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

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 

机构地区：[1]Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]School of Medicine&Holistic Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China [3]Centre for Inflammation,Faculty of Science,Centenary Institute,School of Life Sciences,University of Technology Sydney,Sydney NSW 2050,Australia [4]Jiangsu Key Laboratory of Immunity and Metabolism,Department of Pathogenic Biology and Immunology,National Experimental Demonstration Center for Basic Medicine Education,Xuzhou Laboratory of Infection and Immunity,Xuzhou Medical University,Xuzhou 221004,China [5]Department of General Surgery,Jiangsu Province Hospital of Chinese Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China [6]Macquarie Medical School,Faculty of Medicine,Human Health Sciences,Macquarie University,Sydney NSW 2109,Australia

出　　处：《Acta Pharmaceutica Sinica B》2024年第5期2077-2096,共20页药学学报（英文版）

基　　金：This work was financially supported by the projects of National Natural Science Foundation of China(82003991,82101844,and 82304953);Natural Science Foundation of Jiangsu Province(BK20230744,China);Jiangsu Specially Appointed Professorship Foundation(013038021001,China);Postgraduate Research&Practice Innovation Program of Jiangsu Province(KYCX22-2045 and KYCX23-2038,China).

摘　　要：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 progression.Herein,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 agent.SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to hypoxia.Mechanistically,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial glycolysis.More importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner.Our 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 

分 类 号：R730.5[医药卫生—肿瘤]