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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0185010

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.