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Barciszewski 3, Iwona Gawro ´nska 3, Małgorzata Giel-Pietraszuk 3 and Mirosława Z. Naskr˛et-Barciszewska 3, *  \nCitation: Barciszewska, A.-M.; Belter, A.; Barciszewski, J.F.; Gawro ´nska, I.; Giel-Pietraszuk, M.; Naskr˛etBarciszewska, M.Z. Mechanistic Insights on Metformin and Arginine Implementation as Repurposed Drugs in Glioblastoma Treatment. Int. J. Mol. Sci. 2024, 25, 9460. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/ijms25179460](10.3390/ijms25179460)  \nAcademic Editor: Mario Costa  \nReceived: 19 July 2024  \nRevised: 28 August 2024  \nAccepted: 29 August 2024  \nPublished: 30 August 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Intraoperative Imaging Unit, Chair and Department of Neurosurgery and Neurotraumatology, Karol Marcinkowski University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland; [ambarciszewska@ump.edu.pl](ambarciszewska@ump.edu.pl)  \n2 Department of Neurosurgery and Neurotraumatology, University Clinical Hospital, Przybyszewskiego 49, 60-355 Poznan, Poland  \n3 Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Noskowskiego 12, 61-704 Poznan,  \nPoland; [abelter@ibch.poznan.pl](abelter@ibch.poznan.pl) (A.B.); [jbarciszewski@ibch.poznan.pl](jbarciszewski@ibch.poznan.pl) (J.F.B.); [iwonag@ibch.poznan.pl](iwonag@ibch.poznan.pl) (I.G.); [giel@ibch.poznan.pl](giel@ibch.poznan.pl) (M.G.-P.)  \n* [Correspondence: mbarcisz@ibch.poznan.pl](Correspondence: mbarcisz@ibch.poznan.pl); Tel.: +48-61-852-89-19; Fax: +48-61-852-05-32 † These authors have contributed equally to this work.  \nAbstract: As the most common and aggressive primary malignant brain tumor, glioblastoma is still lacking a satisfactory curative approach. The standard management consisting of gross total resection followed by radiotherapy and chemotherapy with temozolomide only prolongs patients’ life moderately. In recent years, many therapeutics have failed to give a breakthrough in GBM treatment. In the search for new treatment solutions, we became interested in the repurposing of existing medicines, which have established safety profiles. We focused on the possible implementation of well-known drugs, metformin, and arginine. Metformin is widely used in diabetes treatment, but arginine is mainly a cardiovascular protective drug. We evaluated the effects of metformin and arginine on total DNA methylation, as well as the oxidative stress evoked by treatment with those agents. In glioblastoma cell lines, a decrease in 5-methylcytosine contents was observed with increasing drug concentration. When combined with temozolomide, both guanidines parallelly increased DNA methylation and decreased 8-oxo-deoxyguanosine contents. These effects can be explained by specific interactions of the guanidine group with m5CpG dinucleotide. We showed that metformin and arginine act on the epigenetic level, influencing the foreground and potent DNA regulatory mechanisms. Therefore, they can be used separately or in combination with temozolomide, in various stages of disease, depending on desired treatment effects.  \nKeywords: metformin; arginine; temozolomide; glioblastoma; 5-methylcytosine; 8-oxo-deoxyguanosine; DNA methylation; epigenetics  \n1. Introduction  \nGlioblastoma, a diffuse glial brain tumor, is the most common primary malignancy in the adult central nervous system (CNS) and is also the most aggressive and lethal entity [1,2] . It invades the adjacent brain tissue and is characterized by uncontrolled proliferation,","cbCairT4svyt3ynD","https://ap.wps.com/l/cbCairT4svyt3ynD","pdf",2279165,15,"English","# Introduction\n## Background on glioblastoma and current therapy\n## Drug repurposing rationale","[{\"question\":\"Why is glioblastoma difficult to treat effectively?\",\"answer\":\"Glioblastoma is highly aggressive and lethal, with invasive growth and strong resistance mechanisms. Standard treatment with temozolomide prolongs life only moderately and is not curative.\"},{\"question\":\"What drugs are evaluated for repurposing in this work?\",\"answer\":\"The study focuses on metformin and arginine, which are well-known medications with established safety profiles. Their potential is tested in the context of glioblastoma treatment.\"},{\"question\":\"How do metformin and arginine affect DNA methylation and oxidative stress?\",\"answer\":\"In glioblastoma cell lines, increasing drug concentration decreases 5-methylcytosine content. When combined with temozolomide, both guanidines increase DNA methylation and reduce 8-oxo-deoxyguanosine content, indicating modulation of epigenetic and oxidative stress-related processes.\"}]","Mechanistic Insights on Metformin and Arginine Implementation as Repurposed Drugs in Glioblastoma Treatment | PDF",1789998329,38]