Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Aktip53 axis in pre-B acute lymphoblastic leukemia cells
Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Aktip53 axis in pre-B acute lymphoblastic leukemia cells
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DOI：
10.1016/j.ejphar.2016.09.006
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发表时间：
2016-11-15
影响因子：
5
通讯作者：
Ghaffari, Seyed H.
中科院分区：
文献类型：
--
作者：
Bayati, Samaneh;Bashash, Davood;Ghaffari, Seyed H.
越来越多的遗传学和癌症生物学研究表明，速激肽NK 1受体（Will）在癌细胞生长和存活中起着重要作用。考虑到急性淋巴细胞白血病（ALL）中的肿瘤性淋巴前体细胞携带3 - 4倍于正常淋巴细胞的NK 1 R表达，使用Will拮抗剂治疗ALL患者似乎值得注意。在这项研究中，我们发现，阿瑞匹坦，一种选择性的高亲和力拮抗剂的人NKiR的抑制意志，发挥细胞毒性和抗增殖作用，对前B ALL衍生的Nalm-6细胞作为单一的药物或与阿霉素组合。我们的数据显示，用抑制剂处理细胞导致凋亡性细胞死亡，至少部分地，通过废除PI 3 K/Akt途径，如通过磷酸/总Akt比率的降低所揭示的。与对Akt的抑制作用一致，我们还发现阿瑞匹坦增加了p21和p27的表达水平，从而导致诱导G1期细胞阻滞。总体而言，这项研究建议的机制途径，将抑制可以增加凋亡细胞死亡通过一个合理的p53依赖性途径，而不是NF-κ B依赖性机制在前B ALL细胞;然而，需要进一步的研究，以更好地表征NK 1 R抑制在临床癌症治疗中的应用。(C)2016爱思唯尔B. V.保留所有权利。
Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK1 receptor (Will) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK1R expression as compared to normal lymphocytes, using Will antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of Will with aprepitant, a selective high-affinity antagonist of the human NKiR, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin. Our data showed that treatment of the cells with the inhibitor resulted in apoptotic cell death, at least partly, through abrogation of PI3K/Akt pathway, as revealed by the reduction of phospho/total Akt ratio. In agreement with the inhibitory effect on Akt, we also found that aprepitant increased the expression level of p21 and p27, which in turn leads to the induction of G1 cell cycle arrest. Overall, this study recommends mechanistic pathways by which inhibition of Will can augment apoptotic cell death through a plausible p53-dependent pathway rather than NF-kappa B-depended mechanism in pre-B ALL cells; however, further studies are needed to better characterize the application of NK1R inhibition in clinical cancer treatment. (C) 2016 Elsevier B.V. All rights reserved.