Epigenetics-Based Tumor Cells Pyroptosis for Enhancing the Immunological Effect of Chemotherapeutic Nanocarriers
Jin-Xuan Fan1, Rong-Hui Deng2, He Wang1
1Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry , Wuhan University , Wuhan 430072 , P.R. China.
Abstract:
Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the DFNA5 gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of DFNA5 (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the DFNA5 gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.
Insights
This study combines decitabine (DAC) with chemotherapy nanodrugs to induce pyroptosis, a cell death pathway, in tumor cells. This epigenetic reprogramming reactivates the GSDME protein, enhancing chemotherapy
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Pyroptosis is an inflammatory programmed cell death pathway.
- Chemotherapy can induce pyroptosis via caspase-3, but GSDME expression is often silenced in tumors due to gene hypermethylation.
- Silenced GSDME limits the effectiveness of pyroptosis-inducing chemotherapy.
Purpose of the Study:
- To develop a novel epigenetic strategy combining decitabine (DAC) with nanochemotherapy to trigger pyroptosis in tumor cells.
- To enhance the anti-tumor immunological effects of chemotherapy.
- To investigate the potential of this approach in tumor immunotherapy.
Main Methods:
- Utilized decitabine (DAC) for epigenetic demethylation of the DFNA5 gene, restoring GSDME expression in tumor cells.
- Administered cisplatin-loaded nanoliposomes (LipoDDP) to activate caspase-3 and induce pyroptosis.
- Evaluated anti-tumor activity, anti-metastasis, and recurrence inhibition in tumor-bearing mice.
Main Results:
- Successfully reversed GSDME silencing in tumor cells through DAC treatment.
- Demonstrated that the combination therapy triggers pyroptosis, enhancing chemotherapy's immunological effects.
- Observed significant anti-tumor activity, reduced metastasis, and inhibited tumor recurrence.
Conclusions:
- The developed pyroptosis-based chemotherapy strategy effectively reactivates GSDME and enhances anti-tumor immunity.
- This epigenetic reprogramming approach offers a promising avenue for improving chemotherapy efficacy and advancing tumor immunotherapy.
- The findings provide valuable insights into overcoming GSDME silencing for cancer treatment.
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