GANODERMA LUCIDUM A POTENTIAL THERAPEUTIC MODULATOR IN CANCER SIGNALING IN SILICO AND IN VITRO ANALYSIS

Abstract

Cancer is a multifactorial disease, causing behavioral and metabolic alterations newlineresulting in excessive cell proliferation with the weakening of immune system. Various newlinestrategies have been formulated for drug synthesis and natural products among them newlineis important. Among natural products, Ganoderma lucidum is a basidiomycetes newlinefungus with terpenoids, proteins, and polysaccharides constituents with a plethora of newlineactivities modulating signaling in cancer. G. lucidum has been reported to activate newlineplasma membrane receptors and controls the process of programmed cell death newline(apoptosis). The present study highlighted the host plant-G. lucidum relationship in newlineenvironmental stress conditions, marked by the enhanced level of phytochemicals, newlinewhich are imperative for growth and development. Host plant-G. lucidum newlineinterdependency and level of phytochemicals were highest with Azadirachta plant newlineresulting in the isolation of ganoderic acid. Isolated ganoderic acid from Azadirachta newlinehost plant significantly decreases cell viability, cell migration, colony formation, newlinesuperoxide ion, mitochondrial membrane potential, with increases in ROS production newlinein A549, PC-3, and MDA-MB-231 cells. The computational study predicted and newlineexposed the various residues, binding interaction, and energy involved in the newlineinteraction of different isoforms of ganoderic acid with receptor tyrosine kinases newline(RTKs) members. Protein-ligand interactions elucidated the strength of binding forces newlineresponsible for lipophilic, hydrogen bonding and and#960;-and#960; stacking during molecular newlinedocking study. Studies were performed in A549, PC-3, and MDA-MB-231 cells which newlinesuppressed the expression of PI3K/Akt/mTOR and modulated the expression of bax, newlinebcl-2, cell cycle, MMP-2, and MMP-9. Ganoderic acid reduces the mitochondrial newlinemembrane potential, induces ROS generation, hampers DNA fragmentation, nuclear newlinefragmentation and targeted cell cycle leading to induction of apoptosis. The enhanced newlinelevel of ROS production caused induction in nuclear shrinkage, chromatin newlinecondensation, and nuclear.