胰腺导管腺癌（PDAC）是最具侵袭性的恶性肿瘤之一。我们之前的工作揭示了几丁质酶 3 样 1 (CHI3L1) 参与 PDAC 对吉西他滨的耐药性，将其确定为一个有前途的治疗靶点。在这里，我们的目的是鉴定假定的 CHI3L1 抑制剂并研究它们在 PDAC 中的化学增敏潜力。CHI3L1 的对接分析鉴定出有前途的 CHI3L1 抑制剂，包括达非那新（毒蕈碱受体拮抗剂）。 PDAC 细胞系 (BxPC-3、PANC-1) 和原代 PDAC 细胞用于评估达非那新 (Sulforhodamine B、SRB) 单独或与吉西他滨或吉西他滨加紫杉醇联合使用对细胞生长的影响。评估了针对正常永生化胰腺导管细胞（HPNE）的细胞毒性。使用重组蛋白来确认达非那新对 CHI3L1 诱导的 PDAC 细胞耐药性的影响（SRB 测定）。通过 ELISA 分析达非那新对 Akt 激活的影响。通过对 68 名患者手术切除的石蜡包埋组织进行免疫组织化学评估，胆碱能受体毒蕈碱 3 (CHRM3) 表达与治疗反应之间的关联。计算机筛选显示达非那新能够高效靶向 CHI3L1。 Darifenacin 抑制 PDAC 细胞生长，BxPC-3 和 PANC-1 细胞中的 GI50 分别为 26 和 13.6 µM。这些结果在原代 PDAC-3 细胞中得到证实，而达非那新对 HPNE 细胞没有显示出细胞毒性。重要的是，达非那新使 PDAC 细胞对标准化疗敏感，恢复了 CHI3L1 诱导的 PDAC 细胞对治疗的耐药性，并降低了 Akt 磷酸化。此外，高 CHMR3 表达与吉西他滨的低治疗反应相关。这项工作强调了达非那新作为 PDAC 治疗化疗增敏剂的潜力。© 2024。作者。

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.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.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.This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.© 2024. The Author(s).