A novel class of chemicals that react with abasic sites in DNA and specifically kill B cell cancers
| Autor: | Ashok S. Bhagwat, Ramin Sakhtemani, Shanqiao Wei, Madusha L. W. Perera |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
B Cells DNA Repair Cell Lines Cultured tumor cells lcsh:Medicine Toxicology Pathology and Laboratory Medicine Biochemistry White Blood Cells chemistry.chemical_compound 0302 clinical medicine Animal Cells DNA-(Apurinic or Apyrimidinic Site) Lyase Medicine and Health Sciences DNA Breaks Double-Stranded Amines lcsh:Science Cytotoxicity Cells Cultured chemistry.chemical_classification B-Lymphocytes Multidisciplinary Nucleotides 3. Good health Chemistry medicine.anatomical_structure Alkynes 030220 oncology & carcinogenesis Physical Sciences MCF-7 Cells Biological Cultures Cellular Types Raji Cells Research Article Azides Lymphoma B-Cell Cell Survival DNA repair Immune Cells Immunology Antineoplastic Agents Daudi Cells Biology Research and Analysis Methods 03 medical and health sciences medicine Humans Uracils HeLa cells Antibody-Producing Cells B cell Blood Cells Nucleobases Toxicity lcsh:R HEK 293 cells Chemical Compounds Biology and Life Sciences Uracil Cell Cycle Checkpoints DNA Cell Biology Cell cultures Hydrocarbons HEK293 Cells 030104 developmental biology Enzyme chemistry Cancer cell lcsh:Q |
| Zdroj: | PLoS ONE, Vol 12, Iss 9, p e0185010 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Most B cell cancers overexpress the enzyme activation-induced deaminase at high levels and this enzyme converts cytosines in DNA to uracil. The constitutive expression of this enzyme in these cells greatly increases the uracil content of their genomes. We show here that these genomes also contain high levels of abasic sites presumably created during the repair of uracils through base-excision repair. We further show that three alkoxyamines with an alkyne functional group covalently link to abasic sites in DNA and kill immortalized cell lines created from B cell lymphomas, but not other cancers. They also do not kill normal B cells. Treatment of cancer cells with one of these chemicals causes strand breaks, and the sensitivity of the cells to this chemical depends on the ability of the cells to go through the S phase. However, other alkoxyamines that also link to abasic sites- but lack the alkyne functionality- do not kill cells from B cell lymphomas. This shows that the ability of alkoxyamines to covalently link to abasic sites is insufficient for their cytotoxicity and that the alkyne functionality may play a role in it. These chemicals violate the commonly accepted bioorthogonality of alkynes and are attractive prototypes for anti-B cell cancer agents. |
| Databáze: | OpenAIRE |
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