Repurposing thioridazine for inducing immunogenic cell death in colorectal cancer via eIF2α/ATF4/CHOP and secretory
Thu-Ha Tran1,2, Ming Kao2, Hsiao-Sheng Liu3,4,5
1Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 112, Taiwan.
Background:
Colorectal cancer (CRC) is a highly prevalent cancer type with limited targeted therapies available and 5-year survival rate, particularly for late-stage patients. There have been numerous attempts to repurpose drugs to tackle this problem. It has been reported that autophagy inducers could augment the effect of certain chemotherapeutic agents by enhancing immunogenic cell death (ICD).
Methods:
In this study, we employed bioinformatics tools to identify thioridazine (THD), an antipsychotic drug, and found that it could induce autophagy and ICD in CRC. Then in vitro and in vivo experiments were performed to further elucidate the molecular mechanism of THD in CRC.
Results:
THD was found to induce endoplasmic reticulum (ER) stress in CRC cells by activating the eIF2α/ATF4/CHOP axis and facilitating the accumulation of secretory autophagosomes, leading to ICD. In addition, THD showed a remarkable ICD-activating effect when combined with oxaliplatin (OXA) to prevent tumor progression in the mouse model.
Conclusions:
Together, our findings suggest that the repurposed function of THD in inhibiting CRC involves the upregulation of autophagosomes and ER stress signals, promoting the release of ICD markers, and providing a potential candidate to enhance the clinical outcome for CRC treatment. Video Abstract.
Insights
Thioridazine, an antipsychotic, shows potential in treating colorectal cancer (CRC) by inducing autophagy and immunogenic cell death (ICD). Combining it with oxaliplatin may improve treatment outcomes for CRC patients.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Colorectal cancer (CRC) presents a significant global health challenge with limited effective targeted therapies, especially for advanced stages.
- Drug repurposing offers a promising avenue for novel CRC treatments.
- Autophagy inducers have shown potential in enhancing chemotherapy by promoting immunogenic cell death (ICD).
Discussion:
- Thioridazine (THD) activates the eIF2α/ATF4/CHOP axis, inducing endoplasmic reticulum (ER) stress and promoting secretory autophagosome accumulation in CRC cells.
- This mechanism culminates in immunogenic cell death (ICD), a process that enhances anti-tumor immunity.
- The combination of THD and oxaliplatin (OXA) demonstrated synergistic effects in preventing tumor progression in preclinical models.
Key Insights:
- Thioridazine (THD), an antipsychotic, functions as an autophagy inducer and triggers immunogenic cell death (ICD) in colorectal cancer (CRC).
- THD-induced ICD is mediated by endoplasmic reticulum (ER) stress via the eIF2α/ATF4/CHOP pathway.
- Combined THD and oxaliplatin (OXA) therapy significantly inhibited tumor progression in vivo.
Outlook:
- Repurposed thioridazine (THD) offers a novel therapeutic strategy for colorectal cancer (CRC) by modulating autophagy and ER stress.
- THD enhances ICD marker release, suggesting improved clinical outcomes for CRC patients.
- Further clinical investigation of THD, potentially in combination with chemotherapy, is warranted for CRC treatment.
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