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Pyroptosis-Inducing Platinum(IV) Prodrugs via GSDME Pathway for Chemoimmunotherapy and Metastasis Inhibition in
Xinda Yang1, Chuansheng Xu1, Youliang Zeng2
1School of Chemical Science and Engineering, Department of Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Tongji University, Shanghai, 200092, P. R. China.
Abstract:
Pyroptosis has attracted significant attention for its role in cancer chemotherapy and immunotherapy. However, few drugs have been reported to induce pyroptosis via the Caspase-3/gasdermin E (GSDME) pathway. Herein, three novel PtIV prodrugs, MRP, DRP, and HRP are rationally designed by conjugating DNA methyltransferase (DNMT) inhibitor (RG108) and/or histone deacetylase (HDAC) inhibitor (PhB) to the PtIV center. These prodrugs can be easily reduced to cisplatin (CDDP) due to the high glutathione (GSH) levels in tumors, liberating the coordinated ligands. Released RG108 reactivates the GSDME gene and reduces pyroptosis in low GSDME-expressing tumor cells. Meanwhile, PhB-induced chromatin loosening enhances CDDP-DNA binding, which not only increases Caspase-3 expression, but also upregulates GSDME. HRP demonstrates superior ability to suppress tumor growth and metastasis while reducing systemic toxicity compared with CDDP. By reactivating GSDME and loosening chromatin, HRP effectively boosts tumor cell pyroptosis and exhibits the most pronounced anticancer performance. These findings highlight HRP's potential as a therapeutic agent for triple-negative breast cancer (TNBC) and offer innovative strategies for combining chemotherapy with immunotherapy. To the best of current knowledge, this is the first report of platinum complexes inducing pyroptosis via the Caspase-3/GSDME pathway in low GSDME-expressing tumor cells.
Insights
Novel platinum (PtIV) prodrugs, HRP, DRP, and MRP, were developed to induce pyroptosis, a form of programmed cell death, in cancer cells. HRP shows significant potential in treating triple-negative breast cancer by enhancing chemotherapy and immunotherapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Immunotherapy
Background:
- Pyroptosis is a key mechanism in cancer chemotherapy and immunotherapy.
- Limited drugs effectively induce pyroptosis through the Caspase-3/gasdermin E (GSDME) pathway.
Purpose of the Study:
- To design and synthesize novel platinum (PtIV) prodrugs to induce pyroptosis via the Caspase-3/GSDME pathway.
- To evaluate the efficacy of these prodrugs, particularly HRP, in suppressing tumor growth and metastasis.
Main Methods:
- Rational design of three PtIV prodrugs (MRP, DRP, HRP) by conjugating DNMT inhibitor (RG108) and/or HDAC inhibitor (PhB) to the PtIV center.
- Assessment of prodrug reduction to cisplatin (CDDP) in tumor environments rich in glutathione (GSH).
- Evaluation of RG108's role in GSDME gene reactivation and PhB's effect on chromatin structure and CDDP-DNA binding.
Main Results:
- The prodrugs were effectively reduced to CDDP in tumors, releasing RG108 and PhB.
- RG108 reactivated GSDME in low-GSDME-expressing tumor cells, while PhB enhanced CDDP-DNA binding and upregulated GSDME expression.
- HRP demonstrated superior tumor growth and metastasis suppression with reduced systemic toxicity compared to CDDP, effectively boosting pyroptosis.
Conclusions:
- HRP effectively induces pyroptosis via the Caspase-3/GSDME pathway, even in tumors with low GSDME expression.
- HRP shows significant therapeutic potential for triple-negative breast cancer (TNBC) by combining chemotherapy and immunotherapy.
- This study presents the first report of platinum complexes inducing pyroptosis through the Caspase-3/GSDME pathway in low GSDME-expressing tumor cells.
