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Open Access 03-09-2024 | Darifenacin | Original Article

Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma

Authors: Sofia M. Sousa, Helena Branco, Amir Avan, Andreia Palmeira, Luca Morelli, Lúcio L. Santos, Elisa Giovannetti, M. Helena Vasconcelos, Cristina P. R. Xavier

Published in: Cancer Chemotherapy and Pharmacology

Abstract

Purpose

Pancreatic 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.

Methods

Docking 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.

Results

In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI₅₀ of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine.

Conclusion

This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.

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Title: Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma
Authors: Sofia M. Sousa
Helena Branco
Amir Avan
Andreia Palmeira
Luca Morelli
Lúcio L. Santos
Elisa Giovannetti
M. Helena Vasconcelos
Cristina P. R. Xavier
Publication date: 03-09-2024
Publisher: Springer Berlin Heidelberg
Keywords: Darifenacin
Pancreatic Cancer
Pancreatic Cancer
Published in: Cancer Chemotherapy and Pharmacology
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-024-04712-1

EASD 2024

Springer Medicine

Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma

Abstract

Purpose

Methods

Results

Conclusion

EASD 2024

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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