In Vitro and In Vivo Efficacy of DNA Damage Repair Inhibitor Veliparib in Combination with Artesunate against Echinococcus granulosus
| Autor: | Y H Gong, Jing Wang, X Zheng, C Y Tian, B Chen, H J Gao, S Lu, Juan Zhao, L M Wen, G D Lv, Y F Li |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Ribosomal Proteins
0301 basic medicine Medicine (General) Time Factors Article Subject DNA Repair Veliparib medicine.medical_treatment Clinical Biochemistry Mebendazole Administration Oral Artesunate Down-Regulation Albendazole Mice 03 medical and health sciences chemistry.chemical_compound R5-920 0302 clinical medicine Echinococcosis In vivo Oral administration Genetics medicine Animals Echinococcus granulosus Molecular Biology Cells Cultured Chemotherapy Sheep Dose-Response Relationship Drug biology Ribosomal Protein S9 Chemistry Biochemistry (medical) General Medicine biology.organism_classification Molecular biology In vitro Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Benzimidazoles Drug Therapy Combination Female Research Article medicine.drug |
| Zdroj: | Disease Markers Disease Markers, Vol 2020 (2020) |
| ISSN: | 1875-8630 0278-0240 |
| DOI: | 10.1155/2020/8259820 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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