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. © 2013 The Authors.
Li, X., Liu, S., Huang, H., Liu, N., Zhao, C., Liao, S., … Liu, J. (2013). Gambogic Acid Is a Tissue-Specific Proteasome Inhibitor In Vitro and In Vivo. Cell Reports, 3(1), 211–222. https://doi.org/10.1016/j.celrep.2012.11.023