The Potential Therapeutic Impact of Metformin in Glioblastoma Multiforme

Abstract

In terms of frequency and aggressiveness, glioblastoma multiforme (GBM) is undoubtedly the most frequent and fatal primary brain tumor. Despite advances in clinical management, the response to current treatments is dismal, with a 2-year survival rate varying between 6 and 12 percent. Metformin, a derivative of biguanide widely used in treating type 2 diabetes, has been shown to extend the lifespan of patients with various malignancies. There is limited evidence available on the long-term survival of GBM patients who have taken metformin. This research examined the literature to assess the connection between metformin's anticancer properties and GBM development. Clinical findings, together with the preclinical data from animal models and cell lines, are included in the present review. This comprehensive review covers not only the association of hyperactivation of the AMPK pathway with the anticancer activity of metformin but also other mechanisms underpinning its role in apoptosis, cell proliferation, metastasis, as well as its chemo-radio-sensitizing behavior against GBM. Current challenges and future directions for developments and applications of metformin-based therapeutics are also discussed.

Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes

“…Conversely, glioblastomas exhibiting a mitochondrial-driven phenotype, such as the T98G cells, may benefit from therapies that disrupt mitochondrial metabolism. The dependency of these cells on oxidative phosphorylation and mitochondrial processes suggests that inducing oxidative stress or impairing mitochondrial function with agents like metformin or phenformin could selectively compromise their viability [ 54 , 55 ]. Moreover, leveraging antibiotics that inhibit mitochondrial translation—akin to their action on bacterial ribosomes, such as tetracyclines and macrolides—could offer a novel therapeutic pathway by limiting the metabolic adaptability of these cells [ 56 ].…”

Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp

“…A wealth of clinical and preclinical studies support the potential of metformin against glioblastoma due to its ability to strongly support the standard care strategy toward improving overall and progression-free survival [ 176 ]. For instance, metformin hyperactivates the AMPK pathway and plays a role in apoptosis induction, cell proliferation reduction, metastasis inhibition, and chemo-radio-sensitizer behavior against glioblastoma multiforme [ 177 ]. However, a more profound knowledge of the anti-angiogenic effect of metformin in glioblastoma is needed.…”

“…Another exciting anti-diabetic drug is metformin, which inhibits different cancers by modulating similar on-targets (diabetes and cancer) and off-targets (only in cancer). For instance, metformin induces cell cycle arrest (colon [ 85 ], skin [ 217 ], and myeloma [ 228 , 229 ]), induces apoptosis (prostate [ 120 ], ovarian [ 164 , 165 ], glioblastoma [ 177 ], and myeloma [ 228 , 229 ]), induces pyroptosis (esophageal squamous cell carcinoma [ 210 ]), induces autophagy (prostate [ 120 ]), decreases metastasis (colon [ 102 , 164 ], ovarian [ 164 , 165 ], glioblastoma [ 177 ], and skin [ 217 ]), and inhibits CSC (breast [ 102 , 137 ] and kidney [ 191 ]). In addition, the pathways modulated repeatedly by metformin are the STAT pathway (breast [ 103 , 138 ]), and the mTOR pathway (breast [ 104 , 166 ], prostate [ 120 ], kidney [ 191 ], and myeloma [ 228 , 229 ]).…”

“…In addition, the pathways modulated repeatedly by metformin are the STAT pathway (breast [ 103 , 138 ]), and the mTOR pathway (breast [ 104 , 166 ], prostate [ 120 ], kidney [ 191 ], and myeloma [ 228 , 229 ]). Nevertheless, the striking effect of metformin is inducing its effect by activation of AMPK (AMPK dependent), the same on-target in diabetes, in the lung [ 140 , 146 , 147 , 148 , 149 ], glioblastoma [ 177 ], skin [ 217 ], and myeloma [ 229 ]. Therefore, it is no wonder that metformin is in 37 trials due to its pleiotropic effects.…”