Bleomycin analogues preferentially cleave at the transcription start sites of actively transcribed genes in human cells.
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 IC50values were 2.9μM for 6'-deoxy-BLM Z, 3.2μM for BLM Z, 4.4μM for BLM and 7.9μM 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 IC50values 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.
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
Jon K
JK
Chen
Department of Chemistry, Department of Molecular Therapeutics, and Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA.
Dong
D
Yang
Department of Chemistry, Department of Molecular Therapeutics, and Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, Jupiter, FL 33458, USA.
Ben
B
Shen
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia. Electronic address: v.murray@unsw.edu.au.
Vincent
V
Murray
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D024363:Transcription Initiation Site / Q000502:physiology*
D000970:Antineoplastic Agents; D001761:Bleomycin
Anti-tumour agent; Bleomycin analogue; Chromatin structure; DNA cleavage; Next-generation sequencing; Zorbamycin