In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis.
In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis.
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EGFR/MEK/ERK 信号抑制剂治疗肺泡包虫病的体外和体内疗效
DOI：
10.1128/aac.00341-20
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发表时间：
2020-07-22
影响因子：
4.9
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Cheng Z;Xu Z;Tian H;Liu F;Li X;Luo D;Wang Y
泡状棘球蚴病是由多房棘球绦虫幼虫引起的一种致死性疾病。由于目前的化疗在AE治疗中显示出有限的效率，因此迫切需要新的治疗选择。在这项研究中，我们评估了表皮生长因子受体（EGFR）/MEK/细胞外信号调节激酶（ERK）信号传导抑制剂（包括BIBW 2992、CI-1033和U 0126）对E.多房的摘要泡状棘球蚴病（AE）是由多房棘球绦虫幼虫引起的一种致死性疾病。由于目前的化疗在AE治疗中显示出有限的效率，因此迫切需要新的治疗选择。在这项研究中，我们评估了表皮生长因子受体（EGFR）/MEK/细胞外信号调节激酶（ERK）信号传导抑制剂（包括BIBW 2992、CI-1033和U 0126）对E.多房的我们的数据显示，BIBW 2992、CI-1033和U 0126均显示出对E.多室后囊虫这些抑制剂也表现出杀原生寄生虫的活动，并造成严重的超微结构的改变，寄生虫。此外，BIBW 2992和CI-1033对E.多房后囊虫引人注目的是，发现大部分凋亡细胞是萌发细胞。体内研究表明，BIBW 2992和U 0126显著降低了寄生虫负荷，从BIBW 2992处理小鼠中获得的寄生虫显示出生殖层结构完整性受损。总之，这些发现证明EGFR介导的信号传导作为开发新型抗AE药物的靶点的潜力。EGFR抑制剂BIBW 2992代表了一种有前途的候选药物和/或抗AE化疗的先导化合物。
Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor receptor (EGFR)/MEK/extracellular signal-regulated kinase (ERK) signaling inhibitors, including BIBW2992, CI-1033, and U0126, on E. multilocularis. ABSTRACT Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor receptor (EGFR)/MEK/extracellular signal-regulated kinase (ERK) signaling inhibitors, including BIBW2992, CI-1033, and U0126, on E. multilocularis. Our data showed that BIBW2992, CI-1033, and U0126 all displayed in vitro effects on the viability of the E. multilocularis metacestode. These inhibitors also showed protoscolicidal activities and caused severe ultrastructural alterations in the parasite. Moreover, BIBW2992 and CI-1033 exhibited potent proapoptotic effects on E. multilocularis metacestodes. Strikingly, a large portion of the apoptotic cells were found to be the germinative cells. In vivo studies showed that BIBW2992 and U0126 significantly reduced parasite burden, and the parasite obtained from BIBW2992-treated mice displayed impaired structural integrity of the germinal layer. In conclusion, these findings demonstrate the potential of EGFR-mediated signaling as a target for the development of novel anti-AE agents. The EGFR inhibitor BIBW2992 represents a promising drug candidate and/or a lead compound for anti-AE chemotherapy.