Prostate cancer stem-like cells (PCSCs) likely participate in tumor progression and recurrence and demonstrate resistance to chemotherapy. The Notch pathway plays a role in the maintenance of the stemness in PCSCs. This study aimed to investigate the efficacy of Notch signaling inhibition as an adjuvant to docetaxel (DOX) in PCSCs. PCSCs derived from the PC-3 cell line were examined for Notch-1 expression. The effect of Notch inhibition on response to DOX was evaluated in PCSCs in vitro and in murine models using a γ-secretase inhibitor (GSI), PF-03084014. Impacts on cell proliferation, apoptosis, cell cycle, and sphere formation were evaluated. PC-3 PCSCs expressed elevated Notch-1 mRNA compared with PC-3 parental cells. The combination of GSI with DOX promoted DOX-induced cell growth inhibition, apoptosis, cell cycle arrest, and sphere formation in PCSCs. In nude mice bearing PC-3 PCSC-derived tumors, the combination of GSI and DOX reduced the tumor growth, which was associated with the decreased Notch-1 expression in tumor tissues. These results reveal that inhibition of the Notch pathway enhances the anti-tumor effect of DOX in PC-3 PCSCs, and suggest that Notch inhibition may have clinical benefits in targeting PCSCs.

中文翻译：

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Notch途径的抑制增强了多西紫杉醇在前列腺癌干样细胞中的抗肿瘤作用。

前列腺癌干样细胞（PCSCs）可能参与肿瘤的进展和复发，并表现出对化学疗法的抵抗力。Notch途径在PCSC的干性维持中起作用。这项研究旨在调查Notch信号抑制作为PCSCs中多西他赛（DOX）佐剂的功效。检查源自PC-3细胞系的PCSC的Notch-1表达。在体外PCSC和鼠模型中，使用γ-分泌酶抑制剂（GSI）PF-03084014评估了Notch抑制对DOX响应的影响。评估了对细胞增殖，凋亡，细胞周期和球形成的影响。与PC-3亲代细胞相比，PC-3 PCSCs表达升高的Notch-1 mRNA。GSI与DOX的组合可促进DOX诱导的细胞生长抑制，凋亡，细胞周期停滞，PCSC中的球形成。在携带PC-3 PCSC衍生肿瘤的裸鼠中，GSI和DOX的组合降低了肿瘤的生长，这与肿瘤组织中Notch-1表达的降低有关。这些结果表明，Notch途径的抑制增强了PC-3 PCSC中DOX的抗肿瘤作用，并表明Notch抑制在靶向PCSC中可能具有临床益处。