Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells

被引:43
作者
Arora, Sanjeevani [1 ]
Heyza, Joshua [2 ]
Zhang, Hao [2 ]
Kalman-Maltese, Vivian [1 ]
Tillison, Kristin [1 ]
Floyd, Ashley M. [2 ]
Chalfin, Elaine M. [1 ]
Bepler, Gerold [2 ]
Patrick, Steve M. [2 ]
机构
[1] Univ Toledo, Dept Biochem & Canc Biol, Hlth Sci Campus, Toledo, OH USA
[2] Wayne State Univ, Dept Oncol, Karmanos Canc Inst, Detroit, MI 48202 USA
基金
美国国家卫生研究院;
关键词
ERCC1-XPF; cisplatin; chemoresistance; DNA repair inhibitor; high-throughput screen; STRUCTURE-SPECIFIC ENDONUCLEASE; NUCLEOTIDE EXCISION-REPAIR; COMPLEX ERCC1-XPF; LUNG-CANCER; IN-SILICO; CHEMOTHERAPY; XPF-ERCC1; MANAGEMENT; RESISTANCE; NUCLEASE;
D O I
10.18632/oncotarget.12072
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease which is essential in multiple DNA repair pathways in mammalian cells. ERCC1-XPF (ERCC1-ERCC4) repairs cisplatin-DNA intrastrand adducts and interstrand crosslinks and its specific inhibition has been shown to enhance cisplatin cytotoxicity in cancer cells. In this study, we describe a high throughput screen (HTS) used to identify small molecules that inhibit the endonuclease activity of ERCC1-XPF. Primary screens identified two compounds that inhibit ERCC1-XPF activity in the nanomolar range. These compounds were validated in secondary screens against two other non-related endonucleases to ensure specificity. Results from these screens were validated using an in vitro gel-based nuclease assay. Electrophoretic mobility shift assays (EMSAs) further show that these compounds do not inhibit the binding of purified ERCC1-XPF to DNA. Next, in lung cancer cells these compounds potentiated cisplatin cytotoxicity and inhibited DNA repair. Structure activity relationship (SAR) studies identified related compounds for one of the original Hits, which also potentiated cisplatin cytotoxicity in cancer cells. Excitingly, dosing with NSC16168 compound potentiated cisplatin antitumor activity in a lung cancer xenograft model. Further development of ERCC1-XPF DNA repair inhibitors is expected to sensitize cancer cells to DNA damage-based chemotherapy.
引用
收藏
页码:75104 / 75117
页数:14
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