Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels
Overcoming resistance to γ-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels
复制标题
DOI：
10.1038/sj.onc.1207357
复制
发表时间：
2004-04-08
期刊：
影响因子：
8
通讯作者：
Rodriguez-Lafrasse, C
中科院分区：
文献类型：
--
作者：
Alphonse, G;Bionda, C;Rodriguez-Lafrasse, C
最近的策略，敏感的放射抗性肿瘤的基础上结合γ-照射与诱导细胞凋亡。我们报告了三种鞘脂代谢抑制剂DL-苏型-1-苯基-2-癸酰氨基-3-吗啉代-1-丙醇的组合。盐酸（DL-PDMP）+丙咪嗪+/-D-赤式-2-（N-肉豆蔻酰氨基）-1-苯基-1-丙醇（D-MAPP），10-戈伊照射可触发抗辐射性SQ 20 B鳞状癌细胞的有丝分裂和细胞凋亡杀伤。在这些细胞中，细胞凋亡是有缺陷的，由于缺乏神经酰胺产生上游，这不能解释为鞘磷脂酶（中性和酸性）缺乏或鞘脂途径的快速衍生。我们目前的证据表明，神经酰胺生成恢复时，一个功能性转导死亡途径，其中涉及的神经元介导的途径耦合到氧化还原状态的改变和执行半胱天冬酶激活。多药治疗恢复细胞凋亡的水平类似于放射敏感性SCC 61鳞状细胞癌细胞中观察到的。同时暴露于γ-照射和多药治疗在SQ 20 B细胞中协同作用，产生线粒体功能障碍和半胱天冬酶裂解的显着增加，这导致在48小时内凋亡增加7.8倍，相对于照射的细胞。此外，结果表明，神经酰胺释放的辐射或多药治疗收敛于共同的细胞靶点。鞘脂代谢抑制剂对内源性神经酰胺水平的调节可能代表了放射抗性肿瘤对γ射线治疗敏感性的新细胞靶点。
Recent strategies to sensitize radioresistant tumours are based on combining gamma-irradiation with inducers of apoptosis. We report that the combination of three inhibitors of sphingolipid metabolism, DL-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol. HCl(DL-PDMP) +imipramine+/-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (D-MAPP), with 10-Gy irradiation triggers both mitotic and apoptotic killing in radioresistant SQ20B squamous carcinoma cells. In these cells, apoptosis is defective due to a lack of ceramide generation upstream, which cannot be explained by sphingomyelinase (neutral and acidic) deficiency or rapid derivation to the sphingolipid pathway. We present evidence of a functional transduction death pathway when ceramide generation is restored, which involves the mitochondrial-mediated pathway coupled to alterations in redox status and to executive caspases activation. The poly-drug treatment restored apoptosis to levels similar to those observed in radiosensitive SCC61 squamous carcinoma cells. Simultaneous exposure to gamma-irradiation and poly-drug treatment acted synergistically in SQ20B cells to produce a marked increase in both mitochondrial dysfunction and caspase cleavage, which led to a 7.8-fold increase in apoptosis within 48 h, relative to irradiated cells. Moreover, the results suggest that the ceramide released by irradiation or poly-drug treatment converges upon common cellular targets. Modulation of endogenous ceramide levels by inhibitors of sphingolipid metabolism may represent a new cellular target for the sensitization of radioresistant tumours to gamma-ray therapy.