去势抵抗性前列腺癌（CRPC）是一种常见的男性恶性肿瘤，由于对其一线治疗多西紫杉醇产生耐药性，因此需要新的治疗策略。维生素 D 对前列腺癌 (PCa) 进展的益处先前已有报道。本研究旨在探讨维生素 D 对 CRPC 化疗耐药的影响。确定了有效维生素 D 类似物的结构功能关系。最有效的类似物和多西紫杉醇的组合在化疗耐药的原发性 PCa 球状体和源自化疗耐药 CRPC 患者的异种移植小鼠模型中进行了探索。在这里，我们表明 Xe4MeCF3 比天然配体更有效地诱导维生素 D 受体（ VDR）转录活性，并且具有更大的治疗窗口。此外，我们证明 VDR 激动剂可恢复 PCa 球体中的多西紫杉醇敏感性。重要的是，Xe4MeCF3 可减少化疗耐药 CRPC 患者来源的异种移植物中的肿瘤生长。此外，这种治疗针对的是与剩余细胞中癌症进展相关的信号通路。总之，这些结果揭示了 VDR 激动剂克服 CRPC 化疗耐药性的效力，并为 PCa 的临床管理开辟了新途径。© 2024 ）。约翰·威利出版的《英国药理学杂志》

Castration-resistant prostate cancer (CRPC) is a common male malignancy that requires new therapeutic strategies due to acquired resistance to its first-line treatment, docetaxel. The benefits of vitamin D on prostate cancer (PCa) progression have been previously reported. This study aimed to investigate the effects of vitamin D on chemoresistance in CRPC.Structure function relationships of potent vitamin D analogues were determined. The combination of the most potent analogue and docetaxel was explored in chemoresistant primary PCa spheroids and in a xenograft mouse model derived from a patient with a chemoresistant CRPC.Here, we show that Xe4MeCF3 is more potent than the natural ligand to induce vitamin D receptor (VDR) transcriptional activities and that it has a larger therapeutic window. Moreover, we demonstrate that VDR agonists restore docetaxel sensitivity in PCa spheroids. Importantly, Xe4MeCF3 reduces tumour growth in a chemoresistant CRPC patient-derived xenograft. In addition, this treatment targets signalling pathways associated with cancer progression in the remaining cells.Taken together, these results unravel the potency of VDR agonists to overcome chemoresistance in CRPC and open new avenues for the clinical management of PCa.© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.