Colorectal Carcinoma Cell Growth Inhibition In Vitro and Identification of Molecular Targets using Molecular Docking

Abstract

Colorectal carcinoma (CRC) is one of the most often detected tumors of the digestive tract and the leading cause of cancer-related mortality worldwide. The present study demonstrates that synthesis and inhibitory potential of 1,3-thiazin-6-ones in vitro against colorectal cancer cells and investigated the underlying mechanism. The study revealed that 1,3-thiazin-6-one effectively targets proliferation potential of HT-29 and HCT116 cells and markedly reduced colony formation capacities without any harmful effect on NCM460 normal cells. Transwell assay showed that 1,3-thiazin-6-one treatment at 32 µM markedly suppressed invasion potential of HT-29 and HCT116 cells. It was observed that 1,3-thiazin-6-one treatment could markedly reduce NRP2 expression in HT-29 and HCT116 cells. It was also observed that the expression level of E‑cadherin was significantly increased while the levels of N‑cadherin and Vimentin were significantly decreased by 1,3-thiazin-6-one treatment in HT-29 and HCT116 cells. In silico data using AutoDock vina and Discovery Studio software revealed that 1,3-thiazin-6-one binds to NRP2 and vimentin proteins with binding affinity of –6.5 and –7.4 kcal/mol, respectively. It was found that vimentin protein binds to 1,3-thiazin-6-one through LEU (D:393), ILE (C:397), ASP (C:394), GLU (D:396), ALA (C:398), and ARG (C:401) amino acid residues. Moreover, the interaction of 1,3-thiazin-6-one with NRP2 protein involves ILE (A:348), ARG (A:421), ARG (A:350), GLN (A:353) and HIS (A:312) amino acid residues. In summary, 1,3-thiazin-6-one inhibited proliferation, colony formation potential and invasiveness of the CRC cells by targeting the expression of NRP2. Moreover, it promoted the expression of E‑cadherin and targeted the levels of N‑cadherin and Vimentin in HT-29 and HCT116 cells. Thus, 1,3-thiazin-6-one may be developed as a therapeutic agent for the treatment of colorectal cancer.