Evaluation of a microbial marine natural product as a potential proteasome inhibitor and its anti-cancer effects

Finding natural products (NPs) targeting cancer is one promising approach to search for novel anticancer drugs. We aimed to develop a pipeline for screening and testing NPs for activity against the 20S proteasome β5 subunit, being a cancer drug target, using computational and functional approaches. Selected genera were included in the study to search for microbial NPs, and virtual screening was performed for 18 of the included genera/groups, in order to predict the binding of the NP to the β5 subunit of the 20S proteasome complex. Marinacarboline C was selected as a top candidate and further synthesized. First the SRB assay was conducted against five cancer cell lines, U937, MCF-7, Kasumi-1, HepG2, HCT-116 and a non-cancer cell line. The highest cytotoxic activity for marinacarboline C was observed against U937 cells with IC₅₀ 60.07 µg mL^-1. Then a proteasome activity assay was performed after exposure of MCF-7 breast cancer cells to marinacarboline C, together with a positive control (MG-132). However, marinacarboline C was found to not significantly decrease the 20S proteasome activity of MCF-7 cells. Cblaster was used to find homologous biosynthetic gene clusters (BGCs) to that producing marinacarboline C, to expand future research and identify microbes possibly producing similar NPs. Our study offers a proof-of-concept pipeline for mining NPs for activity against novel targets and further validation is needed to bring forward more NPs. Our integrated approach paves the way to identify promising natural-product scaffolds for further optimization as potential anticancer agents.