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首页> 外文期刊>Oncogene >Overcoming resistance to |[gamma]|-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels
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Overcoming resistance to |[gamma]|-rays in squamous carcinoma cells by poly-drug elevation of ceramide levels

机译：通过神经药物水平的多药物升高克服对鳞状癌细胞的抗性抗性

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Recent strategies to sensitize radioresistant tumours are based on combining -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 -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 48h, 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 -ray therapy.
机译：最近敏感辐射瘤肿瘤的策略基于与细胞凋亡的诱导剂结合的混合体。我们认为三种抑制剂的三种抑制剂的组合，D1-Threo-1-苯基-2-癸酰胺-3-吗啉-1-丙醇（DL-PDMP）+ IMIPRamine-D-eryTHRO-2-（N- MyRistoylamino）-1-苯基-1-丙醇（D-MAPP），具有10-GY辐射触发辐射患者SQ20B鳞状癌细胞中有丝分裂和凋亡杀死。在这些细胞中，由于上游缺乏神经酰胺产生，细胞凋亡是缺陷的，这不能通过鞘氨基氨基酶（中性和酸性）缺乏或快速衍生给鞘脂途径来解释。当恢复神经酰胺生成时，我们提出了功能性转导死亡途径的证据，这涉及线粒体介导的途径，其与氧化还原状态的改变和执行胱天冬酶激活。多药物治疗将凋亡恢复到类似于在放射敏感的SCC61鳞状癌细胞中观察到的水平。同时暴露于 - 辐射和多药物治疗在SQ20B细胞中协同作用，以产生线粒体功能障碍和胱天蛋白酶切割的显着增加，其导致48h内的细胞凋亡增加7.8倍，相对于辐照细胞。此外，结果表明通过辐射或多药物治疗释放的神经酰胺在常见的细胞靶标中会聚。鞘脂代谢抑制剂的内源神经酰胺水平的调节可以代表一种新的细胞靶，用于对射线治疗的敏化剂肿瘤的敏化。

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