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

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:

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

Acknowledgment

The authors express gratitude to the Sophisticated Analytical Instrument Facility (SAIF) at CDRI for their assistance in cell-based flow cytometry experiments. We further acknowledge Dr. Shahid Parwez (Biochemistry and Structural Biology Division, CSIR-CDRI) for his assistance in molecular docking studies. PM acknowledges financial support from DBT, New Delhi. RSR is thankful for research fellowship support from UGC, New Delhi. RSR also acknowledges Jawaharlal Nehru University, New Delhi. SG expresses gratitude to CSIR, and SK acknowledges support from ICMR.

The authors extend their deep appreciation to CSIR-CDRI, Government of India, for both financial and infrastructural support through project MLP0019, as well as CSIR-Pan-Cancer Grant HCP0040. Additionally, they acknowledge financial support from the Department of Science and Technology (DST-SERB), Government of India (Grant-EMR/2017/002080). Further, DBT-Grant GAP0384 (BT/PR40131/BTIS/137/26/2021) is gratefully acknowledged for computational studies. This manuscript is assigned the CSIR-CDRI manuscript number 10717.

Disclosure statement

The authors declare no competing interests that are financial or personal in nature.

Ethical approval

This declaration is ‘not applicable’.

Authors’ contributions

PM: Conducted experiments, analyzed data, validated results, and contributed to manuscript writing.

RSR: Conducted experiments, acquired data, analyzed findings, and contributed to manuscript writing.

SG: Synthesized compounds for the study.

SK: Conducted in silico analysis and docking studies.

MIS: Conceptualized the study, provided supervision, reviewed the manuscript, and allocated resources.

KVS: Conceptualized the study, synthesized compounds, provided supervision, and allocated resources.

DB: Conceptualized the study, provided supervision, wrote and reviewed the manuscript, secured funding and allocated resources.

All authors read and approved final manuscript.

Availability of data and materials

Any requirement/s for the datasets can be accessed from the corresponding author upon request.

Additional information

Funding

The authors acknowledge CSIR-CDRI, Government of India, for financial and infrastructural support through projects CSIR-Pan-Cancer Grant HCP0040 and MLP0019. Financial support is also acknowledged by the Department of Science and Technology (DST-SERB), Government of India (Grant-EMR/2017/002080).