Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs
Sequential activation and inactivation of G2 checkpoints for selective killing of p53-deficient cells by microtubule-active drugs
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DOI：
10.1038/sj.onc.1205793
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发表时间：
2002-09-12
期刊：
影响因子：
8
通讯作者：
Blagosklonny, MV
中科院分区：
文献类型：
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作者：
Blagosklonny, MV
通过诱导p53依赖性G2停滞，用低浓度的DNA损伤药物（例如，阿霉素，DOX）可以预防由微管活性药物（例如，紫杉醇（paclitaxel），PTX），从而潜在地允许选择性杀死p53缺陷型癌细胞。然而，DOX仍然保护缺乏wt p53的肿瘤细胞系的亚群（HL 60和Jurkat白血病细胞），因此限制了用wt p53保护细胞的效用（例如，正常细胞）。本工作通过添加p53非依赖性检查点的废除者（例如，UCN-01）与D 0X-PTX序列。通过抑制p53非依赖性途径，UCN-01推翻了DOX诱导的G2期阻滞，而在HL 60和Jurkat中诱导G1期阻滞，从而将这些p53缺陷型细胞从G2期推进到G1期。一旦它们进入有丝分裂，细胞就被PTX杀死。诱导G2期阻滞并依次废除p53非依赖性检查点，可对p53缺陷细胞中由PTX引起的Raf-1/Bcl-2过度磷酸化、PARP和Rb裂解以及细胞死亡进行药理学操作。与以前的方法不同，这种策略旨在增加PTX的选择性，而不是细胞毒性。这种诱导p53依赖性和消除p53非依赖性阻滞的合理药物序列代表了用于治疗p53缺陷型肿瘤的癌症选择性策略。
By inducing p53-dependent G2 arrest, the pretreatment with low concentrations of DNA damaging drugs (e.g., doxorubicin, DOX) can prevent cell death caused by microtubule-active drugs (e.g., paclitaxel, PTX), thus potentially permitting selective killing of p53-deficient cancer cells. However, DOX still protects a subset of tumor cell lines lacking wt p53 (HL60 and Jurkat leukemia cells), thus limiting the utility of protection of cells with wt p53 (e.g., normal cells). The present work overcomes this obstacle by adding an abrogator of p53-independent checkpoint (e.g., UCN-01) to the DOX-PTX sequence. By inhibiting a p53-independent pathway, UCN-01 overrode DOX-induced G2 arrest and instead induced G1 arrest in HL60 and Jurkat, thus propelling these p53-deficient cells from G2 to G1. Once they entered mitosis, cells were killed by PTX. Induction of G2 arrest with sequential abrogation of a p53-independent checkpoint allows pharmacological manipulation of Raf-1/Bcl-2 hyperphosphorylation, PARP and Rb cleavage and cell death caused by PTX in p53-deficient cells. Unlike previous approaches, this strategy is intended to increase selectivity, not the cytotoxicity of PTX. This rational sequence of agents that induces p53-dependent and abrogates p53-independent arrest represents a cancer-selective strategy for treatment of p53-deficient tumors.