Gambogic Acid Deactivates Cytosolic and Mitochondrial Thioredoxins by Covalent Binding to the Functional Domain

Yang, Jing; Li, Chenglin; Ding, Li; Guo, Qinglong; Qin, You; Shao-hong, Jin

doi:10.1021/np300118c

Cited by 35 publications

(21 citation statements)

References 46 publications

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“…The activity of upstream components, NADPH and TrxR, in the Trx pathway were slightly increased by GA treatment, consistent with the loss of Trx as an oxidizing substrate. In support of this, a previous report has shown the covalent modification and inhibition of purified, recombinant Trx by GA [ 35 ].…”

Section: Discussionsupporting

confidence: 58%

Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer

et al. 2017

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Advanced prostate cancer (PrCa) is treated with androgen deprivation therapy, and although there is usually a significant initial response, recurrence arises as castrate resistant prostate cancer (CRPC). New approaches are needed to treat this genetically heterogeneous, phenotypically plastic disease. CRPC with combined homozygous alterations to PTEN and TP53 comprise about 30% of clinical samples. We screened eleven traditional Chinese medicines against a panel of androgen-independent Pten/Tp53 null PrCa-derived cell lines and identified gambogic acid (GA) as a highly potent growth inhibitor. Mechanistic analyses revealed that GA disrupted cellular redox homeostasis, observed as elevated reactive oxygen species (ROS), leading to apoptotic and ferroptotic death. Consistent with this, we determined that GA inhibited thioredoxin, a necessary component of cellular anti-oxidative, protein-reducing activity. In other clinically relevant models, GA displayed submicromolar, growth inhibitory activity against a number of genomically-representative, CRPC patient derived xenograft organoid cultures. Inhibition of ROS with N-acetyl-cysteine partially reversed growth inhibition in CRPC organoids, demonstrating ROS imbalance and implying that GA may have additional mechanisms of action. These data suggest that redox imbalances initiated by GA may be useful, especially in combination therapies, for treating the heterogeneity and plasticity that contributes to the therapeutic resistance of CRPC.

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Section: Discussionsupporting

confidence: 58%

Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer

et al. 2017

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“…If we hope to deconvolute the mechanisms of action underlying the biological or therapeutic action of GA, we must understand its molecular targets. GA has been shown to directly bind and inhibit various functionally important proteins, including the proteasome 39 , Hsp90β 40 , IKKβ 41 , topoisomerase IIα 42 , transferrin receptor 43 , thioredoxin 1/2 44 , MDM2 45 , and XPO2 46 . However, the primary cellular target(s) and action mode(s) of GA remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis

et al. 2019

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Gambogic acid (GA), a xanthonoid extracted from the resin of the tree, Garcinia hanburyi, was recently shown to exert anticancer activity in multiple studies, but the underlying action mechanism remains unclear. Here, we show that GA induces cancer cell death accompanied by vacuolation in vitro and in vivo. This GA-induced vacuolation in various cancer cells was derived from dilation of the endoplasmic reticulum (ER) and mitochondria, and was blocked by cycloheximide. These findings suggest that GA kills cancer cells by inducing paraptosis, a vacuolization-associated cell death. We found that megamitochondria formation, which arose from the fusion of swollen mitochondria, preceded the fusion of ER-derived vacuoles. GA-induced proteasomal inhibition was found to contribute to the ER dilation and ER stress seen in treated cancer cells, and megamitochondria formation was followed by mitochondrial membrane depolarization. Interestingly, GA-induced paraptosis was effectively blocked by various thiol-containing antioxidants, and this effect was independent of ROS generation. We observed that GA can react with cysteinyl thiol to form Michael adducts, suggesting that the ability of GA to covalently modify the nucleophilic cysteinyl groups of proteins may cause protein misfolding and subsequent accumulation of misfolded proteins within the ER and mitochondria. Collectively, our findings show that disruption of thiol proteostasis and subsequent paraptosis may critically contribute to the anti-cancer effects of GA.

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“…Thioredoxin (Trx) is a low molecular weight (10- to 12-kDa) redox protein ( 7 ), which affects cell growth and proliferation by regulating the redox status in cells ( 8 ). Trx has two main isoforms: The cytosolic form, Trx-1, and the mitochondrial form, Trx-2 ( 9 ). These Trxs are reduced back by Trx reductase and NADPH following the reduction of oxidative target proteins ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

PX-12-induced HeLa cell death is associated with oxidative stress and GSH depletion

2013

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PX-12, as an inhibitor of thioredoxin (Trx), has antitumor activity. However, little is known about the toxicological effect of PX-12 on cervical cancer cells. In the present study, the growth inhibitory effects of PX-12 on HeLa cervical cancer cells in association with reactive oxygen species (ROS) and glutathione (GSH) levels were investigated. Based on MTT assays, PX-12 inhibited the growth of HeLa cells with an IC50 value of ~7 μM at 72 h. DNA flow cytometry analysis indicated that 5 and 10 μM PX-12 significantly induced a G2/M phase arrest of the cell cycle. PX-12 also increased the number of dead cells and annexin V-fluorescein isothiocyanate-positive cells, which was accompanied by the loss of mitochondrial membrane potential. All the investigated caspase inhibitors significantly rescued certain cells from PX-12-induced HeLa cell death. With respect to ROS and GSH levels, PX-12 increased ROS levels (including O2•−) in HeLa cells and induced GSH depletion. N-acetyl cysteine markedly reduced the levels of O2•− in PX-12-treated HeLa cells, and prevented apoptotic cell death and GSH depletion in these cells. By contrast, L-buthionine sulfoximine intensified cell death and GSH depletion in PX-12-treated HeLa cells. To conclude, this is the first study to demonstrate that PX-12 inhibits the growth of HeLa cells via G2/M phase arrest, as well as inhibiting apoptosis; the effect was associated with intracellular increases in ROS levels and GSH depletion.

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Gambogic Acid Deactivates Cytosolic and Mitochondrial Thioredoxins by Covalent Binding to the Functional Domain

Cited by 35 publications

References 46 publications

Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer

Gambogic acid inhibits thioredoxin activity and induces ROS-mediated cell death in castration-resistant prostate cancer

Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis

PX-12-induced HeLa cell death is associated with oxidative stress and GSH depletion

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