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World J Clin Oncol. Aug 24, 2025; 16(8): 108112
Published online Aug 24, 2025. doi: 10.5306/wjco.v16.i8.108112
Glucose and antidiabetic therapy in temozolomide resistance in glioblastoma
Emir Begagić, Amina Džidić-Krivić, Hakija Bečulić, Ragib Pugonja, Adnana Ljevaković, Binasa Bašić, Adem Nuhović, Elma Milanović, Semir Hadžić, Emir Bećirović, Lemana Buljubašić, Minela Bećirović, Mirza Pojskić
Emir Begagić, Hakija Bečulić, Department of Neurosurgery, Cantonal Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
Amina Džidić-Krivić, Department of Neurology, Cantonal Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
Ragib Pugonja, Department of Otorhinolaryngology, Cantonal Hospital Zenica, Zenica 72000, Bosnia and Herzegovina
Adnana Ljevaković, Binasa Bašić, Department of Neurology, General Hospital Travnik, Travnik 72270, Bosnia and Herzegovina
Adem Nuhović, Department of Infective Diseases, University Clinical Center Sarajevo, Sarajevo 71000, Bosnia and Herzegovina
Elma Milanović, Department of Neurology, University Clinical Center Sarajevo, Sarajevo 71000, Bosnia and Herzegovina
Semir Hadžić, Department of Endocrinology, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Emir Bećirović, Department of Intensive Care, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Lemana Buljubašić, Department of Rehabilitation, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Minela Bećirović, Department of Nephrology, University Clinical Center Tuzla, Tuzla 75000, Bosnia and Herzegovina
Mirza Pojskić, Department of Neurosurgery, University Hospital Marburg, Marburg 35037, Hesse, Germany
Author contributions: Begagić E, Džidić-Krivić A and Bečulić H designed the research study; Pugonja R, Ljevaković A, Bašić B, Nuhović A, Milanović E, Hadžić S, Bećirović E, Buljubašić L and Bećirović M performed the research; Bečulić H and Pojskić M supervised the research; Begagić E, Džidić-Krivić A and Bečulić H, Nuhović A, Milanović E, Hadžić S, Bećirović E, Buljubašić L and Bećirović M wrote the manuscript; All authors have read and approved the final manuscript.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Emir Begagić, MD, Academic Editor, Department of Neurosurgery, Cantonal Hospital Zenica, Crkvice 67, Zenica 72000, Bosnia and Herzegovina. begagicem@gmail.com
Received: April 8, 2025
Revised: April 25, 2025
Accepted: June 25, 2025
Published online: August 24, 2025
Processing time: 136 Days and 12.1 Hours
Abstract

Glioblastoma (GBM) remains a major clinical challenge due to limited therapeutic success despite standard treatments including surgery, radiotherapy, and temozolomide (TMZ). Recent evidence links hyperglycemia to cancer progression, and altered glucose metabolism has emerged as a key factor in GBM development. Metformin, an antidiabetic drug, has shown promise in improving survival in GBM patients, possibly due to its ability to cross the blood-brain barrier and target metabolic pathways involved in tumor growth. Preclinical studies suggest metformin may enhance TMZ efficacy by acting on glioma stem cells and overcoming resistance mechanisms. Its activation of AMPK and modulation of Wnt signaling further support its therapeutic potential. However, while early studies and clinical trials have explored metformin’s safety and efficacy, its direct impact on GBM survival remains unclear. Ongoing research aims to clarify its mechanisms and identify responsive patient subgroups. Novel strategies, including PPARγ agonists and nanoerythrosome-based drug delivery systems, are also under investigation to improve metformin’s therapeutic profile. Rigorous clinical trials and mechanistic studies are essential to determine the role of metformin as adjunct therapy in GBM treatment.

Keywords: Drug resistance; Glioblastoma multiforme; Neoplasms; Glucose metabolism; Antidiabetic drugs

Core Tip: Metformin shows promise as an adjunct therapy in glioblastoma by modulating glucose metabolism, enhancing temozolomide efficacy, and targeting glioma stem cells. Its ability to cross the blood-brain barrier and influence pathways such as AMPK and Wnt highlights its potential. However, its impact on survival remains unclear, requiring further clinical validation.