Anti-mesothelioma mechanism of action studies of a complex Cynara scolymus fraction using in silico target prediction and gene expression profiling

Malignant pleural mesothelioma is an aggressive cancer with no current dedicated therapy [1]. Historically, traditional medicines have been used to treat several diseases as they can target multiple pathways without causing high-level toxicity, hence representing an option for novel indications [2] However, mode of action (MoA) remains elusive for most natural compounds, which in addition often are applied as complex mixtures. In this study RNA-seq data along with ligand-based predictions were used to deduce the MoA underlying the previously reported cytotoxicity induced by Cynara scolymus leaf extract (ABO1) [3] in mesothelioma cell lines.

In silico target prediction for 47 compounds present in ABO1 identified 93 targets that play a role in angiogenesis, metastasis, cancer progression, survival and resistance. In addition, experimental activity against 85 targets was retrieved from ChEMBL. Treatment with ABO1 resulted in 287 differentially expressed genes (DEG). DEG were analysed via Ingenuity Pathway Analysis, identifying 18 significant pathways for further analyses. The pathway analysis predicted HMGB1, Gα, TNFR, CXC4, TGF-β, Wnt, ILK mTOR and IL-8 signalling as inactivated and PPAR signalling as activated. Both canonical and non-canonical NF-kβ signalling, playing a crucial role in cancer initiation and progression [4], were predicted to be inhibited. Matrix metalloproteinases [5] and HIF1α [6] were found to be inhibited, thereby hindering metastasis formation and tumour aggressiveness.

The integrated analysis of modulated genes and predicted targets hence indicates that ABO1 exerts its antitumoral effect by inhibition of tumour growth, cell survival and proliferation, angiogenesis, metastasis and activation of apoptosis. To the knowledge of the authors this represents the first time where the mode-of-action of a traditional medicine has been analysed by a joint bioinformatics (gene expression) and cheminformatics (in silico target prediction) approaches.

Keywords: Genomics, RNA-Seq, Mesothelioma, Network biology, Traditional medicine, Mode of Action, Systems Biology, Polyphamacology, Natural drugs, Cynara Scolymus.

References:

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