ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 60 citations in OpenAlex.
- Article
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- Astrocyte involvement in brain metastasis: from biological mechanisms to therapeutic strategies.Cancer metastasis reviews · 2025Review
- Brain microenvironment orchestrates highly aggressive tumor variants: current trends and therapeutic approaches.Frontiers in aging neuroscience · 2025Review
- Endothelin and the tumor microenvironment: a finger in every pie.Clinical science (London, England : 1979) · 2024Review
- Adult IDH Wild-Type Glioblastoma Ultrastructural Investigation Suggests a Possible Correlation between Morphological Biomarkers and Ki-67 Index.Biomedicines · 2023Article
- Article
- The EDN1/EDNRA/β‑arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation.International journal of oncology · 2023Article
- The Interplay of Tumor Vessels and Immune Cells Affects Immunotherapy of Glioblastoma.Biomedicines · 2022Review
- Glioblastoma Microenvironment and Cellular Interactions.Cancers · 2022Review
- Macitentan improves antitumor immune responses by inhibiting the secretion of tumor-derived extracellular vesicle PD-L1.Theranostics · 2022Article
- Oral administration of a dual ETMolecular vision · 2022Article
- Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application.Frontiers in oncology · 2022Review
- The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence.International journal of molecular sciences · 2021Review
- YAP and endothelin-1 signaling: an emerging alliance in cancer.Journal of experimental & clinical cancer research : CR · 2021Review
- Targeting the endothelin axis as a therapeutic strategy for oral cancer metastasis and pain.Scientific reports · 2020Article
- Article
- β-arrestin1/YAP/mutant p53 complexes orchestrate the endothelin A receptor signaling in high-grade serous ovarian cancer.Nature communications · 2019Article
- Cannabidiol Affects Extracellular Vesicle Release, miR21 and miR126, and Reduces Prohibitin Protein in Glioblastoma Multiforme Cells.Translational oncology · 2019Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
purposeThe objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide through an endothelin-dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. EXPERIMENTAL
designWe evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell-induced protection of glioma cells from temozolomide in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or temozolomide-resistant (LN-229(Res) and D54(Res)) glioblastomas that were treated with macitentan, temozolomide, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy.
resultsOnly dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell-mediated protection of glioma cells from temozolomide. In five independent survival studies, including temozolomide-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus temozolomide had no evidence of disease (P < 0.0001), whereas all mice in other groups died. In another analysis, macitentan plus temozolomide therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus temozolomide. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to temozolomide.
conclusionsMacitentan plus temozolomide are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients.
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