Gambogic Acid Is a Tissue-Specific Proteasome Inhibitor In Vitro and In Vivo

SummaryGambogic 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.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► GA is metabolized by CYP2E1 to produce a metabolite proteasome inhibitor ► Proteasome inhibition is required for GA’s cytotoxicity and anticancer activity ► GA is a more tissue-specific proteasome inhibitor than bortezomib/velcade ► GA is nontoxic to peripheral white blood cells compared to bortezomib