In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis

Zhe Cheng; Zhijian Xu; Huimin Tian; Fan Liu; Xiu Li; Damin Luo; Yanhai Wang

doi:10.1128/AAC.00341-20

In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis

Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00341-20. doi: 10.1128/AAC.00341-20. Print 2020 Jul 22.

Authors

Zhe Cheng^{1

2}, Zhijian Xu^{1

2}, Huimin Tian³, Fan Liu³, Xiu Li^{1

2}, Damin Luo^{1

2}, Yanhai Wang^{4

2}

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
² Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
³ Medical College, Xiamen University, Xiamen, Fujian, China.
⁴ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China wangyh@xmu.edu.cn.

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.

Keywords: EGFR signaling; apoptosis; echinococcosis; germinative cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Echinococcosis* / drug therapy
Echinococcus multilocularis*
ErbB Receptors / genetics
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Mice
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*

Substances

ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase Kinases

Supplementary concepts

Alveolar echinococcosis