2. Academic Validation
  3. Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer

Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer

  • J Biomol Struct Dyn. 2024 Jan 5:1-16. doi: 10.1080/07391102.2023.2297817.
Pooja Maurya 1 2,  Rohit Singh Rawat 1 2,  Sampa Gupta 2 3,  Shagun Krishna 2 4,  Mohammad Imran Siddiqi 4 5,  Koneni V Sashidhara 3 5,  Dibyendu Banerjee 1 5
Affiliations

Affiliations

  • 1 Cancer Biology Division, CSIR-Central Drug Research Institute, Lucknow, India.
  • 2 Jawaharlal Nehru University, New Delhi, India.
  • 3 Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
  • 4 Biochemistry and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, India.
  • 5 Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
PMID: 38179981 DOI: 10.1080/07391102.2023.2297817
Abstract

DNA Topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for Anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in Cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal Cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal Cancer cells. Notably, cells with downregulated hLig I (via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.

Keywords

Bliss synergy score; Synergistic effect; Topo 1; Topotecan; colorectal cancer; compound 27; drug resistance; hLig I.

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