Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 85, Issue -, Pages 56-65Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2017.02.001
Keywords
Anti-tumour agent; Bleomycin analogue; Chromatin structure; DNA cleavage; Next-generation sequencing; Zorbamycin
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Funding
- University of New South Wales, Science Faculty Research Grant Scheme
- Australian Postgraduate Award
- NIH [CA094426]
- Natural Products Library Initiative at The Scripps Research Institute
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Bleomycin (BLM) is a cancer chemotherapeutic agent that is used in the treatment of several types of tumours. The cytotoxicity of three BLM analogues, BLM Z, 6'-deoxy-BLM Z and zorbamycin (ZBM), was determined in human HeLa cells in comparison with BLM. It was found that the IC50 values were 2.9,mu M for 6'-deoxy-BLM Z, 3.2,mu M for BLM Z, 4.4,mu M for BLM and 7.911,mu M for ZBM in HeLa cells. Using next generation Illumina DNA sequencing techniques, the genome-wide cleavage of DNA by the BLM analogues was determined in human HeLa cells and compared with BLM. It was ascertained that BLM, 6'-deoxy-BLM Z and ZBM preferentially cleaved at the transcription start sites of actively transcribed genes in human cells. The degree of preferential cleavage at the transcription start sites was quantified and an inverse correlation with the IC50 values was observed. This indicated that the degree of preferential cleavage at transcription start sites is an important component in determining the cytotoxicity of BLM analogues. (C) 2017 Elsevier Ltd. All rights reserved.
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