Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics

Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects ne...

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Bibliographic Details
Published in:Cancers 2022-03, Vol.14 (6), p.1412
Main Authors: Guarnaccia, Laura, Navone, Stefania E, Masseroli, Matteo M, Balsamo, Melissa, Caroli, Manuela, Valtorta, Silvia, Moresco, Rosa M, Campanella, Rolando, Schisano, Luigi, Fiore, Giorgio, Galiano, Valentina, Garzia, Emanuele, Appiani, Giuseppe C, Locatelli, Marco, Riboni, Laura, Marfia, Giovanni
Format: Article
Language:English
Subjects:
Angiogenesis
Annexin V
Apoptosis
Biopsy
Brain cancer
Brain tumors
Cancer
Cancer therapies
Caspase-3
Cell growth
Cell proliferation
Cell viability
Ceramide
Diabetes
Diabetes mellitus
Endothelial cells
Gene expression
Genomic instability
Glioblastoma
Invasiveness
Kinases
Lipid metabolism
Medical prognosis
Metabolism
Metformin
Molecular modelling
mRNA
Oncology
Patients
Radiation therapy
Sphingosine 1-phosphate
Tumors
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Summary:Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. Here, we tested the efficacy of MET on = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. Data resulting revealed a time- and μ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers14061412