Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231

Ghosh, Kunal; De, Soumasree; Mukherjee, Shankarashis; Das, Sayantani; Ghosh, Amar N.; Sengupta, Srijan

doi:10.1016/j.tiv.2017.07.025

Cited by 42 publications

(33 citation statements)

References 44 publications

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“…The up-regulation of NRF2 pathway genes as observed is consistent with in vivo findings of induced oxidative stress in the two cell lines 58, 63 . These results illustrated multi-targeting of several carcinogenesis processes, including cell proliferation and death, metastasis/invasion and angiogenesis ( Table 3 ) in both TN and LA associated with phenotypes reported in in vitro studies 19,58,61,62,64 .…”

Section: Discussionsupporting

confidence: 60%

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A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

Odongo

Zergeroǧlu

Çakır

2020

Preprint

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7 Background 8 Plant-derived natural products possess poly-pharmacologic 9 mechanisms of action with good tolerability and thus are Results 1 The signalling pathways regulated by the pleiotropic effects of 2 Actein, Withaferin A, Indole-3-Carbinol and Compound 3 Kushen were found to be projected on a set of oncogenesis 4 processes at the transcriptomic level in different breast cancer 5 subtypes (triple negative, luminal A and HER2+). Notably, 6 these compounds indirectly regulated known oncogenes in the 7 different subtypes through their associated pathways in the 8 subnetworks.9

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Section: Discussionsupporting

confidence: 60%

“…It is a vital component of the Indian Ayurvedic medicine. The characteristic anti-cancer effects of Withaferin A is well anchored scientific reports 57–60 and specifically in breast cancer 19, 58, 61, 62 . Here, RTK-RAS-MAPK, TGF-beta, NRF2 and P53 oncogenic signaling pathways were targeted in both TN and LA.…”

Section: Discussionmentioning

confidence: 92%

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

Odongo

Zergeroǧlu

Çakır

2020

Preprint

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“…Withanolide A and Withaferin A are two of the best studied withanolides for their capacity to significantly reduce the survival of various cancer cell lines and decrease the size of breast tumors implanted in rats [230][231][232]. The effect of Withaferin A, in particular, seems related to its capacity to interfere in the pathways of protein degradation and recycling (which are highly active in cancer cells), through inhibition of tubulin polymerization: this inhibition would prevent the formation of autophagy-related structures, which are essential for protein recycling [233].…”

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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“…We report the therapeutic effects of a novel withaferin-A analog, called IMS-088, in transgenic mice expressing hTDP-43 mutants. Withaferin-A, a compound extracted from the medicinal plant Withania somnifera has emerged with a therapeutic potential as inhibitor of NF-κB signalling pathway via NEMO interaction (19) and as inducer of autophagy (39). Withaferin-A treatment conferred protection in two mouse models of ALS (16,40).…”

Section: Discussionmentioning

confidence: 99%

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

Kumar

Phaneuf

Cordeau

et al. 2020

Preprint

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Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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Withaferin A induced impaired autophagy and unfolded protein response in human breast cancer cell-lines MCF-7 and MDA-MB-231

Cited by 42 publications

References 44 publications

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

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

Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

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