Abstract
The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the interaction of bleomycin with DNA. A Fe(II)-bleomycin complex is capable of DNA cleavage and this process is thought to be the major determinant for the cytotoxicity of bleomycin. The DNA sequence specificity of bleomycin cleavage is found to at 5′-GT* and 5′-GC* dinucleotides (where * indicates the cleaved nucleotide). Using next-generation DNA sequencing, over 200 million double-strand breaks were analysed, and an expanded bleomycin sequence specificity was found to be 5′-RTGT*AY (where R is G or A and Y is T or C) in cellular DNA and 5′-TGT*AT in purified DNA. The different environment of cellular DNA compared to purified DNA was proposed to be responsible for the difference. A number of bleomycin analogues have been examined and their interaction with DNA is also discussed. In particular, the production of bleomycin analogues via genetic manipulation of the modular non-ribosomal peptide synthetases and polyketide synthases in the bleomycin gene cluster is reviewed. The prospects for the synthesis of bleomycin analogues with increased effectiveness as cancer chemotherapeutic agents is also explored.
Highlights
The bleomycins (Figure 1) are a group of structurally related metallo-glycopeptide antibiotics discovered by Umezama and colleagues [1] and are clinically used as cancer chemotherapeutic agents
The cellular environment contains many different chemical constituents and the cation bound to bleomycin can vary inside cells where not all of the Cu(I)- or Cu(II)-bleomycin may be exchanged with Fe(II); whereas in the purified experiment, the metal cation bound to bleomycin can be completely controlled
In our genome-wide experiments with bleomycin in HeLa cells, we examined the repair of 3 -phosphoglycolate termini at gene transcription start sites (TSSs) [100]
Summary
The bleomycins (Figure 1) are a group of structurally related metallo-glycopeptide antibiotics discovered by Umezama and colleagues [1] and are clinically used as cancer chemotherapeutic agents. Studies by the Hecht group have highlighted the role of the disaccharide moiety in the selectivity and uptake of bleomycin by tumour cells [31]. The 3-O-carbamoyl-D-mannose moiety appears to be crucial for this function [35,36] This is consistent with related work that provided evidence that this sugar region is involved in tumour cell uptake via glucose transport. Systematic modifications to the substituents of these subunits revealed their importance for the efficiency of bleomycin-mediated DNA cleavage [29,38,39,40]. Analogues methylated at the valerate-threonine amide were reported to have diminished sequence specificity [41] These studies suggest the importance of the linker in inducing an optimal conformation of bleomycin with respect to DNA binding. The X-ray crystal structure revealed that the valerate was hydrogen bonded to the minor groove of DNA [20]
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