The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

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.

Antibiotics for cancer treatment: A double-edged sword

“…When mitomycin bind to DNA, most of them only act on one strand, and some of them form a cross-link to block the disassembly of DNA double strand, thus destroying the stable double helix conformation of DNA to some extent [15,16]. Bleomycin was the first glycopeptide antibiotic isolated from Streptomyces rotundus by metzibinoff of the Japanese institute of microbiology and chemistry [17]. It can effectively inhibit the synthesis of DNA, causing the break of single and double strands of DNA [17].…”

“…Bleomycin was the first glycopeptide antibiotic isolated from Streptomyces rotundus by metzibinoff of the Japanese institute of microbiology and chemistry [17]. It can effectively inhibit the synthesis of DNA, causing the break of single and double strands of DNA [17]. Actinomycin is a class of antibiotics containing cyclic peptides, which can be embedded in the groove of the DNA double helix to form a complex with DNA, thereby inhibiting the function of RNA polymerase and ultimately inhibiting RNA synthesis [18].…”

Screening of an FDA-Approved Library for Novel Drugs against Y. pestis

“…Bleomycin is a radiomimetic compound which forms complexes with iron that reduce molecular oxygen to superoxide and hydroxyl radicals inflicting DNA damage (single and double-strand breaks) that results in preferential inhibition of DNA synthesis in cancer cells [ 14 , 15 ]. This compound is used to treat hematologic (Hodgkin’s and non-Hodgkin’s lymphomas) as well as solid malignancies (testicular, ovarian and cervical cancers).…”

A Novel Method for Controlled Gene Expression via Combined Bleomycin and Plasmid DNA Electrotransfer

“…Because the plasmid DNA needs to reach the nucleus of the cell for the transfection to happen [41,42], it could also facilitate the nuclear entry of this fraction of bleomycin molecules. Because single bleomycin molecule can cleave the DNA ~10 times [43,44,45], the bleomycin molecules that enter the cell while bound to plasmid DNA could still be re-activated and cleave the DNA inside the cell. Alternatively, it is possible that the presence of DNA-membrane complexes changes the local properties around the pore area, facilitating the small molecule transfer into the cells.…”