An active intermediate formed in the reaction of bleomycin-Fe(II) complex with oxygen.

Kojima, Hiroshi; Takahashi, K.; Takita, Tomohisa; Umezawa, Hamao

doi:10.7164/antibiotics.34.576

Cited by 126 publications

(77 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experiments in animals also showed that exposure to air having an elevated concentration of oxygen increased the development of BLM-induced fibrosis (25), while hypoxia decreased it (26). In addition, it is reported (27) that the cytotoxicity of BLM is due to DNA breakage caused by the generation of superoxide free radicals in the presence of iron (II). As we have reported (8), however, tranilast does not suppress the tumorcidal activity of BLM in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 99%

Suppressive Effects of Tranilast on Pulmonary Fibrosis and Activation of Alveolar Macrophages in Mice Treated with Bleomycin: Role of Alveolar Macrophages in the Fibrosis

Mori

Tanaka

Kawada

et al. 1995

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

ABSTRACT-We have reported that tranilast, an anti-allergic drug that inhibits chemical mediator release from mast cells, suppresses bleomycin (BLM)-induced pulmonary fibrosis in mice through mechanisms other than inhibiting chemical mediator release from mast cells. The purpose of this paper is to examine the effect of tranilast on alveolar macrophage (AM) activation and on the development of fibrosis in ICR mice instilled with BLM intratracheally. Twenty eight days after the BLM instillation (0.01 mg/mouse), AM often migrated into alveolar spaces surrounding the fibrotic areas. Flow cytometry analysis for the size and density of AM (MAC-1 positive cells) suggested that AM were activated not only in the earlier acute inflammatory phase, but also in the later chronic phase. The p.o. administration of tranilast suppressed an increase of AM activity to produce reactive oxygen species in BLM-instilled mice, and it inhibited the subsequent development of pulmonary fibrosis. In vitro treatment with tranilast suppressed the reactive oxygen species production from murine peritoneal macrophages. However, several different anti-oxidants failed to inhibit the development of fibrosis. These results suggest that the activation of AM plays an important role in the development of fibrosis, and it is likely that tranilast suppresses fibrosis by inhibiting AM activation but not by scavenging reactive oxygen species.

show abstract

Section: Discussionmentioning

confidence: 99%

Suppressive Effects of Tranilast on Pulmonary Fibrosis and Activation of Alveolar Macrophages in Mice Treated with Bleomycin: Role of Alveolar Macrophages in the Fibrosis

Mori

Tanaka

Kawada

et al. 1995

Japanese Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

“…A possible question is whether this situation could also occur for the antitumour antibiotics which bear a quinone-type moiety [l, 3,4,8,91. In order to answer this question, we performed quantum-mechanical computations (Materials and Methods) using two models displayed in Fig.…”

Section: S-mentioning

confidence: 99%

“…Some provoke strand breakage of DNA as one aspect of their mechanism of action. These include bleomycin [3,41, streptonigrin [5], mitomycin C [6], neocarzinostatin [7] and the anthracyclines [S, 91. Although there are several differcnces in structure and the exact mechanism of action, all appear to form radical species.…”

mentioning

confidence: 99%

Experimental and modelling studies on the DNA cleavage by elsamicin A

Parraga¹,

Orozco²,

Portugal³

1992

European Journal of Biochemistry

View full text Add to dashboard Cite

The ability of elsamicin A, an antitumour antibiotic, to cleave DNA in the presence of ferrous iron and reducing agents, has been analysed using experimental and theoretical approaches. Experimentally, the antibiotic causes DNA breakage in the presence of ferrous ions and a reducing agent. The DNA-cleaving activity appears to be partially blocked by the action of superoxide dismutase and catalase. These results indicate that the elsamicin aglycone moiety (chartarin) can be involved in the production of free radicals. We have performed a broad theoretical study based in the quantummechanical framework, which allow us to determine the redox properties of elsamicin that lead to the generation of radical species. Our results clearly show that elsamicin acts as a true catalyst in the production of superoxide radicals. Moreover, it is suggested that the oxidation/reduction mechanism of the aglycone moiety of elsamicin (a lactone), leading to DNA breakage, is different from the mechanism followed by other well-known anti-cancer drugs, whose chromophore is a quinone. [12]. Fig. 1 shows the chemical structure of chartreusin. At first glance, this molecule resembles the anthracycline group of antibiotics: it also contains a chromophore and a sugar moiety. However, different from anthracyclines, the chromophore moiety (chartarin) is not a quinone, but contains a 5,12-dione portion, and bears a peculiar disaccharide bound to position 10 (Fig. 1). Since reduction and auto-oxidation occur in the quinone moiety of anthracyclines [S], it has been proposed that the 5,12-dione portion of chartreusin might be involved in the formation of free radicals [12]. Due to several drawbacks, chartreusin was not selected as an antitumour drug for clinical trials [13], and, until recently, there were no reports of chartreusin derivatives with improved activity [13, 141. Among them, the related antibiotic elsamicin A (Fig. 1) has been isolated from natural sources [13]. Elsamicin A is structurally related to chartreusin, but contains an amino sugar which makes it more water soluble than chartreusin, since at physiological pH this amino group will be positively charged. Elsamicin is about 30 times more potent than Correspondence to J.

