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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Clofoctol as a novel senolytic drug eliminating therapy-induced senescent glioma cells
Yuxin Zhang1, Zhixing Wang1, Yue Wang1
1State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry & Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Background:
Glioblastoma is the most common malignant brain glioma, accounting for ∼48% of malignant central nervous system tumors. Targeting glioma stem cells and senescent glioma cells represents promising therapeutic strategies. In our previous study, we identified the clofoctol as a candidate drug targeting glioma stem cells with good blood-brain barrier permeability and potent anti-glioblastoma efficacy. Comprehensively demonstrating the impact of clofoctol on glioblastoma might provide novel strategies for the treatment of glioblastoma.
Methods:
By utilizing single-cell RNA sequencing of tumor tissue, we demonstrated the suppression effect of clofoctol on senescent glioma cell. Cellular RNA sequencing, molecular docking and CETSA were used to further confirm target of clofoctol. Ultimately, GL261 and orthotopic patient-derived xenograft animal models was performed to assess whether the senolytic effect of clofoctol could enhance TMZ therapy.
Results:
Clofoctol treatment reduced the senescence level (SASPs, senescence-related genes, and the proportion of senescent cells) in GL261-derived tumor single-cell RNA sequencing. In vitro, clofoctol could target senescent glioma cells and induce cell death through apoptosis and ferroptosis. P53 was identified as the functional protein which elicited the effect of clofoctol. In vivo, clofoctol exhibited senolytic activity and synergized with TMZ, leading to extended survival in glioblastoma mouse model.
Conclusions:
Our study demonstrated the clinical drug clofoctol could target chemotherapy-induced senescent glioma cells through P53 and trigger cell apoptotic and ferroptotic death. We further confirmed a synergistic effect between clofoctol and temozolomide which could be a novel therapeutic approach for glioblastoma therapy.
Insights
Clofoctol effectively targets senescent glioblastoma cells, inducing apoptosis and ferroptosis via P53. This drug synergizes with temozolomide, offering a promising new glioblastoma treatment strategy.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Pharmacology
Background:
- Glioblastoma is the most common malignant brain tumor.
- Targeting senescent glioma cells is a promising therapeutic strategy.
- Clofoctol shows potential for glioblastoma treatment due to blood-brain barrier penetration and efficacy.
Purpose of the Study:
- To investigate the effect of clofoctol on senescent glioma cells.
- To confirm the molecular target of clofoctol.
- To evaluate clofoctol's senolytic activity and its synergy with temozolomide in glioblastoma models.
Main Methods:
- Single-cell RNA sequencing to assess clofoctol's impact on senescent cells.
- Molecular docking and CETSA to identify clofoctol's protein target.
- In vitro and in vivo studies using GL261 and patient-derived xenograft models.
Main Results:
- Clofoctol reduced senescence markers and induced apoptosis and ferroptosis in senescent glioma cells.
- P53 was identified as the key protein mediating clofoctol's effects.
- Clofoctol demonstrated senolytic activity and enhanced survival when combined with temozolomide in vivo.
Conclusions:
- Clofoctol targets chemotherapy-induced senescent glioma cells via P53, inducing cell death.
- Clofoctol and temozolomide exhibit a synergistic effect, presenting a novel therapeutic approach for glioblastoma.
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