Background: 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