Potential antitumor activity of a new plant-derived alkaloid isolated from <i>Petasites hybridus</i> (L.), <i>in silico</i> and <i>in vitro</i>

Introduction. Some cytostatic drugs are based on the compounds of plant origin. Development of the new plant metabolites-derived antitumor drugs is an actual and perspective trend in oncology. Recently we isolated a compound from the rhizome of Petasites hybridus (L.) and identified it as a corynan-like indole alkaloid P1.Aim. To identify of the possibility of the Petasites hybridus (L.)-derived alkaloid to bind with molecular targets mediating carcinogenesis and tumor growth and the assessment of its effect on tumor and normal cell cultures.Materials and methods. The research was performed in silico by molecular docking and in vitro by cultural methods. Molecular docking of alkaloid Р1 with receptors of epidermal growth factor (EGFR), platelet growth factor (PDGFR), MET, MRP2 and NOX4 was carried out using software AutoDock Vina 4.0. The docking area grid was built in AutoDockTools 1.5.7. Cultural experiments were performed on tumor cell line highly expressing EGFR (Н1299) and normal lung fibroblasts. Cells were cultured with various concentrations of the alkaloid, their viability was assessed in ХТТ-test and by direct count of alive and dead cells.Results. Maximal binding energy of alkaloid Р1 with molecular targets was noted for МеТ (–8,6 kcal/M), minimal – for NOX4 (–5,9 kcal/M). Binding energy of alkaloid Р1 with EGFR was –6,4; with PDGFR –7,2; with MRP2 –6,3 kcal/M. Binding of alkaloid P1 occurred with the amino acid residues of the active centers of the majority of the studied receptors. Alkaloid showed the ability to inhibit the growth of H1299 cell line (lung adenocarcinoma) in the wide range of concentrations more actively than of normal fibroblasts: half-maximal inhibitory concentration for P1 was 127,24 and 256,29 μM/l respectively. Maximal difference of the dead cells amount between H1299 line and fibroblasts was observed in alkaloid concentrations 21,7–87 μM/l, but, in spite of some signs of mitotic failure (multinucleate and giantnucleate H1299 cells) mitotic index did not change.Conclusion. Alkaloid isolated from the rhizome of Petasites hybridus (L.) is able to bind with the targets mediating tumor growth and impairs lung adenocarcinoma Н1299 cells. Further research is necessary for detailed study of its` antitumor effect in in vitro and in vivo models.