A novel class of chemicals that react with abasic sites in DNA and specifically kill B cell cancers

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 hi...

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Bibliographic Details
Published in:PloS one 2017-09, Vol.12 (9), p.e0185010-e0185010
Main Authors: Wei, Shanqiao, Perera, Madusha L W, Sakhtemani, Ramin, Bhagwat, Ashok S
Format: Article
Language:English
Subjects:
Alcohol
Alkynes
Amines - chemistry
Amines - pharmacology
Antineoplastic Agents - pharmacology
B-cell lymphoma
B-Lymphocytes - cytology
B-Lymphocytes - drug effects
B-Lymphocytes - metabolism
Biology and Life Sciences
Blood & organ donations
Breast cancer
Cancer
Cell activation
Cell Cycle Checkpoints - drug effects
Cell Survival - drug effects
Cells, Cultured
Chemicals
Chemistry
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - metabolism
DNA Breaks, Double-Stranded - drug effects
DNA repair
DNA Repair - drug effects
DNA-(Apurinic or Apyrimidinic Site) Lyase - antagonists & inhibitors
DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism
Enzymes
Gene expression
Genomes
HEK293 Cells
HeLa Cells
Humans
Immunoglobulins
Lymphocytes B
Lymphoma
Lymphoma, B-Cell - metabolism
Lymphoma, B-Cell - pathology
Mammals
MCF-7 Cells
Medical research
Medicine and Health Sciences
Mutation
Pharmaceutical sciences
Physical Sciences
Prototypes
Repair
Research and Analysis Methods
S phase
Stem cells
Toxicity
Tumors
Uracil
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0185010