Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells

doi:10.1016/j.fct.2020.111892

IOCAS-IR > 实验海洋生物学重点实验室

	Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells
	Wu, Xiaochen 1; Li, Qiqi 1; Zhang, Fan 1; Wang, Lijun 2; Wang, Jun 1; Fan, Junting 3; Di, Guohu 4; Guo, Chuanlong 1
	2021
发表期刊	FOOD AND CHEMICAL TOXICOLOGY
ISSN	0278-6915
卷号	147 页码:10
通讯作者	Guo, Chuanlong(guochuanlong@qust.edu.cn)
摘要	Poly (ADP-ribose) polymerases (PARPs) play a key role in DNA repair. In this study we designed a novel smallmolecular compound, (E)-2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamide (DHC-1), which was a potent and selective PARP-1 inhibitor. DHC-1 selectively inhibited PARP-1 activity with an IC50 value of 41.12 +/- 13.28 nM. Cytotoxicity results showed that DHC-1 selectively inhibited the proliferation of BRCA1 -deficient breast cancer HCC-1937 and BRCA2-deficient pancreatic cancer Capan-1 cells. Mechanism studies found that DHC-1 stabilized PARP-1-DNA complexes and inhibited PAR formation in BRCA2(-/-) Capan-1 cells. Further experiments found that DHC-1 induced DNA double-strand damage in BRCA2(-/-) Capan-1 cells, which was demonstrated by accumulation of gamma-H2AX foci. Flow cytometry experiments revealed that DHC-1 induced G2/M phase arrest and activate mitochondrial-induced apoptotic pathways. Interestingly, we also found that DHC-1 enhanced cell proliferation inhibitory effect of oxaliplatin (OXA). The further in vivo nude mouse studies showed that DHC-1 inhibited the growth of Capan-1 xenografts and showed a similar mechanism to that in vitro. Collectively, our results demonstrate that DHC-1 may be an excellent candidate for treatment of BRCA-deficient pancreatic cancers.
关键词	PARP inhibitor BRCA Pancreatic cancer
DOI	10.1016/j.fct.2020.111892
收录类别	SCI
语种	英语
资助项目	National Natural Science Foundation of China[81773586]
WOS研究方向	Food Science & Technology ; Toxicology
WOS类目	Food Science & Technology ; Toxicology
WOS记录号	WOS:000604748100024
出版者	PERGAMON-ELSEVIER SCIENCE LTD
引用统计	被引频次：5[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.qdio.ac.cn/handle/337002/169930
专题	实验海洋生物学重点实验室
通讯作者	Guo, Chuanlong
作者单位	1.Qingdao Univ Sci & Technol, Coll Chem Engn, Dept Pharm, 53 Zhengzhou Rd, Qingdao 266042, Peoples R China 2.Chinese Acad Sci, CAS Key Lab Expt Marine Biol, Ctr Ocean Megasci, Inst Oceanol, 7 Nanhai Rd, Qingdao 266071, Peoples R China 3.Nanjing Med Univ, Sch Pharm, Dept Pharmaceut Anal, Nanjing 211166, Peoples R China 4.Qingdao Univ, Sch Basic Med, 308 Ningxia Rd, Qingdao 266071, Peoples R China
推荐引用方式 GB/T 7714	Wu, Xiaochen,Li, Qiqi,Zhang, Fan,et al. Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells[J]. FOOD AND CHEMICAL TOXICOLOGY,2021,147:10.
APA	Wu, Xiaochen.,Li, Qiqi.,Zhang, Fan.,Wang, Lijun.,Wang, Jun.,...&Guo, Chuanlong.(2021).Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells.FOOD AND CHEMICAL TOXICOLOGY,147,10.
MLA	Wu, Xiaochen,et al."Novel poly (ADP-ribose) polymerases inhibitor DHC-1 exhibits in vitro and in vivo anticancer activity on BRCA-deficient pancreatic cancer cells".FOOD AND CHEMICAL TOXICOLOGY 147(2021):10.

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