Metal-enriched HSP90 nanoinhibitor overcomes heat resistance in hyperthermic intraperitoneal chemotherapy used for peritoneal metastases

Molecular Cancer

Research

Miaojuan Qiu¹  Jia Li¹  Bin-bin Li¹  Hengxing Chen¹  Leli Zeng²  Bo Bi²  Kuan Li²  Peng Liu²  Changhua Zhang²  Qiang Wang²  Yulong He²  Jing Zhao³  Yuan Yin⁴  Yingfei Wen⁵  Shiqiang Zhang⁵  You Li⁵ 

[1] Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China;Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, China;Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China;Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-Sen University, No. 628 Zhenyuan Road, 518107, Shenzhen, Guangdong, China;Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China;Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China;Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China;Gastric Cancer Center, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Sichuan, China;Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong, China;

关键词: Heat shock protein 90 inhibitor;    Epigallocatechin gallate;    Heat stress resistance;    Pyroptosis;    Hyperthermic intraperitoneal chemotherapy;   

DOI  :  10.1186/s12943-023-01790-2

 received in 2023-03-31, accepted in 2023-05-16,  发布年份 2023

来源: Springer

【 摘 要 】

Clinical hyperthermic intraperitoneal chemotherapy (HIPEC) is regarded as a potential treatment that can prolong survival of patients with peritoneal metastases after cytoreductive surgery. However, treated tumor cells are prone to becoming heat resistant to HIPEC therapy through high expression of heat shock proteins (HSPs). Here, a carrier-free bifunctional nanoinhibitor was developed for HIPEC therapy in the management of peritoneal metastases. Self-assembly of the nanoinhibitor was formed by mixing Mn ion and epigallocatechin gallate (EGCG) in a controllable manner. Such nanoinhibitor directly inhibited HSP90 and impaired the HSP90 chaperone cycle by reduced intracellular ATP level. Additionally, heat and Mn ion synergistically induced oxidative stress and expression of caspase 1, which activated GSDMD by proteolysis and caused pyroptosis in tumor cells, triggering immunogenic inflammatory cell death and induced maturation of dendritic cells through the release of tumor antigens. This strategy to inhibit heat resistance in HIPEC presented an unprecedented paradigm for converting “cold” tumors into “hot” ones, thus significantly eradicating disseminated tumors located deep in the abdominal cavity and stimulating immune response in peritoneal metastases of a mouse model. Collectively, the nanoinhibitor effectively induced pyroptosis of colon tumor cells under heat conditions by inhibiting heat stress resistance and increasing oxidative stress, which may provide a new strategy for treatment of colorectal peritoneal metastases.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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