Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo

Xiaofen Li; Shouting Liu; Hongbiao Huang; Ningning Liu; Chong Zhao; Siyan Liao; Changshan Yang; Yurong Liu; Canguo Zhao; Shujue Li; Xiaoyu Lu; Chunjiao Liu; Lixia Guan; Kai Zhao; Xiaoqing Shi; Wenbin Song; Ping Zhou; Xiaoxian Dong; Haiping Guo; Guanmei Wen; Change Zhang; Lili Jiang; Ningfang Ma; Bing Li; Shunqing Wang; Huo Tan; Xuejun Wang; Q Ping Dou; Jinbao Liu

doi:10.1016/j.celrep.2012.11.023

Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo

Cell Rep. 2013 Jan 31;3(1):211-22. doi: 10.1016/j.celrep.2012.11.023. Epub 2012 Dec 21.

Affiliation

¹ Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong 510182, China.

PMID: 23260670
DOI: 10.1016/j.celrep.2012.11.023

Abstract

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

Publication types

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

MeSH terms

Animals
Caspases / metabolism
Cell Death / drug effects
Cell Proliferation / drug effects
Cytochrome P-450 CYP1A2 / metabolism
Cytochrome P-450 CYP2E1 / metabolism
Drug Screening Assays, Antitumor
Endoplasmic Reticulum Stress / drug effects
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Gene Silencing / drug effects
Hep G2 Cells
Humans
K562 Cells
Leukemia / metabolism
Leukemia / pathology
Lymphocytes / drug effects
Lymphocytes / metabolism
Lymphocytes / pathology
Mice
Molecular Docking Simulation
Organ Specificity / drug effects*
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / chemistry
Proteasome Inhibitors / pharmacology*
RNA, Small Interfering / metabolism
Survival Analysis
Trypsin / metabolism
Ubiquitination / drug effects
Xanthones / chemistry
Xanthones / pharmacology*

Substances

Proteasome Inhibitors
RNA, Small Interfering
Xanthones
gambogic acid
Cytochrome P-450 CYP2E1
Cytochrome P-450 CYP1A2
Trypsin
Caspases
Proteasome Endopeptidase Complex

Associated data

GEO/GSE38730