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

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

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


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.

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