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Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights
Hengzeng Li1, Yahui Wu2, Yue Chen1
1Department of Medical Genetics & Cell Biology, School of Basic Medical Sciences, Zhengzhou University, Kexue Avenue 100, Zhengzhou, 450001, Henan, China.
Abstract:
Temozolomide (TMZ) remains the cornerstone chemotherapy for glioma, yet intrinsic and acquired resistance mechanisms significantly limit its clinical effectiveness. This review summarizes the multifaceted molecular pathways contributing to TMZ resistance, including enhanced DNA repair mechanisms such as O6-methylguanine-DNA methyltransferase (MGMT), mismatch repair (MMR), and base excision repair (BER). Additional resistance factors include genetic mutations that affect the drug response, dysregulated non-coding RNAs (miRNAs, lncRNAs, and circRNAs), glioma stem cells (GSCs), cytoprotective autophagy, an immunosuppressive tumor microenvironment (TME), altered signaling pathways, and active drug efflux transporters. Recent advancements to overcome these resistance mechanisms, including enhancing TMZ bioavailability through nanoparticle-based delivery systems and the inhibition of efflux transporters, have been explored. Novel therapeutic approaches that target DNA repair pathways and manipulate autophagy are highlighted. Immunotherapeutic interventions reversing immune suppression and metabolic strategies targeting tumor metabolism offer additional avenues. Emerging therapies such as CRISPR-based gene editing, phytochemical combinations, repurposed drugs, and novel TMZ analogs designed to bypass MGMT-mediated resistance are also discussed. This review highlights current developments and identifies emerging areas, with the goals of enhancing clinical outcomes and prolonging survival for glioma patients.
Insights
Temozolomide resistance in glioma is complex, involving DNA repair, genetic mutations, and the tumor microenvironment. New strategies target these pathways to improve chemotherapy effectiveness and patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Temozolomide (TMZ) is a primary chemotherapy for glioma.
- Intrinsic and acquired resistance limit TMZ's clinical efficacy.
- Understanding resistance mechanisms is crucial for improving glioma treatment.
Purpose of the Study:
- To review molecular pathways contributing to TMZ resistance in glioma.
- To summarize recent advancements and novel therapeutic approaches to overcome TMZ resistance.
- To identify emerging strategies for enhancing glioma patient outcomes.
Main Methods:
- Comprehensive literature review of molecular mechanisms of TMZ resistance.
- Analysis of current and emerging therapeutic strategies targeting resistance pathways.
- Discussion of novel drug delivery systems, targeted therapies, and immunotherapies.
Main Results:
- Key resistance mechanisms include enhanced DNA repair (MGMT, MMR, BER), genetic mutations, non-coding RNAs, glioma stem cells, autophagy, and the tumor microenvironment.
- Advancements include nanoparticle delivery, efflux transporter inhibition, and targeting DNA repair and autophagy.
- Emerging therapies involve immunotherapy, metabolic strategies, CRISPR gene editing, and novel TMZ analogs.
Conclusions:
- Overcoming TMZ resistance requires a multifaceted approach targeting various molecular pathways.
- Novel therapeutic strategies show promise in enhancing TMZ efficacy and prolonging survival for glioma patients.
- Continued research into emerging therapies is essential for advancing glioma treatment.
