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Abstract：
BACKGROUND: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC).
METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells.
RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model.
CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.
METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells.
RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model.
CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.
摘要：
背景：大多数睾丸生殖细胞肿瘤（GCTs）患者接受基于顺铂（CP）的化疗。然而,其中一些可能发展为CP耐药性,因此是一项临床挑战.细胞周期蛋白依赖性激酶5（CDK5）参与不同类型癌症的化疗耐药。这里,我们研究了dinaciclib靶向的CDK5和其他CDKs在非精原细胞瘤细胞模型（CP敏感性和CP抗性）中的可能作用，评估CDK抑制剂dinaciclib作为单一/联合药物治疗晚期/转移性睾丸癌（TC）的潜力。
方法：用MTT法和直接计数法评价dinaciclib和CP对敏感和抗性NT2/D1和NCCIT细胞活力和增殖的影响。进行流式细胞术细胞周期分析。通过Western印迹评估蛋白质表达。在用TC细胞异种移植的斑马鱼胚胎中进行体内实验。
结果：在所有分析的CDK中，在CP抗性模型中CDK5蛋白表达显著较高。Dinaciclib降低了每个细胞模型中的细胞活力和增殖，诱导细胞周期分布的变化。在药物组合实验中，dinaciclib在体外和斑马鱼模型中均增强CP作用。
结论：Dinaciclib，当与CP结合时，可用于改善非精原细胞瘤TC对CP的反应。
方法：用MTT法和直接计数法评价dinaciclib和CP对敏感和抗性NT2/D1和NCCIT细胞活力和增殖的影响。进行流式细胞术细胞周期分析。通过Western印迹评估蛋白质表达。在用TC细胞异种移植的斑马鱼胚胎中进行体内实验。
结果：在所有分析的CDK中，在CP抗性模型中CDK5蛋白表达显著较高。Dinaciclib降低了每个细胞模型中的细胞活力和增殖，诱导细胞周期分布的变化。在药物组合实验中，dinaciclib在体外和斑马鱼模型中均增强CP作用。
结论：Dinaciclib，当与CP结合时，可用于改善非精原细胞瘤TC对CP的反应。
