Mechanistic and metabolic exploration of neohesperidin against lung cancer cell lines through ROS-mediated mitochondrial apoptosis: An in-silico and in-vitro approach

Abstract

Lung cancer is a significant contributor to global mortality rates in the human population. However, the results of current treatment options are still unsatisfactory. Thus, the study explores low-toxic natural substances that release caspases and trigger apoptosis. Neohesperidin (NHP), a flavonoid, has anticancer efficacy although its molecular mechanism is unknown. In the current work, through in-silico and in-vitro screening, we discovered that NHP significantly reduces the expression of x-linked inhibitor of apoptosis protein (xIAP) and ATP on its administration, leading to apoptosis in human and mice lung (A549 and LLC-1) cancerous cells. Furthermore, NHP promoted the production of second-mitochondria-derived-activator-of-caspase (SMAC) and triggers mitochondrial dysfunction which also promotes apoptosis (51.1 %) as well as necrosis (25.8 %). This mechanism is regulated by mitochondria-mediated (Bax and Bcl-2) caspases-dependent apoptotic and ROS mediated pathway which increases SMAC expression by 21.2 % along with lowering the xIAP level (by 36.5 %). Moreover, network pharmacology was utilized to delineate the interactions of the compounds within biological networks, emphasizing their potential to target multiple pathways. In addition, we investigated the alterations in metabolites within A549 cells caused by NHP using liquid-chromatography-high-resolution-mass-spectrometry (LC-HRMS)-based metabolomics. The results revealed perturbations in metabolomes that are involved in multiple pathways. Therefore, this study indicates that NHP is a potential therapeutic agent to mitigate and control the proliferation of lung cancer and also regulates the energy metabolism.