Adenanthin targets proteins involved in the regulation of disulphide bonds

Muchowicz, Angelika; Firczuk, Małgorzata; Chlebowska, Justyna; Nowis, Dominika; Stachura, Joanna; Barankiewicz, Joanna; Trzeciecka, Anna; Kłossowski, Szymon; Ostaszewski, Ryszard; Zagożdżon, Radosław; Pu, Jian‐Xin; Sun, Handong; Gołąb, Jakub

doi:10.1016/j.bcp.2014.02.022

Cited by 30 publications

(32 citation statements)

References 18 publications

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“…24 As shown in the Supplementary material (Fig. S1), incubating the NK cells with ADNT resulted in a statistically significant, though very modest decrease in TXN-TXNRD activity.…”

Section: Adenanthin Dysregulates Redox Homeostasis In Nk Cellsmentioning

confidence: 99%

“…23 Our team 24 and others 25 have further described that such actions are mediated by the regulation of intramolecular or intermolecular disulphide bonds. The result of such actions can be detected in non-reducing SDS-PAGE, where enzymatically inactive PRDX monomers can be observed in lysates from ADNTtreated cells and this phenomenon is accompanied by a deep defect in H 2 O 2 metabolism.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

“…The result of such actions can be detected in non-reducing SDS-PAGE, where enzymatically inactive PRDX monomers can be observed in lysates from ADNTtreated cells and this phenomenon is accompanied by a deep defect in H 2 O 2 metabolism. 26 ADNT has also been proposed to inhibit other enzymes of the PRDX-related chain, namely thioredoxin (TXN) 24 and thioredoxin reductase (TXNRD), 25 which can hamper the regeneration rate of PRDX. Hence, the effects of ADNT on PRDX metabolism can be in a direct or indirect manner.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

“…The experiment was performed as described in ref. 24. Briefly, NK cells that had been isolated from two different donors were seeded at 2 9 10 6 /well in a 96-well plate and incubated with ADNT or DMSO (control group) in the cell culture medium for 2 hr at 37°in two independent experiments.…”

Section: Determination Of Glutathione Levelsmentioning

confidence: 99%

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Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

et al. 2015

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SummaryNatural killer (NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin 1 (PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease.

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“…24 As shown in the Supplementary material (Fig. S1), incubating the NK cells with ADNT resulted in a statistically significant, though very modest decrease in TXN-TXNRD activity.…”

Section: Adenanthin Dysregulates Redox Homeostasis In Nk Cellsmentioning

confidence: 99%

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

Section: Determination Of Glutathione Levelsmentioning

confidence: 99%

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Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

et al. 2015

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“…Actually, we showed that adenanthin exerts effective preventive and therapeutic effects on experimental autoimmune encephalomyelitis, which might be mediated via its inhibitory action on NF-B signaling pathway [43]. More recently, it was also shown that, next to Prx I/II, adenanthin also targets and inhibits the activity of additional proteins including the thioredoxin-thioredoxin reductase (TrxR) system and protein disulfide isomerase [44], as well as glutathione (GSH) [45]. However, Siernicka et al [46] recently report that adenanthin only slightly reduces the total GSH in natural killer (NK) cells, which are considered critical components of the innate and adaptive immune responses as reviewed in this issue [47].…”

Section: Adenanthinmentioning

confidence: 99%

Natural products against hematological malignancies and identification of their targets

Xü

Liu

et al. 2015

Sci. China Life Sci.

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Targeting the thioredoxin system as a novel strategy against B‐cell acute lymphoblastic leukemia

et al. 2019

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B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR‐ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP‐ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP‐ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP‐ALL cell lines and pediatric and adult BCP‐ALL primary cells, including primary cells cocultured with bone marrow‐derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL ‐rearranged patient‐derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP‐ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti‐BCP‐ALL drugs should be continued.

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Adenanthin targets proteins involved in the regulation of disulphide bonds

Cited by 30 publications

References 18 publications

Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

Adenanthin, a new inhibitor of thiol‐dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

Natural products against hematological malignancies and identification of their targets

Targeting the thioredoxin system as a novel strategy against B‐cell acute lymphoblastic leukemia

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