ArticleNeuro-oncology2023
A novel compound EPIC-0412 reverses temozolomide resistance via inhibiting DNA repair/MGMT in glioblastoma.
Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 56 citations in OpenAlex.
- Pyroptosis as a novel therapeutic target in glioblastoma multiforme: Mechanisms, molecular insights, and therapeutic potential.Molecular therapy. Nucleic acids · 2026Review
- Enhancer of Zeste Homolog 2 (EZH2): From Glioblastoma Biology to Potential Epigenetic Therapy.International journal of molecular sciences · 2026Review
- Exosomal circ_0050688 Shapes a Chemoresistant Microenvironment by Driving Spatial Resistance Spreading in Glioblastoma via the MDM2 Pathway.Biomolecules · 2026Article
- Deciphering the glioblastoma microenvironmental landscape with multi-modal radiogenomics to guide prognosis and personalized therapy.Journal of translational medicine · 2026Article
- Coptidis Rhizoma extract mitigates sleep deprivation-induced cognitive impairment and neurodegeneration: Insights into hormonal, glymphatic, and molecular mechanisms.Journal of traditional and complementary medicine · 2026Article
- Review
- Advancements in Drug Delivery Systems in Glioblastoma Therapy.International journal of molecular sciences · 2026Review
- Human papillomavirus16 E7 enhances cell stemness by regulating the APC2/SPIN4/β-catenin axis in cervical cancer.Oncogenesis · 2026Article
- 20(S)-protopanaxadiol enhances temozolomide responsiveness in MGMT-expressing glioblastoma: Wnt/β-catenin attenuation and MGMT downregulation.Frontiers in medicine · 2026Article
- The therapeutic effect and specific mechanism involved active Chinese medicine component biochaninA in glioma.Frontiers in immunology · 2026Article
- Co-activation of the super-enhancer complex SOX2 and HDAC1 confers temozolomide resistance by promoting PDGFB transcription in glioblastoma.Neuro-oncology · 2026Article
- Rat Glioma 101.8 Tissue Strain: Molecular and Morphological Features.International journal of molecular sciences · 2025Article
- Role of the TLR signaling pathway in the pathogenesis of glioblastoma multiforme with an emphasis on immunotherapy.Biochemistry and biophysics reports · 2025Review
- Review
- Autophagy modulates glioblastoma cell sensitivity to Selinexor-mediated XPO1 inhibition.Neuro-oncology · 2025Article
- Overcoming temozolomide resistance in glioma: recent advances and mechanistic insights.Acta neuropathologica communications · 2025Review
- Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.Oncogene · 2025Review
- Glioblastoma multiforme: an updated overview of temozolomide resistance mechanisms and strategies to overcome resistance.Discover oncology · 2025Review
- The Hypoxia-Associated High-Risk Cell Subpopulation Distinctly Enhances the Progression of Glioma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Long Non-Coding RNAs in Malignant Human Brain Tumors: Driving Forces Behind Progression and Therapy.International journal of molecular sciences · 2025Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTemozolomide (TMZ) resistance has become an important obstacle affecting its therapeutic benefits. O6-methylguanine DNA methyltransferase (MGMT) is primarily responsible for the TMZ resistance in Glioblastoma multiforme (GBM) patients. In addition, active DNA damage repair pathways can also lead to TMZ resistance. Here, we reported a novel small-molecule inhibitor EPIC-0412 that improved the therapeutic efficacy of TMZ by inhibiting the DNA damage repair pathway and MGMT in GBM via epigenetic pathways.
methodsThe small-molecule compound EPIC-0412 was obtained through high-throughput screening. RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), and chromatin immunoprecipitation (ChIP) assays were used to verify the effect of EPIC-0412. Co-immunoprecipitation (Co-IP) was used to elucidate the interactions of transcription factors at the MGMT promoter region. Animal experiments using a mouse model were performed to verify the efficacy of EPIC-0412 in sensitizing GBM cells to TMZ.
resultsEPIC-0412 physically interrupts the binding of HOTAIR and EZH2, leading to the upregulation of CDKN1A and BBC3, causing cell cycle arrest and apoptosis in GBM cells. EPIC-0412 inhibits DNA damage response in GBM cells through the p21-E2F1 DNA damage repair axis. EPIC-0412 epigenetically silences MGMT through its interaction with the ATF3-p-p65-HADC1 axis at the MGMT promoter region. The application of EPIC-0412 restored the TMZ sensitivity in GBM in vivo experiments.
conclusionThis study discovered a small-molecule inhibitor EPIC-0412, which enhanced the chemotherapeutic effect of TMZ by acting on the p21-E2F1 DNA damage repair axis and ATF3-p-p65-MGMT axis, providing evidence for combining epigenetic drugs to increase the sensitization toward TMZ in GBM patients.
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