ArticlePloS one2015
NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage, Senescence and Apoptosis in Colorectal Cancer Cells.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- Noncompetitive Inhibition of DNA Polymerase β by a Nonnative Nucleotide.The Journal of organic chemistry · 2025Review
- Review
- Correlation of senescence-related gene FEN1 on neuroblastoma progression and cisplatin chemotherapy sensitivity.Oncology research · 2025Article
- Cellular senescence in colorectal cancer: its occurrence, effect and therapy.Frontiers in oncology · 2025Review
- Impact of DNA ligase inhibition on the nick sealing of polβ nucleotide insertion products at the downstream steps of base excision repair pathway.Mutagenesis · 2024Article
- Molecular editing ofRSC medicinal chemistry · 2024Article
- Impact and potential value of immunosenescence on solid gastrointestinal tumors.Frontiers in immunology · 2024Review
- TATDN2 resolution of R-loops is required for survival of BRCA1-mutant cancer cells.Nucleic acids research · 2023Article
- Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.International journal of molecular sciences · 2023Review
- EEPD1 promotes repair of oxidatively-stressed replication forks.NAR cancer · 2023Article
- In Vitro Reconstitutive Base Excision Repair (BER) Assay.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Base excision repair accessory factors in senescence avoidance and resistance to treatments.Cancer drug resistance (Alhambra, Calif.) · 2022Review
- Suppression of DNA Polymerase β Activity Is Synthetically Lethal in BRCA1-Deficient Cells.ACS chemical biology · 2021Article
- Protein Domain Specific Covalent Inhibition of Human DNA Polymerase β.Chembiochem : a European journal of chemical biology · 2021Article
- Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.RSC chemical biology · 2021Review
- Selective Inhibition of DNA Polymerase β by a Covalent Inhibitor.Journal of the American Chemical Society · 2021Article
- Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers.Oncogene · 2021Article
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach.International journal of molecular sciences · 2020Review
- Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies.Oncotarget · 2018Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.