13-[CH2CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein

Abstract

Guanyu Li,1,2 Yi Ren,1,2 Xiaoyi Zhang,1,2 Shurui Zhao,1,2 Yaonan Wang,1,2 Jianhui Wu,1,2 Shiqi Peng,1,2 Ming Zhao1–3 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; 2Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, People’s Republic of China; 3Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University Of Chemical Technology, Beijing 100026, People’s Republic of ChinaCorrespondence: Shiqi Peng; Ming ZhaoDepartment of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University, No. 10, Youanmenwaixitoutiao, Fengtai District, Beijing 100069, People’s Republic of ChinaTel [phone]; [phone]Fax [phone]Email [email protected]; [email protected]: The discovery of novel derivative of berberine (BBR) having higher anti-tumor activity in vivo is of clinical importance. In this profile, 13-[CH2CO-Cys-(Bzl)-OBzl]-berberine (13-Cys-BBR) was prepared for related assays.Purpose: The object of preparation and evaluation is to show the advantages of 13-Cys-BBR over BBR in both in vitro and in vivo anti-tumor actions, furthermore to correlate the proliferation of cancer cells with ROS formation and anti-apoptosis protein (XIAP) expression inside cancer cells.Methods: Transwell chamber was used to simulate the intestinal and cell wall for bioavailability evaluation; MTT assay was used to evaluate the in vitro anti-proliferation activity; fluorescein isothiocyanate content was used to represent ROS level in HCT-8 cells; Western blot assay was used to quantify the expression of XIAP, caspase-3, and poly ADP-ribose polymerase in HCT-8 cells; and S180 mouse model was used to evaluate the in vivo anti-tumor activity.Results: In vitro the IC50 values (∼15–40 μM) of 13-Cys-BBR against the proliferation of eight cancer cell lines were significantly lower than those of BBR (∼25–140 μM); the content of ROS formed inside HCT-8 cells treated by 13-Cys-BBR was ∼3.44-folds higher than that inside HCT-8 cells treated by BBR; the expression of XIAP in HCT-8 cells treated by 13-Cys-BBR was ∼1.21-folds lower than that in HCT-8 cells treated by BBR; the tumor weight of S180 mice orally treated by 2 μmol/kg/day of 13-Cys-BBR (∼1.5 g) was significantly lower than that of S180 mice orally treated by 2 μmol/kg/day of BBR (∼2.5 g); and the active pocket of XIAP was more suitable for 13-Cys-BBR than for BBR.Conclusion: The anti-tumor action correlates with ROS and apoptosis protein, which suggests 13-Cys-BBR is a promising candidate for preclinical study.Keywords: berberine, 13-position modification, anti-tumor, ROS, XIAP

Keywords

• berberine
• 13-position modification
• anti-tumor
• ros
• xiap