Low doses of paclitaxel potently induce apoptosis in human retinoblastoma Y79 cells by up-regulating E2F1
Low doses of paclitaxel potently induce apoptosis in human retinoblastoma Y79 cells by up-regulating E2F1
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DOI：
10.3892/ijo_00000053
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发表时间：
2008-10-01
影响因子：
5.2
通讯作者：
Vento, Renza
中科院分区：
文献类型：
--
作者：
Drago-Ferrante, Rosa;Santulli, Andrea;Vento, Renza
紫杉醇（PTX）是一种抗癌药物，目前正在进行II期临床试验。这项研究首次表明，低剂量的PTX（5 nM）有效地诱导人视网膜母细胞瘤Y 79细胞凋亡。PTX的作用伴随着E2 F1的有效诱导，E2 F1似乎在PTX诱导的作用中起关键作用。PTX诱导了剂量和时间依赖性效应，G（2）/M阻滞，细胞周期蛋白A、E和B1积累以及Cdc 2-细胞周期蛋白B1复合物（G（2）/M检查点的主要参与者）状态的显著改变。细胞凋亡发生于G（2）/M期阻滞。p53表达的早期和长期增加，通过磷酸化和乙酰化及其核WAR易位而稳定。因此，PTX增加p21（WAF 1）bax和MDM 2水平，表明p53是转录活性的。在E2 F1上调和P14（ARF）水平增加后，p53积累，P14（ARF）与MDM 2相互作用，阻止p53的泛素化和蛋白酶体降解。外源性（E2 FI/Fas/JNK/caspase-2激活）和内源性（Bcl-2磷酸化，Bid片段化和Bax增加）途径似乎都参与其中。显示线粒体电位丧失以及线粒体和执行性半胱天冬酶-3、-6和-7的活化。与不可逆的泛半胱天冬酶抑制剂Z-VAD-FMK或SP 600125（JNK的选择性抑制剂）或pifithrin alpha（有效的p53抑制剂）孵育，可显著抑制PTX诱导的效应。
Paclitaxel (PTX) is an anticancer drug currently in phase II clinical trials. This study shows for the first time that low doses of PTX (5 nM) potently induce apoptosis in human retinoblastoma Y79 cells. The effect of PTX is accompanied by a potent induction of E2F1 which appears to play a critical role in the effects induced by PTX. PTX induced a dose- and time-dependent effect, with G(2)/M arrest, cyclines A, E and B1 accumulation and a marked modification in the status of Cdc2-cyclin B1 complex, the major player of the G(2)/M checkpoint. Apoptosis followed G(2)/M arrest. An early and prolonged increase In p53 expression with its stabilization by phosphorylation and acetylation and its nuclear WAR translocation occurred. Consistently, PTX increased p21(WAF1) bax and MDM2 levels, suggesting that p53 is transcriptionally active. p53 accumulated following both E2F1 up-regulation and increase in the levels of P14(ARF) which interacts with MDM2 preventing ubiquitination and proteosomal degradation of p53. Both extrinsic (E2FI/Fas/JNK/caspase-2 activation) and intrinsic (Bcl-2 phosphorylation, Bid fragmentation and Bax increase) pathways seemed to be involved. Loss of mitochondrial potential and activation of apoptosome and executive caspase-3,-6 and-7 was shown. Incubation with either the irreversible pan-caspase inhibitors Z-VAD-FMK, or SP600125, a selective inhibitor of JNK, or pifithrin alpha, a potent p53 inhibitor, significantly inhibited the effects induced by PTX.