Gambogic acid promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells

Li, Chenglin; Qi, Qi; Lu, Na; Dai, Qinsheng; Li, Fanni; Wang, Xiaotang; Qin, You; Guo, Qing

doi:10.1139/o2012-030

Cited by 57 publications

(46 citation statements)

References 46 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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“…The molecular formula of GA is C 38 H 44 O 9 (molecular weight, 628.34 g/mol) and its chemical structure is known. GA is an effective anti-tumor agent that has been shown to have multiple effects on several types of solid human tumors in vitro and in vivo (14,15 lymphoma-2 (Bcl-2), inhibiting tumor cell apoptosis (16,17). GA has also been implicated in several mechanisms of cisplatin resistance (18).…”

Section: Introductionmentioning

confidence: 99%

Role of gambogic acid and NaI131 in A549/DDP cells

et al. 2016

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Abstract. Resistance to platinum in tumor tissue is a considerable barrier against effective lung cancer treatment. Radionuclide therapy is the primary adjuvant treatment, however, the toxic side effects limit its dosage in the clinical setting. Therefore, the present study aimed to determine whether an NaI 131 radiosensitizer could help reduce the toxic side effects of radionuclide therapy. In vitro experiments were conducted to determine whether NaI 131 can inhibit platinum resistance in A549/DDP cells, which are cisplatin-resistant non-small cell lung cancer cells, and whether gambogic acid (GA) is an effective NaI 131 radiosensitizer. Cell proliferation following drug intervention was analyzed using MTT and isobolographic analysis. Apoptosis was assessed by flow cytometry. In addition, the mechanisms of drug intervention were analyzed by measuring the expression of P-glycoprotein (P-gP), B cell lymphoma 2 (Bcl-2), Bcl2-associated X protein (Bax) and P53 using western blot analysis and immunocytochemistry. According to isobolographic analysis, a low concentration of NaI 131 combined with GA had a synergistic effect on the inhibition of A549/DDP cell proliferation, which was consistent with an increased rate of apoptosis. Furthermore, the overexpression of Bax, and the downregulation of P-gP, P53 and Bcl-2 observed demonstrated the potential mechanism(s) of NaI 131 and GA intervention. NaI 131 may induce apoptosis in A549/DDP cells by regulating apoptosis-related proteins. A low concentration combination of NaI 131 and GA was able to significantly inhibit A549/DDP cell proliferation and induce cell apoptosis. Thus, the two drugs appear to have a synergistic effect on apoptosis of A549/DDP cells.

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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 promotes apoptosis and resistance to metastatic potential in MDA-MB-231 human breast carcinoma cells

Cited by 57 publications

References 46 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

Role of gambogic acid and NaI131 in A549/DDP cells

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

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