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

• Type: Article in International Scientific Journal
• Date: 2024

Authors

Sousa, SM (Author) Other; Branco, H (Author) Other; Avan, A (Author) Other; Palmeira, A (Author) FFUP; Morelli, L (Author) Other; Santos, LL (Author) Other; Giovannetti, E (Author) Other; Helena Vasconcelos, MH (Author) FFUP; Xavier, CPR (Author) Other

Journal

Title: Cancer Chemotherapy and Pharmacology

ISSN: 0344-5704

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 0 Citations

Other information

Authenticus ID: P-016-XV3

DOI: 10.1007/s00280-024-04712-1

Abstract (EN): 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 GI50 of 26 and 13.6 mu M 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.ConclusionThis work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13