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Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal
Yu Luo1,2, Bing Guan1, Xiaoqi Deng3
1The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361003, P. R. China.
Abstract:
The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.
Insights
This study reveals that SGI-1027, a DNMT1 inhibitor, synergizes with everolimus to overcome everolimus resistance in renal cell carcinoma (RCC). The combination induces cell death via apoptosis and pyroptosis, offering a new therapeutic strategy for advanced RCC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Everolimus is an mTOR inhibitor used for renal cell carcinoma (RCC).
- Drug resistance to everolimus limits its effectiveness in advanced RCC.
- Novel therapeutic strategies are needed to overcome everolimus resistance.
Purpose of the Study:
- To investigate the efficacy of SGI-1027, a DNMT1 inhibitor, in overcoming everolimus resistance in RCC.
- To explore the synergistic effects of SGI-1027 and everolimus in renal cancer cells.
- To elucidate the underlying mechanisms of the combination therapy.
Main Methods:
- Cytotoxicity assays were performed to evaluate SGI-1027 and everolimus.
- Combination treatments were assessed for effects on cell growth, migration, and invasion.
- Apoptosis, pyroptosis, and lysosomal membrane permeability were analyzed.
- In vivo studies in a subcutaneous tumor model were conducted.
Main Results:
- SGI-1027 induces cell vacuolation and methuosis, demonstrating novel cytotoxicity.
- SGI-1027 and everolimus exhibit synergistic effects, suppressing renal cancer cell proliferation, migration, and invasion.
- The combination triggers apoptosis and GSDME-dependent pyroptosis via lysosomal membrane permeability.
- Combination therapy showed effective anti-tumor activity and good tolerability in vivo.
Conclusions:
- SGI-1027 possesses unique cytotoxic properties and synergizes potently with everolimus.
- The combination therapy offers a promising strategy for treating advanced RCC and overcoming everolimus resistance.
- Upregulation of GSDME and enhanced lysosomal activity present a therapeutic window for this drug combination.
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