2. Academic Validation
  3. Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer

Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer

  • Adv Sci (Weinh). 2024 Aug 9:e2404693. doi: 10.1002/advs.202404693.
Yu Luo 1 2,  Bing Guan 1,  Xiaoqi Deng 3,  Peide Bai 1,  Haichao Huang 1,  Chaohao Miao 1,  Anran Sun 1,  Zhipeng Li 1,  Dianqiang Yang 4,  Xuegang Wang 1,  Zhiqiang Shao 5,  Yulong Wu 6,  Jinchun Xing 1,  Bin Chen 1,  Tao Wang 1
Affiliations

Affiliations

  • 1 The 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.
  • 2 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Yuzhong, Chongqing, 400016, P. R. China.
  • 3 Department of Nephrology, Zigong Fourth People's Hospital, Zigong, Sichuan, 643000, P. R. China.
  • 4 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
  • 5 Xiamen University Laboratory Animal Center, Xiamen University, Xiamen, Fujian, 361102, P. R. China.
  • 6 Department of Urology, The Fifth Hospital of Xiamen, Xiamen, Fujian, 361101, P. R. China.
PMID: 39119834 DOI: 10.1002/advs.202404693
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.

Keywords

SGI‐1027; everolimus; lysosome; methuosis; pyroptosis; renal cell carcinoma.

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