Curcumin and Resveratrol as Dual Modulators of the STAT3 Pathway in Lung Cancer: A Comprehensive Review

Lung cancer, primarily consisting of nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC), remains a significant health challenge despite advancements in treatment. This comprehensive review investigates the therapeutic potential of natural compounds curcumin (CUR) and resveratrol (RES) in targeting the STAT3 signaling pathway, which plays a crucial role in lung cancer progression and metastasis. Specifically, CUR inhibits STAT3 phosphorylation and activation in lung cancer cells, leading to a 40%-60% reduction in tumor size and a significant decrease in the expression of STAT3 target genes such as cyclin D1, VEGF, MMP2, and MMP9. RES demonstrates similar effects by suppressing STAT3 signaling, resulting in a 30%-50% reduction in tumor growth and a marked decrease in the M2 polarization of tumor-associated macrophages, thereby disrupting the communication between cancer cells and the tumor microenvironment. CUR analogues, such as L48H37 and compound 5 k, also exhibit anticancer effects by blocking the STAT3 pathway. L48H37 suppresses the motility, migration, and invasion of human osteosarcoma cells by inhibiting the JAK/STAT pathway and urokinase plasminogen activator (uPA) expression. Compound 5 k inhibits NSCLC cell growth by regulating the NF-κB/STAT3 signaling pathways. RES inhibits STAT3 activation and downstream signaling in NSCLC cells, reducing cell migration and invasion while increasing apoptosis by 20%-30%. In vivo studies show that RES can suppress tumor growth by 40%-50% by inhibiting the STAT3/HIF-1α/VEGF axis. RES also shows promise in overcoming drug resistance in SCLC by inhibiting the STAT3/VEGF pathway and P-glycoprotein function, potentially resensitizing resistant cells to chemotherapy. These findings underscore the potential of CUR and RES as promising therapeutic agents against lung cancer by targeting the STAT3 signaling pathway and related processes such as angiogenesis, metastasis, and drug resistance. Further research is needed to optimize their bioavailability, understand their molecular mechanisms, and assess their clinical efficacy in combination with standard therapies.