Therapeutic effects of coptisine derivative EHLJ7 on colorectal cancer by inhibiting PI3K/AKT pathway

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world with high mortality rate. EHLJ7 is a quaternary coptisine derivative synthesized by our institute. In this study, the role and mechanism of EHLJ7 on CRC are further elucidated. Using target fishing, colon cancer-associated target screening and molecular docking analysis, PI3K/AKT pathway was selected for the target of EHLJ7 at CRC. Results of Flow cytometry, wound healing assay and transwell migration assay confirmed that EHLJ7 could inhibit migration and apoptosis of colon cancer cells by specifically inhibiting PI3K/AKT pathway in vitro. Xenograft tumor models and a newly established azoxymethane (AOM)/dextran sulfate sodium (DSS)/Peptostreptococcus anaerobiu (P.anaerobius)-induced CRC mouse model are applied to access the anti-cancer action and mechanism of EHLJ7 using western-blot, immunohistochemistry and analysis of exosomes. The key findings in this study are listed as follows: (1) EHLJ7 exerts superior anti-tumor effect with good safety on Xenograft tumor model and CRC model; (2) EHLJ7 exerted its anti-CRC effect by specifically inhibiting PI3K/AKT pathway and apoptosis in vivo and in vitro. In summary, we demonstrated that EHLJ7 exerts therapeutic effect against CRC by PI3K/AKT pathway, which made it possible as a potentially effective compound for the treatment of CRC.

Keywords: Apoptosis; Colorectal cancer; Coptisine; Exosome; PI3K/AKT.