Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia
Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia
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mTOR抑制剂雷帕霉素与下调FAK治疗急性淋巴细胞白血病的协同作用
DOI：
10.1186/s13045-016-0241-x
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发表时间：
2016-02
影响因子：
28.5
通讯作者：
Fang Jian-Pei
中科院分区：
文献类型：
--
作者：
Shi Pei-Jie;Xu Lu-Hong;Lin Kang-Yu;Weng Wen-Jun;Fang Jian-Pei
研究背景急性淋巴细胞白血病（acute lymphoblastic leukemia，ALL）是一种侵袭性淋巴祖细胞的恶性疾病，可发生于儿童和成人。虽然现代治疗的改进和新治疗策略的开发使ALL儿童的治愈率大幅提高，但复发率仍然很高，复发儿童ALL的预后很差。分子靶向治疗已经成为癌症治疗中的主要治疗方法。多细胞毒性药物方案已经取得了成功，但许多针对靶向治疗的研究仅集中在一种单一药物上。在这项研究中，我们试图研究雷帕霉素靶蛋白（mTOR）抑制剂雷帕霉素与粘着斑激酶（FAK）下调在ALL治疗中的作用是否具有协同作用。在人前体B急性淋巴细胞白血病细胞REH中研究了细胞凋亡，在非肥胖糖尿病/严重联合免疫缺陷患者中研究了生存时间和白血病进展。结果与FAK下调联合应用时，雷帕霉素诱导的细胞增殖抑制、G 0/G1期阻滞和凋亡明显增强。此外，与注射REH空载体细胞并接受雷帕霉素治疗的小鼠相比，注射REH细胞并接受雷帕霉素和短发夹RNA（shRNA）下调FAK的NOD/SCID小鼠的存活时间显着延长，白血病进展缓慢。此外，B细胞CLL/淋巴瘤-2（BCL-2）基因家族被证明参与增强，通过联合治疗，REH细胞apoptosis.ConclusionsFAK下调增强了雷帕霉素对REH细胞生长的体外和体内抑制作用，表明同时靶向mTOR和FAK相关通路可能为治疗ALL提供一种新的和强大的策略。
BackgroundAcute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells in both children and adults. Although improvements in contemporary therapy and development of new treatment strategies have led to dramatic increases in the cure rate in children with ALL, the relapse rate remains high and the prognosis of relapsed childhood ALL is poor. Molecularly targeted therapies have emerged as the leading treatments in cancer therapy. Multi-cytotoxic drug regimens have achieved success, yet many studies addressing targeted therapies have focused on only one single agent. In this study, we attempted to investigate whether the effect of the mammalian target of rapamycin (mTOR) inhibitor rapamycin is synergistic with the effect of focal adhesion kinase (FAK) down-regulation in the treatment of ALL.MethodsThe effect of rapamycin combined with FAK down-regulation on cell proliferation, the cell cycle, and apoptosis was investigated in the human precursor B acute lymphoblastic leukemia cells REH and on survival time and leukemia progression in a non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model.ResultsWhen combined with FAK down-regulation, rapamycin-induced suppression of cell proliferation, G0/G1cell cycle arrest, and apoptosis were significantly enhanced. In addition, REH cell-injected NOD/SCID mice treated with rapamycin and a short-hairpin RNA (shRNA) to down-regulate FAK had significantly longer survival times and slower leukemia progression compared with mice injected with REH-empty vector cells and treated with rapamycin. Moreover, the B-cell CLL/lymphoma-2 (BCL-2) gene family was shown to be involved in the enhancement, by combined treatment, of REH cell apoptosis.ConclusionsFAK down-regulation enhanced the in vitro and in vivo inhibitory effects of rapamycin on REH cell growth, indicating that the simultaneous targeting of mTOR- and FAK-related pathways might offer a novel and powerful strategy for treating ALL.
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影响因子：
1.9
作者：
M. Litzow
通讯作者：
M. Litzow
影响因子：
14.8
作者：
Tiscornia, Gustavo;Singer, Oded;Verma, Inder M.
通讯作者：
Verma, Inder M.
影响因子：
28.5
作者：
Fan D;Li W;Yang Y;Zhang X;Zhang Q;Yan Y;Yang M;Wang J;Xiong D
通讯作者：
Xiong D
影响因子：
4.6
作者：
Gomez-Martin, Carlos;Bustamante, Javier;Sangro, Bruno
通讯作者：
Sangro, Bruno
影响因子：
6.2
作者：
Koehl, GE;Andrassy, J;Geissler, EK
通讯作者：
Geissler, EK