In Vitro and In Vivo Efficacy of DNA Damage Repair Inhibitor Veliparib in Combination with Artesunate against Echinococcus granulosus.

Y F Li,J H Wang,X Zheng,L M Wen,S Lu,Y H Gong,G D Lv,S Lu,B Chen,H J Gao,J Zhao,C Y Tian

doi:10.1155/2020/8259820

Abstract

Cystic echinococcosis (CE), caused by the cestode Echinococcus granulosus, is a worldwide chronic zoonosis. Albendazole (ABZ) and mebendazole are effective against CE, but a high dosage in a long-term period is usually required. In this study, we evaluate the effects of DNA damage repair inhibitor (i.e., Veliparib) in combination with artesunate (AS) on hydatid cysts. For the in vitro assay, protoscoleces of E. granulosus (E.g PSCs) were incubated with low AS (AS-L, 65 μM), moderate AS (AS-M, 130 μM), and high AS (AS-H, 325 μM), AS-L/M/H+Veliparib (10 μM), and ABZ (25 μM), respectively. The AS-H+Veliparib group showed the maximal protoscolicidal effects. Ultrastructural change revealed that germinal layer (GL) cells were reduced, and lipid droplets appeared. AS could induce DNA injuries in PSCs. The 8-OHdG was expressed in the PSCs and GL of the cysts in mice, especially in the presence of Veliparib. The most severe DNA damages were observed in the AS-H+Veliparib group. Meanwhile, the expression of ribosomal protein S9 (RPS9) gene in the AS-H+Veliparib group was significantly lower than that in the AS-H group. The in vivo chemotherapeutic effects of AS-L (50 mg/kg), AS-H (200 mg/kg), and AS-H+Veliparib (25 mg/kg) were assessed in experimentally infected mice. Upon 6 weeks of oral administration, ultrasonography was used to monitor the volume change of vesicles. Maximum potentiation was seen on day 15 with values (versus AS) of 34 (P < 0.05) for AS-H + Veliparib. It led to the reduction of cyst weight (55.40%) compared with the model group (P < 0.01), which was better than AS alone (52.84%) and ABZ-treated mice (55.35%). Analysis of cysts collected from AS-H+Veliparib-treated mice by transmission electron microscopy revealed a drug-induced structural destruction. The structural integrity of the germinal layer was lost, and the majority of the microtriches disappeared. In conclusion, our study demonstrates that AS or AS in combination with Veliparib is effective for treating CE, especially the combination group. On this basis, AS represented promising drug candidates in anti-CE chemotherapy.

Highlights

Cystic echinococcosis (CE), known as cystic hydatid disease, is a zoonotic infection caused by larval stage of Echinococcus granulosus [1, 2]
We determined the activity of PSCs after treatment using Eosin staining, which indicated that the PSCs activity decline was the most obvious in the AS-H+Veliparib group
Our data showed that the activity of alkaline phosphatase (ALP) showed an obvious increase in the AS-H+Veliparib group

Summary

Introduction

Cystic echinococcosis (CE), known as cystic hydatid disease, is a zoonotic infection caused by larval stage of Echinococcus granulosus [1, 2]. Benzimidazole compounds, the albendazole (ABZ), have been reported to be effective against CE [3]. These compounds, with poor water solubility, were classified as type II drugs on the Biopharmaceutical Classification System [4]. The low dissolution rate of ABZ triggers insufficient absorp-. Disease Markers tion in the gastrointestinal tract, resulting in a low plasma drug level [5]. Long-term medication of ABZ results in severe adverse events in these patients. Novel chemotherapeutic agents with good efficacy are urgently required

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