Nutlin-1 strengthened anti-proliferation and differentiation-inducing activity of ATRA in ATRA-treated p-glycoprotein deregulated human myelocytic leukemia cells
Nutlin-1 strengthened anti-proliferation and differentiation-inducing activity of ATRA in ATRA-treated p-glycoprotein deregulated human myelocytic leukemia cells
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DOI：
10.1007/s10637-010-9512-5
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发表时间：
2012-02
影响因子：
3.4
通讯作者：
Lei Zhang;Yan Yan-Yan;Difeng Zhu;Wei Yang;Weisi Wang;Yongzhou Hu;Bo Yang;Qiaojun He
中科院分区：
文献类型：
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作者：
Lei Zhang;Yan Yan-Yan;Difeng Zhu;Wei Yang;Weisi Wang;Yongzhou Hu;Bo Yang;Qiaojun He
与其对p53功能细胞系的细胞毒性不同，小鼠双微体（MDM 2）的小分子抑制剂Nutlin-1显著增强全反式维甲酸（ATRA）对HL 60和NB 4细胞（p53-非功能细胞）的分化诱导活性，但对U937细胞（p53野生型细胞）的分化诱导活性无明显影响。此外，我们证明了Nutlin-1与ATRA的协同分化诱导活性以ap 53非依赖性方式出现。本研究发现，ATRA可选择性地诱导HL 60和NB 4细胞P-糖蛋白（P-gp）的表达，但对U937细胞无此作用。对p-gp-ATPase活性的研究表明Nutlin-1和ATRA可能是p-gp的转运底物。此外，Nutlin-1还能增强ATRA诱导髓系分化相关转录因子C/EBPβ表达和降低c-myc表达的能力。此外，在ATRA与Nutlin-1联合处理的细胞中，视黄酸受体α（RARα）的表达进一步降低。Nutlin-1与ATRA协同诱导分化的机制可能是Nutlin-1与p-gp竞争性结合，抑制ATRA的外排，从而进一步激活相关的分化途径。Nutlin-1可能是ATRA治疗P-gp过表达所致维甲酸耐药白血病的有效辅助治疗药物。
Unlike its cytotoxicity inp53-functional cell lines, Nutlin-1, the small-molecule inhibitor of murine double minute (MDM2), significantly enhanced the differentiation-inducing activity of all-trans retinoic acid (ATRA) in HL60 and NB4 cells (p53-nonfunctional) but not in U937 cells (p53wild-type). Moreover, we demonstrated that the synergistic differentiation-inducing activity of Nutlin-1 combined with ATRA appeared in ap53-independent manner. In the present study, we found that ATRA could selectively induce expression of p-glycoprotein (p-gp) in HL60 and NB4 cells but not in U937 cells. Investigation of p-gp-ATPase activity showed that Nutlin-1 and ATRA were likely to act as p-gp transport substrates. Furthermore, Nutlin-1 enhanced the ability of ATRA to induce expression of the myeloid differentiation-related transcription factor C/EBPβ and to reduce expression of c-myc. Additionally, the expression of retinoic acid receptor α (RARα) was further reduced in cells treated with ATRA in combination with Nutlin-1. Taken together, the mechanisms of synergistic differentiation-inducing activity of Nutlin-1 combined with ATRA could be attributed to Nutlin-1 competitive binding to p-gp, leading to ATRA efflux inhibition, and then the differentiation pathways involved were therefore further activated. Nutlin-1 might be a useful adjuvant with ATRA for patients with retinoid-resistant leukemia induced by overexpression of p-gp.