Jiaying Zheng,1,* Qiqi Feng,1,* Qi Gao,1 Yaonan Wang,1 Shurui Zhao,1 Xiaoyi Zhang,1 Ming Zhao1,2 

1Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China; 2Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Department of Biomaterials, College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing, 100026, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ming Zhao, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China, Tel +861083911535, Fax +861083911533, Email maozhao@126.com Xiaoyi Zhang, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, No. 10, Youanmenwaixitoutiao, Fengtai District, Beijing, 100069, People’s Republic of China, Tel +861083911530, Fax +861083911533, Email zhangdd@ccmu.edu.cn

Purpose: The clinical translation of 18β-Glycyrrhetinic acid (GA) is impeded by its relatively low antitumor potency and poor aqueous solubility, we developed a novel derivative of GA by incorporating the Leu-Asp-Val (LDV) tripeptide to enhance its anti-tumor and anti-metastatic activities both in vitro and in vivo, thereby increasing its potential as a therapeutic agent for cancer treatment.
Methods: The water solubility of GA-LDV was evaluated. The inhibitory effects of GA-LDV on cell viability were assessed in four different human cancer cell lines. In vitro assays were conducted to measure the compound’s impact on tumor cell adhesion, migration, and invasion. In vivo studies were performed using S180 and LLC xenograft models to evaluate the tumor inhibition and anti-metastatic properties.
Results: GA-LDV water solubility was increased 4.1 folds compared with GA. In vitro assays suggested that GA-LDV, at a concentration of 25 μM, significantly impeded the adhesion, migration, and invasion of LLC tumor cell lines, with inhibition rates of 52.7%, 55.5% (vs GA 16.9%, P < 0.05) and 35.9% (vs GA 27.5%, P < 0.05). Moreover, GA-LDV demonstrated stronger tumor inhibition ability than GA (P < 0.05), and anti-metastasis activities in a dose-dependent manner, at the concentration of 5 μmol/kg/d, 1 μmol/kg/d, 0.2 μmol/kg/d with lung metastatic nodules 7.5 (P < 0.01 compared with the control group), 9.8 (P < 0.05 compared with the control group) and 14.5. And GA-LDV had almost no systemic toxicity in S180 or LLC xenograft models.
Conclusion: The newly synthesized GA-LDV derivative demonstrates superior water solubility and significantly enhanced anti-tumor and anti-metastatic activities. The in vitro and in vivo studies indicate that GA-LDV is a promising candidate for further development as a cancer therapeutic agent, with the benefit of potentially reduced systemic toxicity.

Keywords: 18β-Glycyrrhetinic acid, anti-tumor, anti-metastasis activity, lung cancer, MMP