ABSTRACT:
The cure rates in cancer chemotherapy are affected by the development of drug resistance and severe side effects. Due to these limitations, there is an urgent need for improved therapeutics. Bioactive compounds from medicinal plants represent a valuable resource for novel anticancer drugs. To gain a systematic approach, we have established a library of more than 2400 cytotoxic natural products derived from traditional Chinese medicine. A total of 531 compounds revealed considerable cytotoxicity against 60 cancer cell lines of the National Cancer Institute (NCI), USA. The IC50 values of 60 cell lines for these 531 natural products were correlated with the microarray-based mRNA expression of 95 genes involved in metabolism and signalling of nitric oxide (NO), in order to identify candidate compounds as NO inhibitors. The cut-off value for the Pearson's correlation analysis was R>0.6. The best correlation was found between the mRNA expression of TXNRDI (thioredoxin reductase 1) and bis(helenaliny)glutarate. Experimental validation of this in silico approach was performed with NO measurement using RAW264.7 mouse macrophages. Indeed, we showed that bis(helenalinyl)glutarate at concentrations of 2 or 4ug/ml strongly inhibited NO generation. As a next step, the 95 genes related to NO metabolism and signalling were analyzed for their association with this compound, in order to elucidate underlying signalling pathways. In conclusion, approaches using natural compound libraries and in silico screening techniques are suitable to identify novel NO inhibitors as shown with bischelenaliny) glutarate.