期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 237, 期 -, 页码 115-124出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2015.05.024
关键词
Ligase inhibitor; DNA ligase 1; Replication; Colon cancer; Hepatic cancer; Apoptosis; PBD derivatives
资金
- CSIR-CDRI, Govt of India
- Department of Biotechnology (DBT), Govt of India [BT/PR6421/GBD/27/436/2012]
- Department of Science and Technology (DST), Govt. of India [SB/FT/LS-163/2012]
- CSIR network project GENESIS [BSC0121]
- Senior Research fellowships from University Grant Commission (UGC)
- Indian Council of Medical Research, New Delhi, India
Human DNA ligasel (hLig1) is the major replicative enzyme in proliferating mammalian cells that join Okazaki fragments of the lagging strand during DNA replication. Interruptions in the process of ligation cause DNA damage to accumulate, resulting in cytotoxicity and cell death. In the present study we demonstrate that pyrrolo[1,4] benzodiazepine (PBD) derivatives exhibit anticancer properties by targeting the nick sealing activity of hLigl as opposed to the DNA interaction activity known for such compounds. Our in silico and in vitro assays demonstrate the binding of these molecules with amino acid residues present in the DNA binding domain (DBD) of the hLigl enzyme. Two of these hLigl inhibitors S010-015 and S010-018 demonstrated selective cytotoxicity against DLD-1 (colon cancer) and HepG2 (hepatic cancer) cells in a dose dependant manner. The molecules also reduced cell viability and colony formation at concentrations of <= 20 mu M in DLD-1 and HepG2 cells and induced apoptotic cell death. In yet another significant finding, the molecules reduced the migration of cancer cells in wound healing experiments, indicating their anti-metastatic property. In summary, we report the anticancer activity of PBD derivatives against DLD-1 and HepG2 cells and propose a new molecular target for their activity. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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