PARP inhibitor veliparib and HDAC inhibitor SAHA synergistically co-target the UHRF1/BRCA1 DNA damage repair complex in prostate cancer cells

作者：Linglong Yin, Youhong Liu, Yuchong Peng, Yongbo Peng, Xiaohui Yu, Yingxue Gao, Bowen Yuan, Qianling Zhu, Tuoyu Cao, Leye He, Zhicheng Gong, Lun‐Quan Sun, Xuegong Fan, Xiong Li · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2018 · DOI：10.1186/s13046-018-0810-7 · 被引用次数：128 · 研究领域：PARP inhibition in cancer therapy、Prostate Cancer Treatment and Research、Prostate Cancer Diagnosis and Treatment

BACKGROUND: The poly ADP ribose polymerase (PARP) inhibitor olaparib has been approved for treating prostate cancer (PCa) with BRCA mutations, and veliparib, another PARP inhibitor, is being tested in clinical trials. However, veliparib only showed a moderate anticancer effect, and combination therapy is required for PCa patients. Histone deacetylase (HDAC) inhibitors have been tested to improve the anticancer efficacy of PARP inhibitors for PCa cells, but the exact mechanisms are still elusive. METHODS: Several types of PCa cells and prostate epithelial cell line RWPE-1 were treated with veliparib or SAHA alone or in combination. Cell viability or clonogenicity was tested with violet crystal assay; cell apoptosis was detected with Annexin V-FITC/PI staining and flow cytometry, and the cleaved PARP was tested with western blot; DNA damage was evaluated by staining the cells with γH2AX antibody, and the DNA damage foci were observed with a fluorescent microscopy, and the level of γH2AX was tested with western blot; the protein levels of UHRF1 and BRCA1 were measured with western blot or cell immunofluorescent staining, and the interaction of UHRF1 and BRCA1 proteins was detected with co-immunoprecipitation when cells were treated with drugs. The antitumor effect of combinational therapy was validated in DU145 xenograft models. RESULTS: PCa cells showed different sensitivity to veliparib or SAHA. Co-administration of both drugs synergistically decreased cell viability and clono...