International Journal of Molecular Sciences

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Dear Colleagues,

Glioblastoma multiforme (GBM) is a rare cancer which, being responsible for 4% of all cancer deaths with a 5-year survival of 2%, is one of the deadliest human cancers with a median survival ranging from 14 to 30 months depending on the molecular subtype of the tumor. DNA methylation plays a key role in the pathogenesis and progression of GBM. Indeed, GBM harbors many genetic alterations that interfere with numerous cancer-related pathways. Furthermore, some subtypes of GBM are resistant to the action of temozolomide (TMZ), the most widely used alkylating agent in the treatment of GBM, as they have the promoter of the protein O6-methylguanine DNA methyltransferase (MGMT). Epigenetic modifications are gaining strong relevance in glioblastoma because they can be both clinical biomarkers and potential drug targets, as suggested by many preclinical studies.

The purpose of this Special Issue is to highlight new advances in molecular mechanisms and new therapeutic approaches to eradicate GBM in order to improve our current understanding of the molecular and cellular mechanisms of GBM initiation, progression and therapy resistance.

Dr. Laura Mosca
Dr. Cristina Pagano
Dr. Chiara Laezza
Guest Editors

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Keywords

GBM
epigenetics
temozolomide
MGMT

Published Papers (2 papers)

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Research

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10 pages, 740 KiB

Open AccessArticle

D-Loop Mutations as Prognostic Markers in Glioblastoma—A Pilot Study

by Bartosz Szmyd, Patrycja Stanisławska, Małgorzata Podstawka, Karol Zaczkowski, Patryk M. Izbiński, Dominika Kulczycka-Wojdala, Robert Stawski, Karol Wiśniewski, Karolina Janczar, Marcin Braun, Piotr Białasiewicz, Dariusz J. Jaskólski and Ernest J. Bobeff

Int. J. Mol. Sci. 2024, 25(8), 4334; https://doi.org/10.3390/ijms25084334 - 14 Apr 2024

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Abstract

Glioblastoma, a highly aggressive brain tumor, poses significant treatment challenges. A deeper investigation into its molecular complexity is essential for the identification of novel prognostic biomarkers and therapeutic strategies, potentially improving patient outcomes in terms of survival and quality of life. While nuclear DNA mutations have been extensively studied, the role of mitochondrial DNA (mtDNA) mutations, specifically in the D-loop region, remains poorly understood. This prospective case-control study aimed to assess the prognostic significance of the mtDNA D-loop m.16126T>C variant in glioblastoma patients. Immunohistochemistry and droplet digital PCR (ddPCR) were employed for mutation analysis, complemented by statistical analyses and a literature review. The study cohort comprised 22 glioblastoma patients (mean age 59.36 ± 14.17, 12 (54.55%) females), and 25 controls (59.48 ± 13.22, 12 (80%) females). The D-loop m.16126T>C variant was observed in four (18%) of the glioblastoma samples and was associated with shorter median survival (9.5 vs. 18 months; p = 0.016, log-rank test). This study underscores the importance of investigating mtDNA, especially D-loop variants, in glioblastoma, suggesting its potential as a prognostic biomarker and, therefore, its possible therapeutic targets, warranting further exploration. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Glioblastoma)

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Review

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13 pages, 1386 KiB

Open AccessReview

Betulinic Acid for Glioblastoma Treatment: Reality, Challenges and Perspectives

by Sílvia Fernandes, Mariana Vieira, Cristina Prudêncio and Ricardo Ferraz

Int. J. Mol. Sci. 2024, 25(4), 2108; https://doi.org/10.3390/ijms25042108 - 09 Feb 2024

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Abstract

Betulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Betulinic acid has been investigated for its potential therapeutic properties, and exhibits anti-inflammatory, antiviral, antimalarial, and antioxidant activities. Notably, its ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies. This review aims to compile information about the impact of betulinic acid as an antitumor agent, particularly in the context of glioblastoma. Importantly, betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types. Compelling evidence published highlights the acid’s therapeutic action in suppressing the Akt/NFκB-p65 signaling cascade and enhancing the cytotoxic effects of the chemotherapeutic agent temozolomide. Interesting findings with betulinic acid also suggest a focus on researching the reduction of glioblastoma’s invasiveness and aggressiveness profile. This involves modulation of extracellular matrix components, remodeling of the cytoskeleton, and secretion of proteolytic proteins. Drawing from a comprehensive review, we conclude that betulinic acid formulations as nanoparticles and/or ionic liquids are promising drug delivery approaches with the potential for translation into clinical applications for the treatment and management of glioblastoma. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Glioblastoma)

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