DH9, a novel PPARγ agonist suppresses the proliferation of ADPKD epithelial cells: An association with an inhibition of β-catenin signaling

Moyan Liu; Lili Fu; Chunyan Liu; Xishan Xiong; Xiang Gao; Min Xiao; Houan Cai; Huimin Hu; Xueqi Wang; Changlin Mei

doi:10.1007/s10637-009-9313-x

DH9, a novel PPARγ agonist suppresses the proliferation of ADPKD epithelial cells: An association with an inhibition of β-catenin signaling

Invest New Drugs. 2010 Dec;28(6):783-90. doi: 10.1007/s10637-009-9313-x. Epub 2009 Sep 16.

Authors

Moyan Liu¹, Lili Fu, Chunyan Liu, Xishan Xiong, Xiang Gao, Min Xiao, Houan Cai, Huimin Hu, Xueqi Wang, Changlin Mei

Affiliation

¹ Nephrology institute of PLA, Department of Internal Medicine, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People's Republic of China.

PMID: 19756375
DOI: 10.1007/s10637-009-9313-x

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that exclusively progresses to renal failure. An important target for the treatment of ADPKD is to reduce cystic cell proliferation. PPARγ agonists such as TZDs are insulin sensitizing agents that have also been reported to decrease tumor growth. Here we tested DH9, a newly synthesized PPARγ agonist on the proliferation of an ADPKD cell line, WT9-12. DH9 showed a potent anti-proliferative activity against ADPKD cells. At high concentration, DH9 also induced apoptotic cell death. The effect of DH9 on cell proliferation was mediated by a PPARγ independent mechanism. Since DH9 decreased the levels of β-catenin in cells via a GSK3β mediated degradation pathway, this acts as a mechanism for growth inhibition by DH9.

Publication types

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

MeSH terms

Animals
Apoptosis / drug effects
Cell Line
Cell Proliferation / drug effects
Cinnamates / chemistry
Cinnamates / pharmacology*
Epithelial Cells / drug effects*
Epithelial Cells / metabolism
Epithelial Cells / pathology*
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Kidney / drug effects
Kidney / metabolism
Kidney / pathology
Mice
PPAR gamma / agonists*
Phenylpropionates / chemistry
Phenylpropionates / pharmacology*
Polycystic Kidney, Autosomal Dominant / enzymology
Polycystic Kidney, Autosomal Dominant / metabolism
Polycystic Kidney, Autosomal Dominant / pathology*
Protein Processing, Post-Translational / drug effects
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rosiglitazone
Signal Transduction / drug effects*
Thiazolidinediones / pharmacology
Transcription, Genetic / drug effects
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Cinnamates
PPAR gamma
Phenylpropionates
Pyrimidines
Thiazolidinediones
beta Catenin
Rosiglitazone
cinnamic acid
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3