Mechanistic insights into <i>Retama raetam</i>’s anti-proliferative and pro-apoptotic effects in A549 lung cancer cells: targeting PI3K/Akt pathway and ROS production

Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer-related deaths worldwide. This study investigates the molecular mechanisms behind the anti-cancer effects of the tropical desert plant <i>Retama raetam (R. raetam)</i> on the A549 NSCLC cell line. The research examined <i>R. raetam's</i> anti-proliferative effects, cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential, and cell morphology in NSCLC A549 and L-132 cells. In addition, the influence of <i>R. raetam</i> on DNA fragmentation, apoptotic signaling, and PI3K/Akt pathways for its anti-cancer mechanism was examined. Our results indicated that <i>R. raetam's</i> effects were dose- and time-dependent to exhibit anti-proliferative effects on A549 cells. <i>R. raetam</i> treatment promoted apoptotic cell death cycle arrest, increased apoptotic cells, depolarized the mitochondrial membrane, and induced morphological alterations in cells and nuclei. It also inhibited A549 cell migration (<i>P</i> < 0.05), colonization, and invasiveness. Moreover, the study demonstrated that <i>R. raetam</i> treatment resulted in the upregulation of Bax expression, downregulation of Bcl-2 expression, and apoptotic fragmented DNA in A549 cells. The top five bioactive compounds derived from <i>R. raetam</i> exhibited molecular interactions that inhibit PIK3CA and AKT1. This inhibition leads to an increased frequency of apoptosis and subsequent death of cancer cells. Additionally, <i>R. raetam</i> extract induced an increase in ROS formation and cytochrome c levels, indicating that its toxic effects on A549 cells involve both ROS-dependent cytotoxicity through the disruption of mitochondrial transmembrane potential ΔΨm and ROS-independent cell cycle arrest through downregulation BCL-2, PARP, E-Cadherin, PI3K, and Akt expressions pathways.