Curcumin in pancreatic cancer: A comprehensive review of anticancer mechanisms, EMT modulation, and clinical...

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by aggressive local invasion, early metastasis, and profound chemoresistance. Epithelial-mesenchymal transition (EMT) is a critical driver of these aggressive phenotypes, promoting tumor cell dissemination and therapeutic failure. Curcumin, a naturally occurring polyphenol derived from Curcuma longa, has emerged as a promising adjunctive agent due to its ability to modulate diverse molecular pathways, including those governing EMT.

In this review, we synthesized findings from published studies investigating the anti-EMT effects of curcumin and its analogs in PDAC. Data were extracted from in vitro, in vivo, and clinical studies, focusing on molecular mechanisms, signaling pathways, non-coding RNA networks, and therapeutic outcomes.

Curcumin and its synthetic analogs suppress EMT in PDAC cells through multiple interconnected mechanisms, including inhibition of TGF-β/Smad, Hedgehog, PI3K/Akt/NF-κB, and IL-6/ERK/NF-κB signaling pathways. These effects are accompanied by upregulation of epithelial markers (E-cadherin) and downregulation of mesenchymal markers (vimentin, Snail, Slug), leading to reduced migration, invasion, and metastasis. Curcumin also modulates the tumor microenvironment by reversing the mesenchymal phenotype of cancer-associated fibroblasts and inhibiting stellate cell-induced EMT. A number of non-coding RNAs, including miRNAs (miR-7, miR-340, miR-221), lncRNAs (PVT1), and circRNAs (circ_0001535, circ_0079440) are associated the anti-EMT, anti-cancer or chemosensitizing effects of curcumin. Curcumin enhances the sensitivity of PDAC cells to gemcitabine, cisplatin, and TRAIL-induced apoptosis. However, clinical translation is limited by poor oral bioavailability and gastrointestinal tolerability at high doses, though nanoparticle-based formulations and analogs show improved pharmacokinetic profiles.

Curcumin exerts potent anti-EMT effects in PDAC through multi-targeted regulation of signaling pathways, non-coding RNAs, and stromal-tumor interactions. These findings support further investigation of optimized formulations and combination strategies to overcome the pharmacokinetic limitations and translate curcumin's preclinical promise into clinical benefit for pancreatic cancer patients.