Molecular dissection of anti-colon cancer activity of NARI-29: special focus on H2O2 modulated NF-& kappa;B and death receptor signaling

Accumulating evidence attributes the role of aldose reductase (AR) in modulating ROS and inflammation which are the main factor responsible for cancer progression and drug resistance. Epalrestat is the only AR inhibitor being used in Asian countries. It did not make it to the markets of the USA and Europe due to marginal efficacy as an antioxidant and anti-inflammatory agent owing to difficulty reaching intracellular targets. In our previous studies, we attempted to synthesize the epalrestat analogs and reported that the compound 4-((Z)-5-((Z)-2-Cyano-3-phenylallylidene)-4-oxo-2-thioxothiazolidin-3-yl) benzoic acid named as NARI-29 has potent AR inhibition compared to epalrestat. In the current study, we aimed to find the effect of NARI-29 on ROS-induced cancer progression and TRAIL resistance in colon cancer in vitro models. In the first part of the study, we demonstrated that the NARI-29 has specific AKR1B1 inhibition and superior drug-like properties than epalrestat using bioinformatics tools. In the second part of the study, it was proven that NARI-29 has induced the hydrogen peroxide-triggered TRAIL-induced apoptosis in the colon cancer cells via modulating the AKR1B1/4HNE/FOXO3a/DR axis. The selective cytotoxicity of NARI-29 (10-fold) compared to epalrestat (4-fold) toward cancer cells is due to its differential ROS regulation and anti-inflammatory activities. Altogether, these data show that NARI-29 may be a potential candidate for AR inhibitors, which will be used to prevent colon cancer progression and as adjuvant therapy for preventing TRAIL resistance.