Synthetic modified pyrrolo[1,4] benzodiazepine molecules demonstrate selective anticancer activity by targeting the human ligase 1 enzyme: An in silico and in vitro mechanistic study

Mohammad Shameem, Ravi Kumar, Shagun Krishna, Chandan Kumar, Mohammad Imran Siddiqi, Bijoy Kundu, Dibyendu Banerjee

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Human DNA ligase1 (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 hLig1 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 hLig1 enzyme. Two of these hLig1 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 μM 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.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalChemico-Biological Interactions
Volume237
DOIs
StatePublished - Jun 19 2015

Bibliographical note

Funding Information:
The authors acknowledge CSIR-CDRI , Govt of India for financial and infrastructural support. Financial support is also acknowledged from Department of Biotechnology (DBT), Govt of India (Grant- BT/PR6421/GBD/27/436/2012 ), the Department of Science and Technology (DST), Govt. of India (Grant- SB/FT/LS-163/2012 ) and CSIR network project GENESIS ( BSC0121 ). The authors are also thankful to Mr. A.L. Vishwakarma for his support during flow cytometry experiments. MS and SK are the recipients of Senior Research fellowships from University Grant Commission (UGC), and Indian Council of Medical Research, New Delhi, India, respectively.

Publisher Copyright:
© 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords

  • Apoptosis
  • Colon cancer
  • DNA ligase 1
  • Hepatic cancer
  • Ligase inhibitor
  • PBD derivatives
  • Replication

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