Marine <em>Streptomyces paradoxus</em> VITALK03 derived gancidin W mediated cytotoxicity through Ras-Raf-MEK-ERK signalling pathway

Abstract

The aim of the present study was to identify cytotoxic secondary metabolite produced by marine <em>Streptomyces paradoxus </em> VITALK03 and to study its mechanism of anticancer activity. Bioactivity guided screening of secondary metabolites from <em>S. paradoxus </em> VITALK03 resulted in identification of (3R,8aR)-3-(2‐methylpropyl)-octahydropyrrolo[1,2-a]piperazine-1,4-dione (gancidin W). The anticancer cytotoxic potential of gancidin W was screened by <em>in silico</em> docking analysis using 22 cancer drug target proteins. Gancidin W showed the least binding energy of –7.55 Kcal/mol with breast cancer protein KRas of pERK pathway, and showed a Ki value of 2.94 µM and formation of 4 H-bonds during the interaction. The results of <em>in silico </em> docking and molecular dynamic studies were further confirmed by <em>in vitro</em> and <em>in vivo</em> anticancer cytotoxicity studies. Gancidin W showed selective cytotoxicity on breast cancer cells (MCF-7) with an IC₅₀ value 1.56 µg/mL, while value of the same was 12.5 µg/mL in case of VERO cells (control). Administration of gancidin W (3 µg/d) for 14 d to MCF-7 injected (grafted) zebra fish resulted in 50% reduction in tumour progression. This is the first cumulative (preclinical) report on <em>in vitro</em>, <em> in vivo </em> and <em>in silico </em> anticancer activity of gancidin W. The results of <em>in vitro</em>,<em> in vivo</em>, molecular docking and molecular dynamic stimulation studies suggest that gancidin W could be probed further to develop as a breast cancer drug.