The imidazoline I receptor agonist 2-BFI enhances cytotoxic activity of hydroxychloroquine by modulating oxidative stress, energy-related metabolism and autophagic influx in human colorectal adenocarcinoma cell lines.

Recently, interest in imidazoline receptors (IRs) has been increasing. Over the years, a growing number of studies have highlighted the therapeutic potential of ligands targeting these receptors, however, the potential role of imidazoline I receptor agonists in cancer treatment has not been thoroughly investigated. Colorectal cancer (CRC) is among the most prevalent and lethal forms of cancer worldwide. The complexity of CRC necessitates individualized approaches. One promising area of research within CRC therapy is the regulation of autophagy. Recent studies have explored the relationship between autophagy and cancer progression, revealing that autophagy modulation could be a potential strategy for CRC treatment. However, the mechanisms underlying autophagy regulation remain poorly understood. This study aimed to evaluate the effect of the imidazoline I receptor agonist, namely 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI), on colorectal cancer cells, HT-29 and HCT-116 cell lines, particularly its impact when co-incubated with the autophagy inhibitor, hydroxychloroquine (HCQ). The results showed that 2-BFI synergistically increased the cytotoxic effect of HCQ by inducing oxidative stress and apoptosis. Furthermore, our investigation indicated impairment autophagic influx in colon cancer cells treated by 2-BFI. The comprehensive metabolomic analysis revealed significant alterations in key metabolic pathways including MAO activity, oxidative stress responses, energy-related metabolites and amino acids metabolism. Altogether, these findings demonstrate potential a new therapeutic strategy based on autophagy regulation and the selective induction of oxidative stress in colorectal cancer cells. Moreover, this study provides a foundation for further investigation into the therapeutic potential of imidazoline receptor agonists in cancer therapy.