Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells

Gu, Hong-Yan; Wang, Xiaotang; Rao, Shuyun; Wang, Jia; Zhao, Jie; Ren, Fang; Mu, Rong; Yang, Yong; Qi, Qi; Liu, Wei; Lu, Na; Liu, Hua; Qin, You; Guo, Qinglong

doi:10.1158/1535-7163.mct-08-0212

Cited by 84 publications

(53 citation statements)

References 30 publications

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“…GBA potently inhibits cancer cell proliferation in vitro and in mouse xenograft models (37)(38)(39)(40)(41). Although GBA is reported to have multiple effects in cancer cells (42,43), recent studies have ascribed some of GBA's antitumor activity to its binding to Hsp90 (44,45).…”

Section: Significancementioning

confidence: 99%

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Yim

Prince

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.

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Section: Significancementioning

confidence: 99%

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Yim

Prince

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1,2 One naturally active product isolated from gamboge resin taken from the Garcinia hanburyi tree is gambogic acid (GA), which has significant antitumor activity. [3][4][5] GA can also induce the apoptosis of cancer cell by suppressing the nuclear factor-κB (NF-κB)-signaling pathway, which in turn suppresses the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway. [6][7][8][9] The content of many active components extracted from TCM is very low, and drug research and exploitation based on TCM is costly.…”

Section: Introductionmentioning

confidence: 99%

Synergetic effect of functional cadmium–tellurium quantum dots conjugated with gambogic acid for HepG2 cell-labeling and proliferation inhibition

Xu¹,

Li²,

Shi³

et al. 2013

IJN

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“…This motif is further decorated via A-ring substitutions and peripheral oxidations to produce a variety of natural products with a broad range of bioactivities (11). Gambogic acid (GBA), the archetype of this family, potently inhibits cancer cell proliferation in solid tumors (13)(14)(15)(16)(17) and hematological malignancies (18) and has entered clinical trials in China for patients with non-small-cell lung, colon, and renal cancers (19). In addition, the potent cytotoxicity of several CGXs at low micromolar concentrations has been well documented (20)(21)(22)(23).…”

mentioning

confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells

Abstract: Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-

Cited by 84 publications

References 30 publications

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Synergetic effect of functional cadmium–tellurium quantum dots conjugated with gambogic acid for HepG2 cell-labeling and proliferation inhibition

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

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Gambogic acid mediates apoptosis as a p53 inducer through down-regulation of mdm2 in wild-type p53-expressing cancer cells

Abstract: Gambogic acid (GA) is a natural product with potent apoptotic activity. Here, we showed that GA broadly inhibited the growth of cancer cells that expressed wild-type p53 as determined by 3-(4,5-dimethylthiazol-

Cited by 84 publications

References 30 publications

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Synergetic effect of functional cadmium&ndash;tellurium quantum dots conjugated with gambogic acid for HepG2 cell-labeling and proliferation inhibition

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

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Synergetic effect of functional cadmium–tellurium quantum dots conjugated with gambogic acid for HepG2 cell-labeling and proliferation inhibition