An integrated role of trans resveratrol and calcitriol against methylglyoxal mediated RAGE expression in colorectal cancer cell line

Abstract

Colorectal cancer CRC incidence is rising in younger population attributed to modern lifestyle with high consumption of processed foods rich in advanced glycation end products AGEs AGEs interact with its receptor RAGE activating MAPKPI3KERK pathway which promotes oxidative stress and inflammation leading to DNA damage and genetic instability Moreover calcitriol CAL deficiency is associated with increased CRC burden and its use as an anticancer agent is uncertain due to its inefficient dosage and adverse hypercalcemic effects Thus complementing CAL with phytocompounds may be beneficial TransResveratrol RES a polyphenol stilbene possesses antiglycation activity and known to enhance CALs effect Thus this study aimed to investigate the combined effect of CAL and RES against methylglyoxal MG an AGE precursor through in silico and in vitro analyses In silico results of molecular docking showed significant binding affinity of CAL and RES to RAGE and its signaling proteins NFkB PI3K AKT ERK and PKC compared to their reference inhibitors Molecular dynamic simulation studies revealed stable and compact protein ligand complexes In in vitro analysis MG promoted proliferation of HCT116 cells while CAL and RES inhibited this effect Combination index and dose reduction index indicated this combination as synergistic The combination has shown to promote apoptosis via mitochondrial ROS induction and inhibited the cellular migration against MG Notably the combination decreased the gene and protein expression of RAGE while simultaneously increasing the VDR expression It also reduced mRNA expression of ERK2 AKT PI3K and NFkB thus supporting the insilico analysis Thus the combination of CAL and RES could synergistically target the AGE RAGE axis at multiple levels and could be integrated with standard CRC chemodrugs to sensitize their activity and inhibit the cancer progression driven by RAGE newline