The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia
The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia
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DOI：
10.3324/haematol.2010.026997
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发表时间：
2011-01-01
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影响因子：
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通讯作者：
Bendall, Linda J.
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文献类型：
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作者：
Saunders, Philip;Cisterne, Adam;Bendall, Linda J.
背景尽管急性淋巴细胞白血病患者的预后逐渐改善，但仍有大量患者死于这种疾病。雷帕霉素抑制剂的哺乳动物靶标已在体外和体内显示出作为针对包括急性淋巴细胞白血病在内的一系列肿瘤的治疗剂的潜力。设计和方法流式细胞术用于评估急性淋巴细胞白血病细胞系和患者样本中药物诱导的细胞死亡。使用免疫受损小鼠体内的人类异种移植物来评估所选组合的体内效果。使用药理学抑制剂和慢病毒小干扰核糖核酸敲低p53来研究相关细胞杀伤机制。结果在体外和体内均证明了RAD001与细胞毒药物之间的协同相互作用，并增加了caspase依赖性杀伤作用。 RAD001抑制p53和p21反应，而抑制p53并不能阻止杀伤，表明p53独立。 RAD001 和细胞毒性药物激活了 JUN N 末端激酶通路，并且组合进一步增强了 JUN N 末端激酶的激活。 JUN N 末端激酶抑制可减少细胞毒性药物和 RAD001 在 pre-B 急性淋巴细胞白血病细胞系和患者样本中的协同细胞杀伤作用。激活 JUN N 末端激酶途径的硼替佐米和 MG132 也可与 RAD001 协同杀死 pre-B 急性淋巴细胞白血病细胞。当 RAD001 与蛋白酶体抑制剂联合使用时，杀伤力比与细胞毒性药物联合使用时更大。结论这些观察结果表明，将哺乳动物靶点的雷帕霉素抑制剂与常规化疗或选定的新型药物相结合，有可能改善 B 期前急性淋巴细胞白血病患者的临床反应。
BackgroundDespite incremental improvements in outcomes for patients with acute lymphoblastic leukemia, significant numbers of patients still die from this disease. Mammalian target of rapamycin inhibitors have shown potential in vitro and in vivo as therapeutic agents against a range of tumors including acute lymphoblastic leukemia.Design and MethodsFlow cytometry was used to evaluate drug-induced cell death in acute lymphoblastic leukemia cell lines and patients' samples. Human xenografts in immunocompromised mice were used to assess the in vivo effects of selected combinations. Pharmacological inhibitors and lentiviral small interfering ribonucleic acid knock-down of p53 were used to investigate the mechanism of cell killing involved.ResultsSynergistic interactions between RAD001 and cytotoxic agents were demonstrated in vitro and in vivo, with increased caspase-dependent killing. RAD001 suppressed p53 and p21 responses, while suppression of p53 did not prevent killing, indicating p53 independence. RAD001 and cytotoxic agents activated the JUN N-terminal kinase pathway and the combination further increased JUN N-terminal kinase activation. JUN N-terminal kinase inhibition reduced synergistic cell killing by cytotoxic agents and RAD001 in pre-B acute lymphoblastic leukemia cell lines and patients' samples.Bortezomib and MG132, which activate the JUN N-terminal kinase pathway, also synergized with RAD001 in killing pre-B acute lymphoblastic leukemia cells. Killing was greater when RAD001 was combined with proteasome inhibitors than with cytotoxic drugs.ConclusionsThese observations suggest that combining mammalian target of rapamycin inhibitors with conventional chemotherapy or selected novel agents has the potential to improve clinical responses in patients with pre-B acute lymphoblastic leukemia.