Phytochemical Triad in Lung Cancer: Synergistic Mechanisms and Clinical Translation of Genistein, Piperine, and Resveratrol

Lung cancer remains a leading cause of cancer-related mortality worldwide, with therapeutic resistance and toxicity limiting the effectiveness of conventional treatments. Natural compounds have attracted significant interest as adjuncts to modern oncology owing to their ability to modulate multiple oncogenic pathways with comparatively low toxicity. Among these, genistein (GEN), piperine (PIP), and resveratrol (RES) represent particularly promising candidates. GEN, a phytoestrogen, exerts antiproliferative and pro-apoptotic effects through phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), and NF-κB (Nuclear Factor kappa B) signaling. PIP, an alkaloid, not only demonstrates cytotoxicity and cell-cycle arrest but also improves the bioavailability of co-administered therapeutics. RES, a polyphenolic compound, regulates AMP-activated protein kinase (AMPK), PI3K/Akt, and MAPK pathways, inhibits angiogenesis and metastasis, and sensitizes cancer cells to chemotherapy. Synergistic combinations of these phytochemicals have shown enhanced apoptotic responses and significantly reduced IC₅₀ values in cancer, underscoring their potential as multitargeted therapeutic agents. Despite encouraging preclinical and early clinical findings, challenges such as poor solubility and bioavailability hinder clinical translation. This review critically explores their synergistic effects while highlighting the challenges in translating these findings into clinical applications for lung cancer. By elucidating the underlying molecular mechanisms and therapeutic synergy, these natural compounds emerge as promising adjuncts for lung cancer therapy, warranting further mechanistic and clinical investigation.