Pharmacological levels of Withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells
Szarc vel Szic K, Op de Beeck K, Ratman D, Wouters A, Beck IM, Declerck K, Heyninck K, Fransen E, Bracke M, De Bosscher K, Lardon F, Van Camp G, Vanden Berghe W
PloS one · 59 citas
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- Estudio in vitro o de mecanismos (clasificado por nuestro filtro de IA)
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- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Universidad u hospital
- Universiteit Antwerpen
- Universidad u hospital
- Bijzonder Onderzoeksfonds UGent
Según 2 financiadores declarados y la declaración de financiación del texto completo.
Publicación
- Publicado
- 2014-02-03 · PLoS One · vol. 9 · número 2 · pág. e87850
- Editorial
- Public Library of Science
- Citado
- 105 citas · más que el 100% de estudios similares · 26.2× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 64 trabajos
- Acceso
- Acceso abierto (revista) · CC-BY
- Áreas de investigación
- Phytochemicals and Medicinal Plants
- Palabras clave
- Withaferin A, Withania somnifera, Cancer research, Biology, Metastasis, Cancer cell, Triple-negative breast cancer, Cancer, Breast cancer, Cell cycle, Pathology, Medicine
- MeSH
- tumor cells, cultured, humans, rna, messenger, blotting, western, phytotherapy, oligonucleotide array sequence analysis, gene expression profiling, reverse transcriptase polymerase chain reaction, cell cycle, apoptosis, cell proliferation, female, withanolides, real-time polymerase chain reaction, triple negative breast neoplasms, biomarkers, tumor
13 autores
- Katarzyna Szarc vel Szic🇧🇪University of Antwerp
- Ken Op de Beeck🇧🇪University of Antwerp
- Dariusz Ratman🇧🇪Ghent University
- An Wouters🇧🇪University of Antwerp
- Ilse M. E. Beck🇧🇪Ghent University; Cancer Research Institute Ghent
- Ken Declerck🇧🇪University of Antwerp
- Karen Heyninck🇧🇪Ghent University
- Erik Fransén🇧🇪University of Antwerp; Statistics Belgium
- Marc Bracke🇧🇪Ghent University; Cancer Research Institute Ghent
- Karolien De Bosscher🇧🇪Ghent University
- Filip Lardon🇧🇪University of Antwerp
- Guy Van Camp🇧🇪University of Antwerp
- Wim Vanden Berghe🇧🇪 · autor de correspondenciaUniversity of Antwerp
Resumen
El texto original del estudio, en el idioma en que se publicó.
Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial (CC BY).
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