title: Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo.
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.
authors.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangzhou, Guangdong 510182, China.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.forename: Yurong
authors.initials: Y
authors.lastname: Liu
authors.forename: Canguo
authors.initials: C
authors.lastname: Zhao
authors.forename: Shujue
authors.initials: S
authors.lastname: Li
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lu
authors.forename: Chunjiao
authors.initials: C
authors.lastname: Liu
authors.forename: Lixia
authors.initials: L
authors.lastname: Guan
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Shi
authors.forename: Wenbin
authors.initials: W
authors.lastname: Song
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Dong
authors.forename: Haiping
authors.initials: H
authors.lastname: Guo
authors.forename: Guanmei
authors.initials: G
authors.lastname: Wen
authors.forename: Change
authors.initials: C
authors.lastname: Zhang
authors.forename: Lili
authors.initials: L
authors.lastname: Jiang
authors.forename: Ningfang
authors.initials: N
authors.lastname: Ma
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Shunqing
authors.initials: S
authors.lastname: Wang
authors.forename: Huo
authors.initials: H
authors.lastname: Tan
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D062105:Molecular Docking Simulation; D009928:Organ Specificity / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D016019:Survival Analysis; D014357:Trypsin / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D044004:Xanthones; C052659:gambogic acid; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D014357:Trypsin; D020169:Caspases; D046988:Proteasome Endopeptidase Complex