Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Suppresses macrophage capping protein beyond STING activation

Zhiyong Xiao; Xia Cui; Feng Liu; Ying Wang; Xiao Liu; Wenxia Zhou; Yongxiang Zhang

doi:10.1016/j.bbadis.2024.167149

Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Suppresses macrophage capping protein beyond STING activation

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 1;1870(5):167149. doi: 10.1016/j.bbadis.2024.167149. Online ahead of print.

Authors

Zhiyong Xiao¹, Xia Cui², Feng Liu³, Ying Wang³, Xiao Liu², Wenxia Zhou⁴, Yongxiang Zhang⁵

Affiliations

¹ Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: zy-xiao@163.com.
² Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China.
⁴ Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: zhouwx@bmi.ac.cn.
⁵ Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: zhangyx@bmi.ac.cn.

PMID: 38565383
DOI: 10.1016/j.bbadis.2024.167149

Abstract

The vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) induces apoptosis in vascular endothelial cells and leads to tumor hemorrhagic necrosis. While DMXAA has been proven to be a potent agonist of murine stimulator of interferon genes (mSTING), it has little effect on human-STING (hSTING). This species selectivity of DMXAA may explain its effectiveness against solid tumors in mice and its failure in clinical trials. However, DMXAA did reduce tumor volume in some patients during clinical trials. These paradoxical results have prompted us to investigate the anti-tumor mechanism of DMXAA beyond STING in the destruction of tumor vasculature in humans. In this study, we demonstrated that DMXAA binds to both human and mouse macrophage capping protein (CapG), with a KD of 5.839 μM for hCapG and a KD of 2.867 μM for mCapG, as determined by surface plasmon resonance (SPR) analysis. Homology modeling and molecular docking analysis of hCapG indicated that the critical residues involved in the hydrogen bond interaction of DMXAA with hCapG were Arg153, Thr151, and GLN141, Asn234. In addition, electrostatic pi-cation interaction occurred between DMXAA and hCapG. Further functional studies revealed that CapG protein plays a crucial role in the effects of DMXAA on human umbilical endothelial vein cell (HUEVC) angiogenesis and migration, as well as the expression of cytoskeletal proteins actin and tubulin, and the invasion of A549 lung adenocarcinoma cells. Our study has originally uncovered a novel cross-species pathway underlying the antitumor vascular disruption of DMXAA extends beyond STING activation. This finding deepens our understanding of the multifaceted actions of flavonoid VDAs in animal models and in clinical settings, and may provide insights for the precise therapy of DMXAA based on the biomarker CapG protein.

Keywords: DMXAA; Macrophage capping protein; Stimulator of interferon genes; Vascular destruction.