Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents
| Autor: | Seol Kim, Jung Suk Choi, Edward A. Motea, Anthony J. Berdis |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
DNA Replication
0301 basic medicine DNA polymerase DNA damage Antineoplastic Agents DNA-Directed DNA Polymerase Precursor T-Cell Lymphoblastic Leukemia-Lymphoma chemotherapy 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor medicine Humans Nucleotide nucleoside analogs Genetics chemistry.chemical_classification DNA polymerization biology Nucleoside analogue DNA synthesis business.industry leukemia DNA Neoplasm humanities genomic DNA 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm biology.protein Cancer research business Nucleoside DNA Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.17254 |
| Popis: | // Jung-Suk Choi 1 , Seol Kim 2 , Edward Motea 3 and Anthony Berdis 1, 2, 4, 5 1 Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA 2 Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA 3 Departments of Radiation Oncology and Pharmacology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA 4 Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA 5 Case Comprehensive Cancer Center, Cleveland, OH 44106, USA Correspondence to: Anthony Berdis, email: a.berdis@csuohio.edu Keywords: DNA damage, DNA polymerization, chemotherapy, nucleoside analogs, leukemia Received: February 24, 2017 Accepted: April 11, 2017 Published: April 19, 2017 ABSTRACT Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anti-cancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine. |
| Databáze: | OpenAIRE |
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