show abstract

“…ABLM is proposed to be a low spin (ls) Fe III ─OOH species (9)(10)(11), that can be formed via the reaction of Fe III BLM with O 2 and an electron or through a shunt reaction between Fe III BLM and H 2 O 2 (8,12).…”

mentioning

confidence: 99%

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Liu

Bell

Wong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bleomycin (BLM) is a glycopeptide anticancer drug capable of effecting single-and double-strand DNA cleavage. The last detectable intermediate prior to DNA cleavage is a low spin Fe III peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4′ hydrogen atom of the deoxyribose sugar unit. Nuclear resonance vibrational spectroscopy (NRVS) aided by extended X-ray absorption fine structure spectroscopy and density functional theory (DFT) calculations are applied to define the natures of Fe III BLM and ABLM as ðBLMÞFe III ─ OH and ðBLMÞFe III ðη 1 ─OOHÞ species, respectively. The NRVS spectra of Fe III BLM and ABLM are strikingly different because in ABLM the δFe─O─O bending mode mixes with, and energetically splits, the doubly degenerate, intense O─Fe─N ax transaxial bends. DFT calculations of the reaction of ABLM with DNA, based on the species defined by the NRVS data, show that the direct H-atom abstraction by ABLM is thermodynamically favored over other proposed reaction pathways.nonheme iron | structure/reactivity T he glycopeptide antibiotic bleomycin (BLM) exhibits high intrinsic anticancer cytotoxicity, and is used in chemotherapy against head, neck, and testicular cancers as well as Hodgkin lymphoma (1, 2). Its cytotoxicity is due to its ability to effect singleand double-strand cleavage of DNA with a number of reduced metal ions and dioxygen (3-5); Fe II displays the highest in vivo activity (6). BLM provides five nitrogen-based ligands ( Fig. 1 A and B) for coordination to the metal ion based on a crystal structure of peroxy Co III BLM (7). The four equatorial ligands are an imidazole nitrogen, a deprotonated amide, a pyrimidine nitrogen, and the secondary amine of the β-aminoalanine. The axial ligand is the primary amine of the β-aminoalanine.Activated BLM (ABLM) is the final intermediate detected before DNA double-strand scission (8). ABLM is proposed to be a low spin (ls) Fe III ─OOH species (9-11), that can be formed via the reaction of Fe III BLM with O 2 and an electron or through a shunt reaction between Fe III BLM and H 2 O 2 (8, 12).A prominent issue has been whether ABLM, a nonheme iron complex, performs heme type chemistry similar to P450 and peroxidase in which heterolytic cleavage of the O─O bond results in an Fe IV species with a radical on the BLM ligand. Experiments and calculations have argued against this heterolytic mechanism and suggested a mechanism where ABLM reacts directly in H-atom abstraction from the DNA backbone sugar (10,13,14). However, a recent theoretical study has postulated that ABLM formation involves reaction of the ðBLMÞFe III ─OH 2 complex with H 2 O 2 to form a ðBLMÞFe III ─O 2 H 2 complex (15). This study found the heterolytic cleavage pathway for the ðBLMÞFe III ─ H 2 O 2 complex to be thermoneutral and therefore feasible. Because ABLM is inaccessible to vibrational characterization by resonance Raman (rR) spectroscopy due to photodecay (16), we employed nuclear resonance vibrational spectroscopy (...

show abstract

An active intermediate formed in the reaction of bleomycin-Fe(II) complex with oxygen.

Cited by 126 publications

References 18 publications

Suppressive Effects of Tranilast on Pulmonary Fibrosis and Activation of Alveolar Macrophages in Mice Treated with Bleomycin: Role of Alveolar Macrophages in the Fibrosis

Suppressive Effects of Tranilast on Pulmonary Fibrosis and Activation of Alveolar Macrophages in Mice Treated with Bleomycin: Role of Alveolar Macrophages in the Fibrosis

Experimental and modelling studies on the DNA cleavage by elsamicin A

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Contact Info

Product

Resources

About