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.

The Fe-S cluster-containing NEET proteins mitoNEET and NAF-1 as chemotherapeutic targets in breast cancer

“…The Garcinia genus of tropical plants has yielded a structurally intriguing family of xanthone-derived natural compounds collectively referred to as caged Garcinia xanthones (CGXs) (5). Gambogic acid, the archetype of this family, inhibits tumor growth in various animal models with minimal side effects and little toxicity on immune and hemopoietic systems (6,7). Its anticancer activity has been associated with mitochondrial membrane polarization, inhibition of the B-cell lymphoma 2 (Bcl-2) family of proteins, accumulation of reactive oxygen species (ROS), suppression the NF-κB signaling pathway, and inhibition of proteasome activity (4)(5)(6)(7)(8)(9)(10).…”

“…Gambogic acid, the archetype of this family, inhibits tumor growth in various animal models with minimal side effects and little toxicity on immune and hemopoietic systems (6,7). Its anticancer activity has been associated with mitochondrial membrane polarization, inhibition of the B-cell lymphoma 2 (Bcl-2) family of proteins, accumulation of reactive oxygen species (ROS), suppression the NF-κB signaling pathway, and inhibition of proteasome activity (4)(5)(6)(7)(8)(9)(10). In previous studies, we determined that cluvenone (CLV) is the pharmacophoric structure of CGX (8,9).…”

Natural products against hematological malignancies and identification of their targets

“…However, its molecular targets have not been thoroughly studied. Liu's group [76] reported that GA inhibits tumor proteasome activity, with potency comparable to bortezomib, the first proteasome inhibitor approved for the treatment of multiple myeloma, but with less toxicity. Their results showed that GA gains the proteasomeinhibitory function after being metabolized by intracellular CYP2E1, that GA induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer action without off-target effects, and that the expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, and thus GA can produce tissue-specific proteasome inhibition and tumor-specific toxicity (Figure 2).…”

“…Huang-Qin (Scutellaria baicalensis Georgi), one of the 50 fundamental herbs used in traditional Chinese medicine, is rich in flavonoids including wogonin (5,7-dihydroxy-8- Figure 2 A schematic illustration of the mechanism for gambogic acid to induce cytotoxicity of cancer cells [76,77]. methoxy-2-phenyl-4H-chromen-4-one) [78][79][80].…”

Inducing cell cycle arrest and apoptosis by dimercaptosuccinic acid modified Fe3O4 magnetic nanoparticles combined with nontoxic concentration of bortezomib and gambogic acid in RPMI-8226 cells

“…13 GA has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients. 14 In addition, it is reported that GA mediates a wide variety of functional antitumor effects, including the induction of cell apoptosis, inhibition of proliferation, and prevention of cancer metastasis and angiogenesis. Hence, previous investigations suggest that GA might be an effective anticancer drug candidate with low toxicity to normal cells.…”