Bruceantin and Brusatol: Molecular Insights and Therapeutic Promise of Quassinoids in Cancer Drug Discovery.

Cancer remains a leading cause of mortality worldwide, with treatment resistance posing a major obstacle to effective therapies. Natural compounds, including quassinoids such as bruceantin and brusatol, derived from Brucea javanica (L.) Merr., have demonstrated potential as novel cancer chemopreventive agents. Bruceantin exhibits cytotoxic effects against diverse cancer cell lines, including leukemia, lymphoma, and myeloma, primarily through inhibition of protein synthesis and induction of apoptosis via caspase and mitochondrial pathways. Similarly, brusatol has shown broad-spectrum anticancer activities by modulating cellular processes such as apoptosis, cell-cycle arrest, autophagy, and attenuation of epithelial-mesenchymal transition. Mechanistically, it targets key oncogenic signaling pathways, including PI3K/AKT/mTOR and Keap1/NRF2, and enhances chemosensitivity and radiosensitivity. This review evaluates preclinical findings on the pharmacological properties, mechanisms of action, and anticancer efficacy of bruceantin and brusatol. Their structural modifications, safety profiles, and challenges such as poor bioavailability and systemic toxicity are also explored. Advances in semi-synthetic derivatives and drug delivery systems are discussed as strategies to enhance therapeutic potential. Comprehensive insights are provided into the molecular and cellular mechanisms underlying their anticancer effects, supported by in vitro and in vivo evidence. Collectively, these findings highlight the promise of bruceantin and brusatol as therapeutic agents and underscore the need for further translational research to optimize their clinical utility. These quassinoids represent a compelling avenue for the development of targeted and adjunctive cancer therapies, potentially overcoming limitations of conventional treatments.