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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme
Filiz Senbabaoglu1, Ahmet Cingoz1, Ezgi Kaya1
1a Koç University School of Medicine , Istanbul , Turkey.
Abstract:
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNA-damaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.
Insights
This study identified FDA-approved drugs that sensitize Glioblastoma Multiforme (GBM) cells to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL). Mitoxantrone combined with TRAIL shows promise for treating this aggressive brain cancer.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) shows promise for cancer treatment but faces resistance.
- Glioblastoma Multiforme (GBM) is an aggressive brain cancer with limited therapeutic options.
- Identifying agents to overcome TRAIL resistance is crucial for effective cancer therapy.
Purpose of the Study:
- To identify FDA-approved compounds that can sensitize Glioblastoma Multiforme (GBM) cells to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL).
- To evaluate the efficacy of identified sensitizing agents, both alone and in combination with TRAIL, in GBM.
- To investigate the molecular mechanisms underlying TRAIL sensitization by specific agents, such as Mitoxantrone.
Main Methods:
- Conducted an extensive drug-re-profiling screen using isogenic GBM cell pairs with varying TRAIL sensitivity.
- Assessed the efficacy of identified compounds as single agents and in combination with TRAIL.
- Investigated downstream apoptosis pathway changes, including Death Receptor (DR4 and DR5) expression and gene expression patterns, following Mitoxantrone treatment.
Main Results:
- Identified 26 TRAIL-sensitizing compounds, with 13 also effective as single agents.
- Cardiac glycosides were a prominent class of TRAIL-sensitizing compounds with single-agent efficacy.
- Mitoxantrone, a DNA-damaging agent, synergized with TRAIL to induce apoptosis in GBM cells without significant toxicity to non-malignant cells.
- Mitoxantrone treatment upregulated DR4 and DR5 expression and shifted gene expression towards apoptosis.
Conclusions:
- Combination therapy of Mitoxantrone and TRAIL presents a promising therapeutic strategy for Glioblastoma Multiforme.
- Drug-re-profiling is an effective approach to identify novel sensitizing agents for cancer treatment.
- Understanding the molecular mechanisms of TRAIL sensitization can guide the development of more effective cancer therapies.
