ArticleCancer chemotherapy and pharmacology2024
Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma.
Article in Cancer chemotherapy and pharmacology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Evaluation of Darifenacin for T-Cell Acute Lymphoblastic Leukemia: Selective Targeting of the Non-Neuronal Cholinergic System and Lysosomal Cathepsins.International journal of molecular sciences · 2026Article
- Perineural Invasion in Pancreatic Ductal Adenocarcinoma: Recapitulating Its Importance and Defining Future Directions.United European gastroenterology journal · 2025Review
- Human chitinases and chitinase-like proteins as emerging drug targets - a medicinal chemistry perspective.RSC medicinal chemistry · 2025Review
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Authors and funding
9 authors.
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Abstract
purposePancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC.
methodsDocking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin's effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin's effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients' cohort.
resultsIn silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI
conclusionThis work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.
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