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. 2012 May 22;1(1):44-63.
doi: 10.3390/microarrays1010044.

In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides

Thomas Efferth  1 , Henry Johannes Greten  2   3
Affiliations

In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides

Thomas Efferth et al. Microarrays (Basel). .

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; natural products; pharmacogenomics.

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Figures

Figure 1
Figure 1
Chemical structures of the 8 withanolides tested.
Figure 2
Figure 2
Mean log10IC50 values of 8 withanolides for tumor cell lines from the NCI drug screening panel as assayed by the sulforhodamine B test.
Figure 3
Figure 3
Dendrogram of hierarchical cluster analysis (complete linkage method) obtained from mRNA expression of 40 genes correlated with log10IC50 values for withaferin A diacetate. The dendrogram shows the clustering of 60 cell lines according to the mRNA expression profile for genes identified by COMPARE analyses (Table 3).
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