Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-018-1069-9
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Funding
- National Research Council Industrial Research Assistance Program [IT06135]
- Mitacs [F15-03171]
- DelMar Pharmaceuticals, Inc. [F14-03316]
- Vancouver Prostate Centre
- National Research Council Industrial Research Assistance Program
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1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N-7-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N-7-guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replicationdependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell cycle arrest and loss of viability. DAG-treated NSCLC cells attempt to repair the DSBs by homologous recombination (HR) and inhibition of the HR repair pathway sensitized NSCLC cells to DAG-induced DNA damage. Accordingly, our work describes a molecular mechanism behind N-7-guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.
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