Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo
Trk inhibitor attenuates the BDNF/TrkB-induced protection of neuroblastoma cells from etoposide in vitro and in vivo
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Trk 抑制剂在体外和体内减弱 BDNF/TrkB 诱导的神经母细胞瘤细胞免受依托泊苷的保护。
DOI：
10.1080/15384047.2015.1016659
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发表时间：
2015-03-01
影响因子：
3.6
通讯作者：
Thiele, Carol J.
中科院分区：
文献类型：
--
作者：
Li, Zhijie;Zhang, Yi;Thiele, Carol J.
脑源性神经营养因子（BDNF）激活TrkB有助于神经母细胞瘤（NB）的化疗耐药性。AZD 6918是一种新型的Trk酪氨酸激酶的强效和选择性抑制剂。在这项研究中，我们评估了AZD 6918对表达TrkB的NB细胞或肿瘤对拓扑异构酶II抑制剂依托泊苷敏感性的影响。在体外存在或不存在BDNF的情况下，用AZD 6918和依托泊苷处理表达TrkB的NB细胞，并测定细胞存活率。用AZD 6918和依托泊苷单独或组合在体内处理NB异种移植肿瘤，并评价抗肿瘤生长效果或小鼠存活优势。我们的研究表明，AZD 6918作为单一药物诱导细胞死亡，并在体外减弱BDNF/TrkB诱导的依托泊苷保护作用。虽然AZD 6918单独使用在体内没有显示出抗肿瘤生长作用或生存优势，但与单独使用任一种药物治疗相比，AZD 6918和依托泊苷的组合具有统计学显著更强的抗肿瘤生长作用和生存优势。我们的数据表明，作为Trk抑制剂，AZD 6918增加了NB对依托泊苷的敏感性。这些结果扩展了细胞毒性药物的范围，其效力与Trk抑制剂组合增加，并支持Trk抑制剂和细胞毒性药物组合用于NB治疗。
TrkB activation by brain-derived neurotrophic factor (BDNF) contributes to chemo-resistance in neuroblastoma (NB). AZD6918 is a novel potent and selective inhibitor of the Trk tyrosine kinases. In this study we evaluated the effect of AZD6918 on the sensitivity of TrkB-expressing NB cells or tumors to etoposide, a topoisomerase II inhibitor. TrkB-expressing NB cells were treated with AZD6918 and etoposide in the presence or absence of BDNF in vitro and cell survival was determined. NB xenograft tumors were treated with AZD6918 and etoposide, either alone or in combination in vivo, and the anti-tumor growth effect or mice survival advantage was evaluated. Our study showed that AZD6918 induced cell death as a single agent and attenuated BDNF/TrkB-induced protection from etoposide in vitro. Although AZD6918 alone didn't show anti-tumor growth effect or survival advantage in vivo, a combination of AZD6918 and etoposide had a statistically significant stronger anti-tumor growth effect and survival advantage compared to treatment with either agent alone. Our data indicate that as a Trk inhibitor AZD6918 increased the sensitivity of NB to etoposide. These results extend the spectrum of cytotoxic drugs whose efficacy is increased in combination with Trk inhibitors and support the combination of Trk inhibitors and cytotoxic drugs for NB treatment.