Approved by FDA in 1973, bleomycin– an kind of antibiotic produced by the bacterium, Streptomyces verticillus — has been employed for clinical treatment, especially for Hodgkin’s lymphoma, squamous cell carcinomas, and testicular cancer. However, its anti-cancer mechanism remain poorly known.
In a new research, investigators depict bleomycin’s property to cut through double-stranded DNA in cancerous cells, like a pair of scissors. Such DNA cleavage always cause some types of cancer to death. The study, lead by Basab Roy, firstly present alternative biochemical mechanisms for DNA cleavage by bleomycin.
Specifically bind DNA regions
Scientists keep on studying several forms of bleomycin and developing a scaled library of variants, with the purpose of designing the best bleomycin analog. Their interests focus on the subtle biochemistry of bleomycin, including the specificity of its binding sites along the DNA strand and the drug ‘s detailed mechanisms of DNA cleavage.
Beomycin A5 in the new study has similar DNA binding and cleaving properties, as well as bleomycin A2 and B2. Previous research has revealed that bleomycin binds with highly specific regions of the DNA strand, typically G-C sites, where a guanosine base pairs with a cytidine. Further, the strength of this binding is closely associated with the degree of double-strand DNA cleavage.
Cut cancer to pieces
As one of attractive feature, Bleomycin can be administered in relatively low doses in the treatment of some many other cancer. Previous research has shown that bleomycin can cause death in aberrant cells by migrating to the cell nucleus, binding with DNA and subsequently causing breaks in the DNA sequence.
Cleavage of DNA is regarded as a major mechanism by which bleomycin kills cancer cells, particularly through double-strand cleavages. It pose a great challenging for the cellular machine to repair. “There are several mechanisms for repairing both single-strand and double-strand breaks in DNA, but double-strand breaks are a more potent form of DNA lesion,” Roy says.
There is a great deal of work required to elucidate the biochemical causes of tight binding by bleomycin. The future discovery on drug-DNA binding aspect will guide improvement of the drug in property and alleviation of toxicity to healthy cells.
References:
1. Hairpin DNA Sequences Bound Strongly by Bleomycin Exhibit Enhanced Double-Strand Cleavage. Journal of the American Chemical Society, 2014; 136 (11): 4382
2. Targeting DNA damage and repair: Embracing the pharmacological era for successful cancer therapy. Pharmacol Ther. 2012 Mar;133(3):334-50.