Impediment of Cancer by Dietary Plant-derived Alkaloids Through Oxidative Stress: Implications of PI3K/AKT Pathway in Apoptosis, Autophagy, and Ferroptosis

Abstract: The adverse toxicities and stemness are two major factors that constrained the usage of therapeutic strategies to target several cancer types. Previous studies explored the efficacy of PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors against several cancer types, and many of them are currently in clinical trials. The current review described the efficacy of alkaloids derived from dietary plant sources in developing a new anti-cancer to reduce the preva-lence of cancer through the modulation of apoptosis, autophagy, and ferroptosis. We have substan-tially collected the information pertinent to several intracellular pathways, including PI3K signaling, apoptosis, ferroptosis, and autophagy in modulating cancer progression mediated by the plant-derived alkaloids such as daurisoline, dauricine, vasicine, vasicinone, 2-Acetyl-benzylamine, nu-ciferine, liensinine, gramine, and berbamine. These alkaloids exhibit significant anti-cancer poten-tial to inhibit cancer cells by enhancing the intracellular ROS level and modulation of several sig-naling pathways, mainly through the PI3K/AKT pathway. These alkaloids can modulate chemo-therapeutic agents' efficacy in various cancer cells, both in vitro and in vivo models. Overall the fu-tures for the continued use of alkaloids from natural sources against cancer have to be extended, with the implementation of significant enhancements in the chemistry of these alkaloids for targeted delivery. In this review, we have selected major bioactive alkaloids of dietary and medicinal plants origin and discussed the anti-cancer and combinatorial therapeutic implications of these compounds with several FDA-approved drugs against various cancer cells.