Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: 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. Methods: Here, we tested the efficacy of MET on n = 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. Results: Data resulting revealed a time- and mu-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. Conclusions: 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.

Guarnaccia, L., Navone, S., Masseroli, M., Balsamo, M., Caroli, M., Valtorta, S., et al. (2022). Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. CANCERS, 14(6) [10.3390/cancers14061412].

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

Moresco, R;
2022

Abstract

Simple Summary Glioblastoma is the most common and malignant primary brain tumor, with a median survival of around 14 months. The aggressiveness of glioblastoma is due to intense cell proliferation, angiogenesis, invasiveness, genetic instability, resistance to therapies and high frequency of relapses. These features render glioblastoma almost incurable, considered an extreme therapeutic challenge. In the last few decades, it has been observed a reduced cancer incidence in diabetic patients treated with metformin, an oral hypoglycemic drug. The reported ability of metformin to arrest cancer cell growth in in vitro and in vivo experimental tumor models, have suggested the possibility to reconsider metformin as an anti-cancer add-on therapy, but further investigations about molecular mechanisms and optimal therapeutic regimens are needed. Here, we tested the efficacy of metformin against primary glioblastoma endothelial cells, responsible for tumor angiogenesis, invasiveness and resistance to therapy, reporting promising results and advancing a novel target of metformin, the "sphingolipid rheostat". Background: 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. Methods: Here, we tested the efficacy of MET on n = 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. Results: Data resulting revealed a time- and mu-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. Conclusions: 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.
Articolo in rivista - Articolo scientifico
angiogenesis; brain tumors; glioblastoma; metformin;
English
10-mar-2022
2022
14
6
1412
open
Guarnaccia, L., Navone, S., Masseroli, M., Balsamo, M., Caroli, M., Valtorta, S., et al. (2022). Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics. CANCERS, 14(6) [10.3390/cancers14061412].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/397466
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