Phytochemicals as Multitarget Therapeutics in Pancreatic Cancer: Mechanisms, Clinical Evidence, and Translational Challenges.
Pancreatic cancer, especially pancreatic ductal adenocarcinoma, is known for its aggressive nature, late diagnosis, and resistance to standard treatments. This review demonstrates the therapeutic potential of phytochemicals as multitarget agents in pancreatic cancer, emphasizing their molecular mechanisms, pharmacological properties, and translational relevance. Important carcinogenic signaling pathways, such as KRAS/MAPK, PI3K/Akt, NF-κB, STAT3, Hedgehog, and Wnt/β-catenin, are modulated by phytochemicals like curcumin, quercetin, resveratrol, and others. These substances demonstrate anticancer effects by suppressing epithelial-mesenchymal transition, inducing apoptosis, reducing proliferation and angiogenesis, and modulating oxidative stress. Preclinical research indicates consistent multipathway targeting and potential enhanced efficacy with traditional chemotherapeutics, although evidence from clinical studies remains limited and inconsistent. New strategies to improve drug stability, target tumors more effectively, and enhance treatment outcomes involve the use of combination medicines and nanotechnology-based delivery systems. The gap between preclinical effectiveness and clinical translation continues due to insufficient large-scale trials, diverse study designs, and a lack of standardized dosing strategies. Phytochemicals show potential as multitarget treatments for pancreatic cancer, but their clinical application is inhibited by pharmacokinetic challenges and insufficient validation.