Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Ye, Qing; Zhang, Yinan; Cao, Yanan; Wang, Xiachang; Guo, Yunlong; Chen, Jing; Horn, Jamie; Ponomareva, Larissa V.; Chaiswing, Luksana; Shaaban, Khaled A.; Wei, Qiou; Anderson, Bradley D.; Clair, Daret K. St.; Zhu, Haining; Leggas, Markos; Thorson, Jon S.; She, Qing‐Bai

doi:10.1016/j.chembiol.2018.11.013

Cited by 33 publications

(39 citation statements)

References 56 publications

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“…We observed that tomentosin treatment decreased the expression of peroxiredoxin-1, one of regulators of ROS production in MG-63 cells. Peroxiredoxin-1 is well known to play an important role in maintaining the ROS level for tumor development [38,39,40]. Furthermore, our results supported that tomentosin-induced intracellular ROS was an important mediator of the proliferation, migration, and apoptosis processes in MG-63 cells.…”

Section: Discussionsupporting

confidence: 85%

Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species

Lee

Nam

et al. 2019

IJMS

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Tomentosin is a natural sesquiterpene lactone extracted from various plants and is widely used as a medicine because it exhibits essential therapeutic properties. In this study, we investigated the anti-carcinogenic effects of tomentosin in human osteosarcoma MG-63 cells by performing cell migration/viability/proliferation, apoptosis, and reactive oxygen species (ROS) analysis assays. MG-63 cells were treated with various doses of tomentosin. After treatment with tomentosin, MG-63 cells were analyzed using the MTT assay, colony formation assay, cell counting assay, wound healing assay, Boyden chamber assay, zymography assay, cell cycle analysis, FITC Annexin V apoptosis assay, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, western blot analysis, and ROS detection analysis. Our results indicated that tomentosin decreased cell viability and migration ability in MG-63 cells. Moreover, tomentosin induced apoptosis, cell cycle arrest, DNA damage, and ROS production in MG-63 cells. Furthermore, tomentosin-induced intracellular ROS decreased cell viability and induced apoptosis, cell cycle arrest, and DNA damage in MG-63 cells. Taken together, our results suggested that tomentosin exerted anti-carcinogenic effects in MG-63 cells by induction of intracellular ROS.

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Section: Discussionsupporting

confidence: 85%

Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species

Lee

Nam

et al. 2019

IJMS

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“…We recently identified the PNQ FB as a potent inhibitor of peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) and determined FB 's antitumor effect to be mediated by inhibition of phosphorylation of 4E-BP1 5. While 4E-BP1 is a cap-dependent translation repressor of oncogenic mRNA translation and tumorigenesis, phosphorylation of 4E-BP1 by mTORC1 relieves its inhibitory control leading to tumor progression 17.…”

Section: Resultsmentioning

confidence: 99%

“…Subsequent biochemical and cell-based studies revealed representative griseusins to inhibit Prx1/Grx3 and 4E-BP1 phosphorylation in manner similar to FB and to inhibit tail regeneration in our recently developed axolotl tail regeneration assay 7. Given the notable demonstrated in vivo efficacy of optimized FB analogs,5 the current study considerably expands the range PNQ pharmacophores available for further optimization of Prx1/Grx3 selectivity and/or ADMET.…”

Section: Introductionmentioning

confidence: 82%

“…Enabled by our efficient divergent strategy for the synthesis of frenolicin B ( FB , a prototypical PNQ-based natural product; Fig. 1),2 f systematic SAR and mechanistic studies revealed FB as the most potent and selective peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) inhibitors reported to date 5. These studies demonstrated Prx1/Grx3 inhibition by FB led to increased intracellular ROS, the consequence of which was inhibition of mTORC1-mediated 4E-BP1 phosphorylation, apoptosis induction and tumor suppression.…”

Section: Introductionmentioning

confidence: 99%

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Total synthesis of griseusins and elucidation of the griseusin mechanism of action

Zhang

Ponomareva

et al. 2019

Chem. Sci.

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“…Our current results are strongly supportive of the validity of this approach by showing that genetic silencing of PRDX1 in TNBC cell lines amplifies the efficacy of one of the most promising prooxidant approaches, i.e., the combination of Asc and Men (Figure 3 and Figure S5D,E). The difficulty of PRDX1 targeting in cancer in the clinical settings is related to the fact that chemical agents known to inhibit PRDX1, such as adenanthin [34,43], AI-44 [44], or frenolicin B [45], or the PRDX1-related antioxidant enzymatic system, such as SK053 [14] or AUR [13], are in most cases fairly unselective and/or do not possess satisfactory pharmacokinetics. The exception for the latter is AUR, the clinically approved drug primarily used in rheumatology and suggested in numerous other indications [46].…”

Section: Discussionmentioning

confidence: 99%

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

et al. 2020

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Triple-negative breast cancer (TNBC) is an aggressive form of mammary malignancy currently without satisfactory systemic treatment options. Agents generating reactive oxygen species (ROS), such as ascorbate (Asc) and menadione (Men), especially applied in combination, have been proposed as an alternative anticancer modality. However, their effectiveness can be hampered by the cytoprotective effects of elevated antioxidant enzymes (e.g., peroxiredoxins, PRDX) in cancer. In this study, PRDX1 mRNA and protein expression were assessed in TNBC tissues by analysis of the online RNA-seq datasets and immunohistochemical staining of tissue microarray, respectively. We demonstrated that PRDX1 mRNA expression was markedly elevated in primary TNBC tumors as compared to non-malignant controls, with PRDX1 protein staining intensity correlating with favorable survival parameters. Subsequently, PRDX1 functionality in TNBC cell lines or non-malignant mammary cells was targeted by genetic silencing or chemically by auranofin (AUR). The PRDX1-knockdown or AUR treatment resulted in inhibition of the growth of TNBC cells in vitro. These cytotoxic effects were further synergistically potentiated by the incubation with a combination of the prooxidant agents, Asc and Men. In conclusion, we report that the PRDX1-related antioxidant system is essential for maintaining redox homeostasis in TNBC cells and can be an attractive therapeutic target in combination with ROS-generating agents.

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Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Cited by 33 publications

References 56 publications

Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species

Tomentosin Displays Anti-Carcinogenic Effect in Human Osteosarcoma MG-63 Cells via the Induction of Intracellular Reactive Oxygen Species

Total synthesis of griseusins and elucidation of the griseusin mechanism of action

Triple Combination of Ascorbate, Menadione and the Inhibition of Peroxiredoxin-1 Produces Synergistic Cytotoxic Effects in Triple-Negative Breast Cancer Cells

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