Activity of bleomycin in iron- and copper-deficient cells

Lyman, Suzanne; Taylor, Pamela; Lornitzo, Frank A.; Wier, Alan; Stone, David L.; Antholine, William E.; Petering, David H.

doi:10.1016/0006-2952(89)90526-1

Cited by 11 publications

(10 citation statements)

References 20 publications

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“…Bleomycin binds iron and oxygen thus forming an activated complex capable of releasing damaging oxidants in close proximity to DNA (El‐Medany et al ., 2005). However, some investigators observed that bleomycin was equally effective in normal and iron‐deprived mice (Lyman et al ., 1989). In another study, O ‐phenanthroline, a metal ion chelator, fully inhibited bleomycin‐induced DNA cleavage (Larramendy et al ., 1989).…”

Section: Introductionmentioning

confidence: 99%

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Kaiserová

Hartog

Šimůnek

et al. 2006

British J Pharmacology

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Background and purpose: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stressmediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. Experimental approach: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H 2 O 2 ) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay.Key results: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H 2 O 2 /Fe 2 þ in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H 2 O 2 /Fe 2 þ . Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H 2 O 2 /Fe 2 þ . Conclusions and implications:We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

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Section: Introductionmentioning

confidence: 99%

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Kaiserová

Hartog

Šimůnek

et al. 2006

British J Pharmacology

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“…HL-60 cells grown in iron-depleted medium displayed a decrease in bleomycin-mediated growth inhibition and DNA damage [38]. The Fe 2+ chelator 1,10-phenanthroline had no effect on Ehrlich cell growth [32]. However, several other reports have indicated that the 1,10-phenanthroline does affect the cell growth inhibitory or DNA damaging properties of bleomycin [33][34][35].…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies in cell systems employing either chelating agents or iron-deficient growth media to deplete iron are mixed in their conclusions regarding the requirement for iron in bleomycin growth inhibitory activity [32][33][34][35][36][37]. HL-60 cells grown in iron-depleted medium displayed a decrease in bleomycin-mediated growth inhibition and DNA damage [38].…”

Section: Discussionmentioning

confidence: 98%

The iron chelating cardioprotective prodrug dexrazoxane does not affect the cell growth inhibitory effects of bleomycin

Patel

Hasinoff

2004

Journal of Inorganic Biochemistry

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“…Iron-, copper-and metal-free bleomycin were each active generated, which are highly reactive species and can, for example, against the Ehrlich ascites tumour in mice [26]; Blm remained abstract hydrogen atoms indiscriminately from organic com-active against this tumour in iron-and copper-deficient mice pounds in their vicinity [3][4][5]. Hydroxyl radicals can be produced [16]; metal-restricted incubation conditions did not affect the by the Fenton reaction, in which a reduced transition metal ion cytotoxic activity of Blm or its Fe or Cu complexes in vitro, or complex (Mn+) delivers an electron to H202: though short-term co-incubation of cells with a toxic level of 1,10-phenanthroline did decrease Blm-induced DNA damage H202 + Mn+ *-+ 'OH + OH-+ M(f+')+…”

Section: Introductionmentioning

confidence: 99%

“…activities of H202, 1, 10-phenanthroline or other metal-binding ligands have also been utilized to compete for cellular metals, EXPERIMENTAL particularly iron, thereby reducing their availability to participate Mateial in the Fenton reaction [14,15]. Although 1,10-phenanthroline aeras has been effective in inhibiting the cytotoxicity of H202, its 1,10-Phenanthroline was purchased from Aldrich Chemical Co., potential for multiple interactions with cells complicates its use Milwaukee, WI, U.S.A. Pyridoxal hydrochloride, isonicotinic [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Iron requirement for cellular DNA damage and growth inhibition by hydrogen peroxide and bleomycin

Radtke

Lornitzo

Byrnes

et al. 1994

Biochemical Journal

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Studies with Euglena gracilis and HL-60 cells have assessed the need for intracellular iron in the mechanisms of inhibition of cell growth and DNA damage by H2O2 and bleomycin. Cell culture media were directly depleted of iron in order to deprive cells of nutrient iron. Major pools of cellular iron were reduced in both cell types. Nevertheless, iron bound in e.s.r.-observable haem protein and ribonucleotide diphosphate reductase in HL-60 cells was not decreased. In both control cell populations, there was a concentration-dependent reduction in proliferation and cell survival caused by H2O2. In comparison, the proliferation rates of both iron-deficient cell types were significantly less sensitive to H2O2. H2O2 caused concentration-dependent single-strand breakage in DNA in control HL-60 and Euglena gracilis cells. Iron deficiency reduced the amount of strand breaks in HL-60 cells at each concentration of H2O2 used. Single-strand breakage caused by H2O2 in Euglena gracilis was a direct function of the concentration of iron in which the cells had been grown. Growth inhibition and both single- and double-strand DNA damage caused by bleomycin were substantially reduced or eliminated in iron-deficient cells. Copper bleomycin behaved like metal-free bleomycin when assayed for the capacity to cause DNA damage in iron-normal and iron-deficient HL-60 cells. In contrast, iron bleomycin was equally active under the two conditions in these cells.

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Activity of bleomycin in iron- and copper-deficient cells

Cited by 11 publications

References 20 publications

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

The iron chelating cardioprotective prodrug dexrazoxane does not affect the cell growth inhibitory effects of bleomycin

Iron requirement for cellular DNA damage and growth inhibition by hydrogen peroxide and bleomycin

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