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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Bleomycin molecules have three distinct regions that are thought to contribute toward their mechanism of action. First, the heterocyclic thiazole rings (i.e., the DNA-binding domain, see Figure 5.56) are thought to intercalate (or “thread”) through DNA base pairs, with the charged terminal sulphonium or guanidinium groups of A2 and B2, respectively, interacting electrostatically with negatively charged backbone phosphates on the other side of the helix to form stable adducts. The sugar groups of the carbohydrate domain (bottom left in Figure 5.56) are thought to interact with functional groups within the DNA minor groove or with histone proteins leading to further stabilization of the adduct. It is also thought that the sugar moieties may contribute to uptake by tumor cells. Once bound to DNA, the metal-binding domain (top left in Figure 5.56), which consists of a β-hydroxyhistidine, a β-aminoalanine, and a pyrimidine, forms an iron (II) complex that interacts with oxygen to generate free radicals, leading to single- and double-strand DNA breaks. It follows that DNA cleavage by bleomycin should depend on the concentration of oxygen and metal ions, and this has been demonstrated in in vitro experiments. For these reasons, bleomycin has been referred to as a “pseudoenzyme” that reacts with oxygen to produce superoxide and hydroxide free radicals that cleave DNA.
Atractylenolide III attenuates bleomycin-induced experimental pulmonary fibrosis and oxidative stress in rat model via Nrf2/NQO1/HO-1 pathway activation
Published in Immunopharmacology and Immunotoxicology, 2020
BLM is a widely used inducer for the formation of animal models of PF [1]. BLM works by chelating with metal ions to form pseudoenzymes, which react with oxygen to produce superoxide and hydroxyl radicals, which in turn lead to the breaking of DNA strands in cells [20,30]. Elevated levels of free radicals can lead to overproduction of reactive oxygen species (ROS), which can lead to inflammatory responses, pulmonary toxicity, fibroblast activation, and subsequent fibrosis [31,32]. BLM hydrolase is a BLM inactivation enzyme, and the level of this enzyme in the lung is low, so it is more susceptible to BLM-induced IPF [33,34]. In the present investigation, fibrosis lesions appeared after BLM administration, and minute ventilation, airway resistance and lung volume decreased. However, AtrIII significantly improved the lung function status in the BLM-induced rats described above in a dose-related manner.
Current models of pulmonary fibrosis for future drug discovery efforts
Published in Expert Opinion on Drug Discovery, 2020
Toyoshi Yanagihara, Sy Giin Chong, Megan Vierhout, Jeremy A. Hirota, Kjetil Ask, Martin Kolb
Bleomycin is a commonly used agent to induce pulmonary fibrosis in animals [7]. Bleomycin, originally isolated from Streptomyces verticillatus, is a chemotherapeutic antibiotic which is used in the treatment of various cancers and is known to cause acute lung injury and fibrosis in humans as a side effect [11]. Bleomycin induces pulmonary fibrosis by breaking single and double-strand DNA in actively dividing cells and thereby interrupts the cell cycle by chelation of metal ions and the reaction of the formed pseudoenzyme with oxygen [12]. This leads to the production of DNA-cleaving superoxide and hydroxide free radicals [12]. The lungs maintain low levels of bleomycin hydrolase, a bleomycin-inactivating enzyme, which makes the lungs more susceptible to bleomycin-induced tissue injury [13].
Dioscin attenuates Bleomycin-Induced acute lung injury via inhibiting the inflammatory response in mice
Published in Experimental Lung Research, 2019
In general, oxidative stress in lung tissues often occurs in ALI and plays a critical role in the pathogenesis of BLM-induced ALI(33). BLM can promote the reaction of formed pseudoenzymes with oxygen, which produces ROS and leads to the inflammatory response.5 MDA is one of the most frequently used markers of oxidative stress. In this work, oxidative stress was evaluated by detecting the MDA level of lung homogenates. Dioscin significantly inhibited BLM-induced MDA production, which suggests that it exhibits anti-oxidative effects on BLM-induced ALI. Qiao et al. also reported that dioscin markedly reduces oxidative stress by adjusting levels of MDA, SOD, and GSH-Px and decreasing ROS production to protect against fructose-induced renal damage.31 Dioscin treatment reduces mitochondrial ROS to relieve oxidative stress and decreases the secretion of inflammatory factors and chemokines (IL-1β, IL-6, and MCP-1) in alveolar macrophages.38