Pinocembrin, an anticancer dihydroxyflavanone: from chemistry to cellular interactions and synergistic prospects

Cancer remains a major global health challenge, with rising incidence and persistent therapy resistance highlighting the need for new multi-targeted therapeutic agents. Pinocembrin (5,7-dihydroxyflavanone), a naturally occurring flavanone found in honey, propolis, and several medicinal plants, has gained increasing attention for its broad-spectrum anticancer potential. Recent studies demonstrate that pinocembrin modulates multiple hallmarks of cancer by regulating the PI3K/Akt/mTOR, STAT3, and NF-κB pathways, resulting in antiproliferative, pro-apoptotic, anti-metastatic, and anti-inflammatory effects. Evidence from diverse cancer models-including breast, prostate, colon, lung, ovarian, and melanoma-shows that pinocembrin induces cell-cycle arrest, activates intrinsic and extrinsic apoptotic pathways, inhibits angiogenesis, and suppresses epithelial-mesenchymal transition. Structure-activity relationship (SAR) analyses further reveal that modifications such as hydroxylation, esterification, and glycosylation enhance its bioavailability and anticancer activity. Despite its therapeutic promise, the clinical utility of pinocembrin is limited by poor solubility and rapid metabolic clearance. Recent nanotechnology-based formulations, including polymeric micelles, liposomes, nanoparticles, and nanoemulsions, have significantly improved their stability, bioavailability, and tumor-targeted delivery. Pinocembrin also exhibits synergistic effects with conventional chemotherapeutics while maintaining low toxicity toward normal cells, underscoring its suitability for combination therapy and chemoprevention. Preliminary clinical data indicate a favorable safety profile, although long-term toxicity, optimal dosing, and pharmacokinetic parameters require further investigation. This review synthesizes current knowledge on the anticancer mechanisms, SAR-driven insights, nanotechnology-enhanced delivery, synergistic actions, and safety considerations of pinocembrin. By integrating recent findings and highlighting research gaps, it provides a comprehensive foundation for advancing pinocembrin toward future preclinical and clinical applications in oncology.