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Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2077-2096页

作者： Cheng Qian Yueke Zhou Teng Zhang Guanglu Dong Mengyao Song Yu Tang Zhonghong Wei Suyun Yu Qiuhong Shen Wenxing Chen Jaesung P.Choi Juming Yan Chongjin Zhong Li Wan Jia Li Aiyun Wang Yin Lu Yang Zhao Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China Centre for Inflammation Faculty of ScienceCentenary InstituteSchool of Life SciencesUniversity of Technology SydneySydney NSW 2050Australia Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Experimental Demonstration Center for Basic Medicine EducationXuzhou Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004China Department of General Surgery Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Macquarie Medical School Faculty of MedicineHuman Health SciencesMacquarie UniversitySydney NSW 2109Australia

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor ***,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic *** was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to ***,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial *** importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent *** findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

关键词： Salvianic acid A Tumor vascular normalization PKM2 β-Catenin Claudin-5 endothelial glycolysis Tight junctions Doxorubicin

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Targeting tumor endothelial hyperglycolysis enhances immunotherapy through remodeling tumor microenvironment

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1825-1839页

作者： Yunlong Shan Qi Ni Qixiang Zhang Mengying Zhang Bin Wei Lingge Cheng Chongjin Zhong Xinyu Wang Qingqing Wang Jiali Liu Jingwei Zhang Jingjing Wu Guangji Wang Fang Zhou Key Laboratory of Drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China Department of Hematology and Oncology the Affiliated Huaian No.1 People’s Hospital of Nanjing Medical UniversityHuai’an 223300China

Vascular abnormality is a hallmark of most solid tumors and facilitates immune *** the abnormal metabolism of tumor endothelial cells(TECs)may provide an opportunity to improve the outcome of ***,in comparison to vascular endothelial cells from adjacent peritumoral tissues in patients with colorectal cancer(CRC),TECs presented enhanced glycolysis with higher glyceraldehyde-3-phosphate dehydrogenase(GAPDH)*** an unbiased screening identified that osimertinib could modify the GAPDH and thus inhibit its activity in ***-dose osimertinib treatment caused tumor regression with vascular normalization and increased infiltration of immune effector cells in tumor,which was due to the reduced secretion of lactate from TECs by osimertinib through the inhibition of ***,osimertinib and anti-PD-1 blockade synergistically retarded tumor *** study provides a potential strategy to enhance immunotherapy by targeting the abnormal metabolism of TECs.

关键词： endothelial glycolysis GAPDH Osimertinib Normalized glycolysis Immunometabolism Colorectal cancer Tumor microenvironment Immunotherapy

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