An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential.
An engineered bivalent neuregulin protects against doxorubicin-induced cardiotoxicity with reduced proneoplastic potential.
复制标题
DOI：
10.1161/circulationaha.113.002203
复制
发表时间：
2013-07-09
期刊：
影响因子：
37.8
通讯作者：
Lee RT
中科院分区：
文献类型：
--
作者：
Jay SM;Murthy AC;Hawkins JF;Wortzel JR;Steinhauser ML;Alvarez LM;Gannon J;Macrae CA;Griffith LG;Lee RT
阿霉素（DOXO）是一种有效的蒽环类化疗药物，但其使用受到累积剂量依赖性心脏毒性的限制。Neuregulin-1β（NRG 1B）是ErbB受体家族配体，在实验模型中可有效对抗DOXO诱导的心肌病，但也具有促肿瘤作用。我们先前表明，与NRG 1B（NRG）的表皮生长因子（EGF）样结构域相比，工程化的二价神经调节蛋白-1 β（NN）具有降低的促肿瘤潜力，这是由受体偏向ErbB 3同型相互作用介导的效应，而天然NRG 1B不常见。在这里，我们假设新配制的共价NN与NRG相比具有降低的促肿瘤作用，具有心脏保护作用。NN在E.杆菌如前所述，NN刺激癌细胞中的抗肿瘤或细胞生长抑制信号和表型，而NRG刺激促肿瘤信号和表型。在新生大鼠心肌细胞（NRCM），NN和NRG诱导类似的下游信号。与NRG一样，NN减弱了NRCM和诱导多能干细胞衍生的人心肌细胞中与DOXO暴露相关的双链DNA断裂。在慢性心肌病模型中，通过盲法超声心动图测量，NN治疗显著减弱了DOXO诱导的缩短分数降低（57.7% ± 0.6% vs. 50.9% ± 2.6%，P=0.004），而天然NRG无显著影响（49.4% ± 3.7% vs. 50.9% ± 2.6%，P=0.813）。NN是一种心脏保护剂，在DOXO诱导的心脏毒性中促进心肌细胞存活并改善心脏功能。鉴于NN相对于NRG的促肿瘤潜力降低，NN在接受蒽环类药物的癌症患者中具有心脏保护的转化潜力。
Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β (NRG1B) is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also pro-neoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced pro-neoplastic potential compared to the epidermal growth factor (EGF)-like domain of NRG1B (NRG), an effect mediated by receptor biasing towards ErbB3 homotypic interactions uncommonly formed by native NRG1B. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced pro-neoplastic effects compared to NRG. NN was expressed as a maltose-binding protein fusion in E. coli. As established previously, NN stimulated anti-neoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated pro-neoplastic signaling and phenotype. In neonatal rat cardiomyocytes (NRCM), NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in NRCM and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7% ± 0.6% vs. 50.9% ± 2.6%, P=0.004), whereas native NRG had no significant effect (49.4% ± 3.7% vs. 50.9% ± 2.6%, P=0.813). NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced pro-neoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in cancer patients receiving anthracyclines.