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

Abstract

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.

Oxidative stress does not play a primary role in the toxicity induced with clinical doses of doxorubicin in myocardial H9c2 cells

“…6 e). DXR alone led to a slight increase in ROS production that corroborates previous findings reporting its weak prooxidant property [ 54 ]. Importantly, although DXR attenuated cell death, it failed to modify the ROS production pattern resulting from DOX treatments in both detached and adherent cells (Fig.…”

Protection by flavonoids against anthracycline cardiotoxicity: from chemistry to clinical trials

“…We compared several well-known iron chelators (ICRF-187, 7-monohydroxyethylrutoside, deferoxamine and pyridoxal isonicotinoyl hydrazone) and found that only ICRF-187 and 7-monohydroxyethylrutoside protected the human lung adenocarcinoma cells A549 against doxorubicin-induced oxidative stress while other chelators did not [14].…”

New iron chelators in anthracycline-induced cardiotoxicity

“…We also found out that both PIH and SIH were able to prevent daunorubicin and doxorubicin-induced loss of CYP450 activities in isolated hepatocytes [18]. Using two different cancer cell lines (HL60, A549) we have further confirmed that the antiproliferative effects of the anthracyclines are not hampered by any of these chelators [19,20]. In the next step, the cardioprotective effects of these chelators have been evaluated in the rabbit model of chronic daunorubicin cardiomyopathy.…”

“…When a more complex cellular model was used (A549, human lung adenocarcinoma cells), it turned out that only DFO and SIH were able to prevent hydrogen peroxide/Fe 2+ -induced oxidative damage as monitored by LDH release, TBARS formation, and cellular GSH levels. In contrast, when oxidative stress was induced with doxorubicin, DFO and SIH were not effective at all, whereas dexrazoxane and monoHER significantly decreased the doxorubicin-induced oxidative damage [19] (Table 3). These results clearly demonstrate that iron-promoted hydroxyl radical formation is not a major determinant of doxorubicin-induced oxidative injury.…”

“…Their ability to prevent hydroxyl radical formation was first investigated by means of EPR spectroscopy and it was found that their efficiency decreased in this order: PIH = SIH > dexrazoxane > DFO > monoHER [19]. When a more complex cellular model was used (A549, human lung adenocarcinoma cells), it turned out that only DFO and SIH were able to prevent hydrogen peroxide/Fe 2+ -induced oxidative damage as monitored by LDH release, TBARS formation, and cellular GSH levels.…”