Gerwing Mirjam, Jacobsen Christine, Dyshlovoy Sergey, Hauschild Jessica, Rohlfing Tina, Oing Christoph, Venz Simone, Oldenburg Jan, Oechsle Karin, Bokemeyer Carsten, von Amsberg Gunhild, Honecker Friedemann
Department of Oncology, Hematology and Bone Marrow Transplantation, University Medical Center Hamburg-Eppendorf, Martinistaße 52, 20246, Hamburg, Germany.
Laboratory of Marine Natural Products Chemistry, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences, Prospect 100 Let Vladivostoku 159, Vladivostok, Russia, 690022.
J Cancer Res Clin Oncol. 2016 Sep;142(9):1979-94. doi: 10.1007/s00432-016-2204-6. Epub 2016 Jul 16.
Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10-30 % of patients develop resistance to cisplatin, requiring salvage therapy. We investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines.
In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array.
Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT.
Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.
基于顺铂的化疗在转移性生殖细胞肿瘤（GCT）中具有高效性。然而，10%-30%的患者会对顺铂产生耐药性，需要进行挽救治疗。我们研究了紫杉醇和新型紫杉烷卡巴他赛在顺铂敏感和耐药的GCT细胞系中的体外活性。
通过增殖试验测定紫杉醇和卡巴他赛的体外活性，并通过蛋白质印迹法以及两种筛选方法，即全蛋白质组分析和人类凋亡阵列，评估卡巴他赛的作用方式。
紫杉醇和卡巴他赛的活性不受顺铂耐药性的影响，这表明在体外这些药物之间不存在交叉耐药性。卡巴他赛治疗对集落形成能力显示出强烈的抑制作用。卡巴他赛在所有细胞系中均诱导经典凋亡，表现为PARP和半胱天冬酶3的裂解，且未引起细胞周期分布的特异性变化。通过蛋白质组学和人类凋亡阵列筛选方法，发现了几种蛋白质的差异调节，包括bcl-2家族成员，这为卡巴他赛在GCT中的作用方式提供了初步见解。
卡巴他赛在GCT细胞中显示出有前景的体外活性，与顺铂耐药水平无关。
