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首页> 外文期刊>Apoptosis >Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells
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Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells

机译：罗斯科丁对喜树碱诱导的神经母细胞瘤细胞DNA损伤的抗凋亡作用

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In the present study dopaminergic neuroblastoma B65 cells were exposed to Camptothecin (CPT) (0.5–10 μM), either alone or in the presence of roscovitine (ROSC). The results show that CPT induces apoptosis through the activation of ataxia telangiectasia mutated (ATM)-induced cell-cycle alteration in neuroblastoma B65 cells. The apoptotic process is mediated through the activation of cystein proteases, namely calpain/caspases. However, whereas a pan-caspase inhibitor, zVADfmk, inhibited CPT-mediated apoptosis, a calpain inhibitor, calpeptin, did not prevent cell death. Interestingly, CPT also induces CDK5 activation and ROSC (25 μM) blocked CDK5, ATM activation and apoptosis (as measured by caspase-3 activation). By contrast, selective inhibition of ATM, by KU55933, and non-selective inhibition, by caffeine, did not prevent CPT-mediated apoptosis. Thus, we conclude that CDK5 is activated in response to DNA damage and that CDK5 inhibition prevents ATM and p53ser15 activation. However, pharmacological inhibition of ATM using KU55933 and caffeine suggests that ATM inhibition by ROSC is not the only mechanism that might explain the anti-apoptotic effects of this drug in this apoptosis model. Our findings have a potential clinical implication, suggesting that combinatory drugs in the treatment of cancer activation should be administered with caution.
机译：在本研究中，多巴胺能神经母细胞瘤B65细胞单独或在存在roscovitine（ROSC）的情况下暴露于喜树碱（CPT）（0.5-10μM）。结果表明，CPT通过激活共济失调性毛细血管扩张症（ATM）诱导的神经母细胞瘤B65细胞的细胞周期改变来诱导细胞凋亡。细胞凋亡过程是通过半胱氨酸蛋白酶即钙蛋白酶/胱天蛋白酶的活化来介导的。然而，尽管泛半胱天冬酶抑制剂zVADfmk抑制CPT介导的细胞凋亡，但钙蛋白酶抑制剂calpeptin不能阻止细胞死亡。有趣的是，CPT还诱导CDK5激活，ROSC（25μM）阻断CDK5，ATM激活和凋亡（通过caspase-3激活测量）。相比之下，KU55933对ATM的选择性抑制和咖啡因对非选择性的抑制不能阻止CPT介导的细胞凋亡。因此，我们得出结论，CDK5响应DNA损伤而被激活，而CDK5抑制阻止了ATM和p53ser15的激活。但是，使用KU55933和咖啡因抑制ATM的药理作用表明，ROSC对ATM的抑制作用并不是唯一可以解释该药物在此凋亡模型中抗凋亡作用的机制。我们的发现具有潜在的临床意义，表明在治疗癌症活化中使用联合用药应谨慎使用。

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