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In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, Germany
Heidelberg School of Chinese Medicine, Karlsruher Straße 12, Heidelberg 69126, Germany
Biomedical Sciences Institute Abel Salazar, University of Porto, Porto 4050-313, Portugal
* Author to whom correspondence should be addressed.
Received: 19 April 2012; in revised form: 9 May 2012 / Accepted: 15 May 2012 / Published: 22 May 2012
Abstract: Withania somnifera (L.) Dunal (Indian ginseng, winter cherry, Solanaceae) is widely used in traditional medicine. Roots are either chewed or used to prepare beverages (aqueous decocts). The major secondary metabolites of Withania somnifera are the withanolides, which are C-28-steroidal lactone triterpenoids. Withania somnifera extracts exert chemopreventive and anticancer activities in vitro and in vivo. The aims of the present in silico study were, firstly, to investigate whether tumor cells develop cross-resistance between standard anticancer drugs and withanolides and, secondly, to elucidate the molecular determinants of sensitivity and resistance of tumor cells towards withanolides. Using IC50 concentrations of eight different withanolides (withaferin A, withaferin A diacetate, 3-azerininylwithaferin A, withafastuosin D diacetate, 4-B-hydroxy-withanolide E, isowithanololide E, withafastuosin E, and withaperuvin) and 19 established anticancer drugs, we analyzed the cross-resistance profile of 60 tumor cell lines. The cell lines revealed cross-resistance between the eight withanolides. Consistent cross-resistance between withanolides and nitrosoureas (carmustin, lomustin, and semimustin) was also observed. Then, we performed transcriptomic microarray-based COMPARE and hierarchical cluster analyses of mRNA expression to identify mRNA expression profiles predicting sensitivity or resistance towards withanolides. Genes from diverse functional groups were significantly associated with response of tumor cells to withaferin A diacetate, e.g. genes functioning in DNA damage and repair, stress response, cell growth regulation, extracellular matrix components, cell adhesion and cell migration, constituents of the ribosome, cytoskeletal organization and regulation, signal transduction, transcription factors, and others.
Keywords: cancer; drug development; medicinal food; microarray; pharmacogenomics; natural products
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Efferth, T.; Greten, H.J. In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides. Microarrays 2012, 1, 44-63.
Efferth T, Greten HJ. In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides. Microarrays. 2012; 1(1):44-63.
Efferth, Thomas; Greten, Henry Johannes. 2012. "In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides." Microarrays 1, no. 1: 44-63.