Introduction: Glioblastoma multiforme (GBM) is the deadliest type of brain cancer with poor response to the available therapies, mainly due to intrinsic resistance mechanisms. Chemotherapy is based on alkylating agents, but DNA-repair mechanisms can revert this cytotoxic effect. O-methylguanine-DNA methyltransferase (MGMT) protein is the primary mechanism for GBM resistance. Therefore, different strategies to suppress its activity have been explored. However, their clinical use has been hindered due to the high toxicity of MGMT inhibitors verified in clinical trials.
Areas Covered: This review article aims to provide the current progress in the development of novel drug delivery systems (DDS) to overcome this resistance. Here, we also review the current knowledge on MGMT-mediated resistance and the clinical outcomes and potential risks of using MGMT inhibitors.
Expert Opinion: To overcome therapeutic limitations, nano-based approaches have been proposed as a suitable solution to improve drug accumulation in the brain tumor tissue and decrease systemic toxicity. DDS to overcome MGMT-mediated resistance in GBM have been mostly developed to deliver MGMT inhibitors and for gene therapy to modulate MGMT gene expression.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1080/17425247.2022.2124967 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Novel strategies to overcome chemoresistance in human glioblastoma.
Biochem Pharmacol
December 2024
Beijing Key Laboratory of Environmental and Viral Oncology, College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China. Electronic address:
Temozolomide (TMZ) is currently the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM). However, the inherent heterogeneity of GBM often results in suboptimal outcomes, particularly due to varying degrees of resistance to TMZ. Over the past several decades, O-methylguanine-DNA methyltransferase (MGMT)-mediated DNA repair pathway has been extensively investigated as a target to overcome TMZ resistance.
View Article and Find Full Text PDFChitosan-PLGA mucoadhesive nanoparticles for gemcitabine repurposing for glioblastoma therapy.
Eur J Pharm Biopharm
July 2024
LEPABE - Laboratory for Process Engineering, Environment, Biotechnology and Energy, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal; ALiCE - Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal. Electronic address:
Glioblastoma (GBM) is a highly deadly brain tumor that does not respond satisfactorily to conventional treatment. The non-alkylating agent gemcitabine (GEM) has been proposed for treating GBM. It can overcome MGMT protein-mediated resistance, a major limitation of conventional therapy with the alkylating agent temozolomide (TMZ).
View Article and Find Full Text PDFQSAR and Chemical Read-Across Analysis of 370 Potential MGMT Inactivators to Identify the Structural Features Influencing Inactivation Potency.
Pharmaceutics
August 2023
Carcinogenesis Department, Paterson Institute for Cancer Research, Manchester M20 9BX, UK.
-methylguanine-DNA methyltransferase (MGMT) constitutes an important cellular mechanism for repairing potentially cytotoxic DNA damage induced by guanine -alkylating agents and can render cells highly resistant to certain cancer chemotherapeutic drugs. A wide variety of potential MGMT inactivators have been designed and synthesized for the purpose of overcoming MGMT-mediated tumor resistance. We determined the inactivation potency of these compounds against human recombinant MGMT using [H]-methylated-DNA-based MGMT inactivation assays and calculated the IC values.
View Article and Find Full Text PDFModulating MGMT expression through interfering with cell signaling pathways.
Biochem Pharmacol
September 2023
Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China. Electronic address:
Guanine O-alkylating agents are widely used as first-line chemotherapeutic drugs due to their ability to induce cytotoxic DNA damage. However, a major hurdle in their effectiveness is the emergence of chemoresistance, largely attributed to the DNA repair pathway mediated by O-methylguanine-DNA methyltransferase (MGMT). MGMT plays an important role in removing the alkyl groups from lethal O-alkylguanine (O-AlkylG) adducts formed by chemotherapeutic alkylating agents.
View Article and Find Full Text PDFBET protein inhibition sensitizes glioblastoma cells to temozolomide treatment by attenuating MGMT expression.
Cell Death Dis
December 2022
Neuroscience Research Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of developing rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres, and identified 6 distinct response patterns.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!