising adjunctive therapy for glioblastoma. Its ability to target cancer cells, including GSCs, and modify the tumor microenvironment offers a multifaceted approach to GBM treatment. Continued research and clinical trials are essential to fully harness metformin's therapeutic potential, paving the way for improved outcomes in GBM patients.
 
In summary, metformin's repurposing in oncology, particularly for glioblastoma, represents a significant step forward in the quest for more effective cancer treatments. By leveraging its dual role in diabetes management and cancer therapy, metformin may hold the key to unlocking new, more effective strategies for combating one of the most challenging malignancies in the CNS.
 
The study findings were published in the peer reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/25/11/5694
 
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