Effects of diphyllin as a novel V-ATPase inhibitor on gastric adenocarcinoma

Weidong Shen; Xiaoping Zou; Min Chen; Pengfei Liu; Yonghua Shen; Shuling Huang; Huimin Guo; Lili Zhang

doi:10.1016/j.ejphar.2011.05.042

Effects of diphyllin as a novel V-ATPase inhibitor on gastric adenocarcinoma

Eur J Pharmacol. 2011 Sep 30;667(1-3):330-8. doi: 10.1016/j.ejphar.2011.05.042. Epub 2011 Jun 2.

Authors

Weidong Shen¹, Xiaoping Zou, Min Chen, Pengfei Liu, Yonghua Shen, Shuling Huang, Huimin Guo, Lili Zhang

Affiliation

¹ Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, PR China.

PMID: 21645513
DOI: 10.1016/j.ejphar.2011.05.042

Abstract

The natural compound diphyllin, a cytostatic lignan isolated from Cleistanthus collinus, can dramatically inhibit the proliferation and induce the apoptosis of human gastric cancer cells, SGC7901. Our study found that diphyllin can inhibit the expression of V-ATPases in a dose-dependent manner, decrease the internal pH (pHi) and reverse the transmembrane pH gradient in SGC7901 cells. Changes of the pH gradient were positively correlated with diphyllin concentration. Further study found that diphyllin treatment caused a decrease in phospho-LRP6, but not in LRP6. β-catenin in Wnt/β-catenin signaling and its target genes, c-myc and cyclin-D1, were also decreased with the inhibition of V-ATPases. Therefore, diphyllin could be characterized as a new V-ATPase inhibitor in treating gastric cancer and inhibiting the phosphorylation of LRP6 in Wnt/β-catenin signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics
Adenocarcinoma / pathology*
Animals
Apoptosis / drug effects
Benzodioxoles
Cell Line, Tumor
Cell Proliferation / drug effects
Dioxolanes / pharmacology*
Dioxolanes / therapeutic use
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / therapeutic use
Extracellular Space / chemistry
Extracellular Space / drug effects
Humans
Hydrogen-Ion Concentration
Intracellular Space / chemistry
Intracellular Space / drug effects
Lignans / pharmacology*
Lignans / therapeutic use
Low Density Lipoprotein Receptor-Related Protein-6 / genetics
Mice
Mice, Inbred BALB C
Neoplasm Invasiveness
Stomach Neoplasms / drug therapy
Stomach Neoplasms / genetics
Stomach Neoplasms / pathology*
Vacuolar Proton-Translocating ATPases / antagonists & inhibitors*
Xenograft Model Antitumor Assays

Substances

Benzodioxoles
Dioxolanes
Enzyme Inhibitors
Lignans
Low Density Lipoprotein Receptor-Related Protein-6
Lrp6 protein, mouse
Vacuolar Proton-Translocating ATPases
diphyllin