文章：

吉西他滨、氯法拉滨和依地福辛在淋巴瘤细胞系中的协同细胞毒性

Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines

原文发布日期：2014-01-10

DOI: 10.1038/bcj.2013.69

类型: Original Article

开放获取: 是

英文摘要：

Treatments for lymphomas include gemcitabine (Gem) and clofarabine (Clo) which inhibit DNA synthesis. To improve their cytotoxicity, we studied their synergism with the alkyl phospholipid edelfosine (Ed). Exposure of the J45.01 and SUP-T1 (T-cell) and the OCI-LY₁₀ (B-cell) lymphoma cell lines to IC₁₀–IC₂₀ levels of the drugs resulted in strong synergistic cytotoxicity for the 3-drug combination based on various assays of cell proliferation and apoptosis. Cell death correlated with increased phosphorylation of histone 2AX and KAP1, decreased mitochondrial transmembrane potential, increased production of reactive oxygen species and release of pro-apoptotic factors. Caspase 8-negative I9.2 cells were considerably more resistant to [Gem+Clo+Ed] than caspase 8-positive cells. In all three cell lines [Gem+Clo+Ed] decreased the level of phosphorylation of the pro-survival protein AKT and activated the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) stress signaling pathway, which in J45.01 cells resulted in the phosphorylation and heterodimerization of the transcription factors ATF2 and c-Jun. The observed rational mechanism-based efficacy of [Gem+Clo+Ed] based on the synergistic convergence of several pro-death and anti-apoptotic signaling pathways in three very different cell backgrounds provides a powerful foundation for undertaking clinical trials of this drug combination for the treatment of lymphomas.

摘要翻译： 

淋巴瘤的治疗药物包括抑制DNA合成的吉西他滨（Gem）和氯法拉滨（Clo）。为增强其细胞毒性，我们研究了它们与烷基磷脂依地福新（Ed）的协同作用。通过多种细胞增殖和凋亡检测发现，将J45.01、SUP-T1（T细胞）及OCI-LY10（B细胞）淋巴瘤细胞系暴露于IC10-IC20浓度药物后，三药联用显示出强烈协同细胞毒性。细胞死亡与组蛋白2AX和KAP1磷酸化增强、线粒体跨膜电位降低、活性氧生成增加及促凋亡因子释放相关。Caspase 8阴性I9.2细胞对[Gem+Clo+Ed]的耐药性显著高于caspase 8阳性细胞。在所有三种细胞系中，[Gem+Clo+Ed]可降低促生存蛋白AKT的磷酸化水平，并激活应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）应激信号通路——该通路在J45.01细胞中导致转录因子ATF2与c-Jun的磷酸化及异源二聚化。基于三种不同细胞背景中多种促死亡与抗凋亡信号通路的协同汇聚，[Gem+Clo+Ed]所展现的合理机制导向疗效，为开展该联合方案治疗淋巴瘤的临床试验奠定了坚实基础。

原文链接：

Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines