Withaferin A, a natural compound with anti-tumor activity, is a potent inhibitor of transcription factor C/EBPβ

Falkenberg, Kim D.; Jakobs, Anke; Matern, Julian C. J.; Dörner, Wolfgang; Uttarkar, Sagar; Trentmann, Amke; Steinmann, Simone; Coulibaly, Anna; Schomburg, Caroline; Mootz, Henning D.; Schmidt, Thomas; Klempnauer, Karl‐Heinz

doi:10.1016/j.bbamcr.2017.05.003

Cited by 21 publications

(24 citation statements)

References 51 publications

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“…Within Solanaceae, the shrub Withania somnifera (L.) Dunal ("Indian ginseng" or "Ashwagandha") has been the focus of several pharmacological studies, given its wide use in Ayurveda (the major system of Indian traditional medicine) as a general tonic to increase vigor and memory and lessen the symptoms associated to rheumatisms, fatigue, and dehydration [207]. On the basis of the anecdotal reports from the Ayurvedic practices, W. somnifera extracts were subjected to intense pharmacological scrutiny and showed to possess promising antitumor and anti-inflammation properties [208][209][210].…”

Section: Withanolidesmentioning

confidence: 99%

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

et al. 2018

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Plants have always been used as medicines since ancient times to treat diseases. The knowledge around the active components of herbal preparations has remained nevertheless fragmentary: the biosynthetic pathways of many secondary metabolites of pharmacological importance have been clarified only in a few species, while the chemodiversity present in many medicinal plants has remained largely unexplored. Despite the advancements of synthetic biology for production of medicinal compounds in heterologous hosts, the native plant species are often the most reliable and economic source for their production. It thus becomes fundamental to investigate the metabolic composition of medicinal plants to characterize their natural metabolic diversity and to define the biosynthetic routes of important compounds to develop strategies to further increase their content. We present here a number of case studies for selected classes of secondary metabolites and we review their health benefits and the historical developments in their structural elucidation and characterization of biosynthetic genes. We cover the cases of benzoisoquinoline and monoterpenoid indole alkaloids, cannabinoids, caffeine, ginsenosides, withanolides, artemisinin, and taxol; we show how the "early" biochemical or the more recent integrative approaches-based on omics-analyses-have helped to elucidate their metabolic pathways and cellular compartmentation. We also summarize how the knowledge generated about their biosynthesis has been used to develop metabolic engineering strategies in heterologous and native hosts. We conclude that following the advent of novel, high-throughput and cost-effective analytical technologies, the secondary metabolism of medicinal plants can now be examined under the lens of systems biology.

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Section: Withanolidesmentioning

confidence: 99%

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

et al. 2018

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“…We noted that some compounds initially identified as potential MYB inhibitors with these cells inhibit the activity of C/EBPβ, a transcription factor cooperating with MYB at the MIM1 gene 28–30 . To be able to search for MYB inhibitors in a more focused manner we have re-designed the MYB reporter cell line and used it to screen a library of natural compounds.…”

Section: Introductionmentioning

confidence: 99%

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Yusenko

Jakobs

Klempnauer

2018

Sci Rep

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The transcription factor MYB plays key roles in hematopoietic cells and has been implicated the development of leukemia. MYB has therefore emerged as an attractive target for drug development. Recent work has suggested that targeting MYB by small-molecule inhibitors is feasible and that inhibition of MYB has potential as a therapeutic approach against acute myeloid leukemia. To facilitate the identification of small-molecule MYB inhibitors we have re-designed and improved a previously established cell-based screening assay and have employed it to screen a natural product library for potential inhibitors. Our work shows that teniposide and etoposide, chemotherapeutic agents causing DNA-damage by inhibiting topoisomerase II, potently inhibit MYB activity and induce degradation of MYB in AML cell lines. MYB inhibition is suppressed by caffeine, suggesting that MYB is inhibited indirectly via DNA-damage signalling. Importantly, ectopic expression of an activated version of MYB in pro-myelocytic NB4 cells diminished the anti-proliferative effects of teniposide, suggesting that podophyllotoxins disrupt the proliferation of leukemia cells not simply by inducing general DNA-damage but that their anti-proliferative effects are boosted by inhibition of MYB. Teniposide and etoposide therefore act like double-edged swords that might be particularly effective to inhibit tumor cells with deregulated MYB.

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“…Among the Withania somnifera constituents, withaferin A has attracted considerable attention due its wide range of multifunctional bioactivities [11][12][13][14]. However, in neurodifferentiation, neuroprotection, and neuroregeneration, withaferin A is not the most active constituent compared to withanolide A and withanoside IV ( Figure 1) [4].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of CR-777, a Glutathione Derivative of Withaferin A, Obtained through the Bioconversion of Withania somnifera (L.) Dunal Extract by the Fungus Beauveria bassiana

Rabhi¹,

Arcile

Goff

et al. 2019

Molecules

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The bioconversion of Withania somnifera extract by the fungus Beauveria bassiana leads to cysteine and glutathione derivatives of withaferin A at the C-6 position. The compounds were purified and fully characterized by 1D-NMR, 2D-NMR, and HRMS analysis. The glutathione derivative CR-777 was evaluated as a neuroprotective agent from damage caused by different neurotoxins mimicking molecular symptoms in Parkinson´s disease (PD), including 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA), and α-synuclein (α-Syn). CR-777, at nanomolar concentrations, protected dopaminergic and cortical neurons. In 6-OHDA-treated neurons, CR-777 increased cell survival and neurite network and decreased the expression of α-Syn. Using specific inhibitors of cell toxicity signaling pathways and specific staining experiments, the observed role of CR-777 seemed to involve the PI3K/mTOR pathway. CR-777 could be considered as a protective agent against a large panel of neuronal stressors and was engaged in further therapeutic development steps.

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Withaferin A, a natural compound with anti-tumor activity, is a potent inhibitor of transcription factor C/EBPβ

Cited by 21 publications

References 51 publications

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

The Integration of Metabolomics and Next-Generation Sequencing Data to Elucidate the Pathways of Natural Product Metabolism in Medicinal Plants

A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity

Neuroprotective Effect of CR-777, a Glutathione Derivative of Withaferin A, Obtained through the Bioconversion of Withania somnifera (L.) Dunal Extract by the Fungus Beauveria bassiana

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