Pharmacological Levels of Withaferin A Withania somnifera Trigger Clinically Relevant Anticancer Effects Specific to Triple Negative Breast Cancer CellsReport as inadecuate




Pharmacological Levels of Withaferin A Withania somnifera Trigger Clinically Relevant Anticancer Effects Specific to Triple Negative Breast Cancer Cells - Download this document for free, or read online. Document in PDF available to download.

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 preclinical development to defeat aggressive metastatic breast cancer.



Author: Katarzyna Szarc vel Szic, Ken Op de Beeck, Dariusz Ratman, An Wouters, Ilse M. Beck, Ken Declerck, Karen Heyninck, Erik Fransen,

Source: http://plos.srce.hr/



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