Academic Journal
Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer
| العنوان: | Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer |
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| المؤلفون: | Pooja Maurya, Rohit Singh Rawat, Sampa Gupta, Shagun Krishna, Mohammad Imran Siddiqi, Koneni V. Sashidhara, Dibyendu Banerjee |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Biochemistry, Medicine, Cell Biology, Molecular Biology, Pharmacology, Biotechnology, Developmental Biology, Cancer, Hematology, Virology, Chemical Sciences not elsewhere classified, Topo 1, hLig I, Topotecan, compound 27, drug resistance, Synergistic effect, colorectal cancer, Bliss synergy score |
| الوصف: | 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 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Synergy_between_human_DNA_ligase_I_and_topoisomerase_1_unveils_new_therapeutic_strategy_for_the_management_of_colorectal_cancer/24948642 |
| DOI: | 10.6084/m9.figshare.24948642.v1 |
| الاتاحة: | https://doi.org/10.6084/m9.figshare.24948642.v1 https://figshare.com/articles/journal_contribution/Synergy_between_human_DNA_ligase_I_and_topoisomerase_1_unveils_new_therapeutic_strategy_for_the_management_of_colorectal_cancer/24948642 |
| Rights: | CC BY 4.0 |
| رقم الانضمام: | edsbas.E55E8289 |
| قاعدة البيانات: | BASE |
| DOI: | 10.6084/m9.figshare.24948642.v1 |
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