新型口服生物可利用 CDK9 抑制剂 Atuveciclib 增敏胰腺癌细胞对 TRAIL 诱导的细胞死亡。
The Novel, Orally Bioavailable CDK9 Inhibitor Atuveciclib Sensitises Pancreatic Cancer Cells to TRAIL-induced Cell Death.
机构信息
Department of General and Visceral Surgery, University of Ulm, Ulm, Germany.
Department of General and Visceral Surgery, University of Ulm, Ulm, Germany
出版信息
Anticancer Res. 2021 Dec;41(12):5973-5985. doi: 10.21873/anticanres.15416.
BACKGROUND/AIM: This study was designed to analyse the effects of the novel, orally bioavailable CDK9-inhibitor Atuveciclib (BAY 1143572) in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) on pancreatic ductal adenocarcinoma (PDAC) cancer cells.
MATERIALS AND METHODS
To assess the effect of combinatorial use of atuveciclib and TRAIL on pancreatic cancer cells, we used an MTT assay, colony formation assay, flow cytometry, and western blot analysis.
RESULTS
Atuveciclib combined with TRAIL significantly reduced the viability of pancreatic cancer cells and their colony formation potential by inducing apoptosis and cell-cycle arrest. Atuveciclib sensitised PDAC cells to TRAIL-induced cell death through the concomitant suppression of cFlip and Mcl-1. A gemcitabine-resistant PDAC cell-line and patient-derived xenograft (PDX) cell lines were also suppressed by this combinatorial approach.
CONCLUSION
This study provides the basis for further preclinical and clinical evaluation of combined treatment with atuveciclib and TRAIL.
背景/目的：本研究旨在分析新型口服生物可利用的 CDK9 抑制剂 Atuveciclib（BAY 1143572）与肿瘤坏死因子相关凋亡诱导配体（TRAIL）联合应用对胰腺导管腺癌（PDAC）癌细胞的影响。
材料和方法
为了评估 Atuveciclib 和 TRAIL 联合使用对胰腺癌细胞的影响，我们使用 MTT 测定法、集落形成测定法、流式细胞术和 Western blot 分析。
结果
Atuveciclib 联合 TRAIL 通过诱导细胞凋亡和细胞周期阻滞，显著降低了胰腺癌细胞的活力及其集落形成能力。Atuveciclib 通过同时抑制 cFlip 和 Mcl-1，使 PDAC 细胞对 TRAIL 诱导的细胞死亡敏感。这种联合治疗方法还抑制了吉西他滨耐药的 PDAC 细胞系和患者来源的异种移植（PDX）细胞系。
结论
本研究为进一步评估 Atuveciclib 和 TRAIL 联合治疗的临床前和临床评价提供了基础。
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