二聚醇与拓扑异构酶抑制剂协同作用以克服肿瘤细胞中的 DNA 修复活性。

Dianhydrogalactitol synergizes with topoisomerase poisons to overcome DNA repair activity in tumor cells.

机构信息

Vancouver Prostate Centre, Vancouver, BC, V6H 3Z6, Canada.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada.

出版信息

Cell Death Dis. 2020 Jul 24;11(7):577. doi: 10.1038/s41419-020-02780-8.

DOI:10.1038/s41419-020-02780-8

PMID:32709853

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7381652/

Abstract

1,2:5,6-Dianhydrogalactitol (DAG) is a bi-functional DNA-targeting agent currently in phase II clinical trial for treatment of temozolomide-resistant glioblastoma (GBM). In the present study, we investigated the cytotoxic activity of DAG alone or in combination with common chemotherapy agents in GBM and prostate cancer (PCa) cells, and determined the impact of DNA repair pathways on DAG-induced cytotoxicity. We found that DAG produced replication-dependent DNA lesions decorated with RPA32, RAD51, and γH2AX foci. DAG-induced cytotoxicity was unaffected by MLH1, MSH2, and DNA-PK expression, but was enhanced by knockdown of BRCA1. Acting in S phase, DAG displayed selective synergy with topoisomerase I (camptothecin and irinotecan) and topoisomerase II (etoposide) poisons in GBM, PCa, and lung cancer cells with no synergy observed for docetaxel. Importantly, DAG combined with irinotecan treatment enhanced tumor responses and prolonged survival of tumor-bearing mice. This work provides mechanistic insight into DAG cytotoxicity in GBM and PCa cells and offers a rational for exploring combination regimens with topoisomerase I/II poisons in future clinical trials.

摘要

1,2:5,6-脱水卫矛醇（DAG）是一种双功能 DNA 靶向药物，目前正在进行治疗替莫唑胺耐药胶质母细胞瘤（GBM）的 II 期临床试验。在本研究中，我们研究了 DAG 单独或与常见化疗药物联合在 GBM 和前列腺癌（PCa）细胞中的细胞毒性活性，并确定了 DNA 修复途径对 DAG 诱导的细胞毒性的影响。我们发现 DAG 产生了依赖复制的 DNA 损伤，这些损伤被 RPA32、RAD51 和 γH2AX 焦点修饰。DAG 诱导的细胞毒性不受 MLH1、MSH2 和 DNA-PK 表达的影响，但 BRCA1 的敲低增强了其作用。在 S 期发挥作用，DAG 与拓扑异构酶 I（喜树碱和伊立替康）和拓扑异构酶 II（依托泊苷）毒物在 GBM、PCa 和肺癌细胞中表现出选择性协同作用，而与多西他赛没有协同作用。重要的是，DAG 与伊立替康联合治疗增强了荷瘤小鼠的肿瘤反应并延长了其生存时间。这项工作为 DAG 在 GBM 和 PCa 细胞中的细胞毒性提供了机制上的见解，并为未来临床试验中探索与拓扑异构酶 I/II 毒物联合治疗方案提供了依据。