Deferiprone protects against doxorubicin-induced myocyte cytotoxicity

Barnabé, Norman; Zastre, Jason; Venkataram, S.; Hasinoff, Brian B.

doi:10.1016/s0891-5849(02)00873-0

Cited by 79 publications

(69 citation statements)

References 33 publications

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“…The results indicate that pretreatment with deferiprone remarkably preserved the contractility of atria, although it could not entirely reverse the negative inotropic effects induced by DOX. A previously published study reported that deferiprone prevented cultured cardiac myocytes from DOXinduced damage monitored with the release of lactate dehydrogenase [13] . Our study further suggests that deferiprone can also protect cardiac contractile function from damage induced by DOX.…”

Section: Discussionmentioning

confidence: 95%

“…A previously published study of cultured hepatocytes showed that by scavenging superoxide radicals, both deferiprone and Fe 3+ -deferiprone complexes were able to protect the cells against hypoxia-reoxygenation injury effectively [11] . Further studies of cultured heart cells showed that deferiprone eliminated DOX-induced cardiac damage [12,13] . Together, these studies support the cardiac protective activity of deferiprone.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanism was possibly related to the iron chelating of deferiprone. As a small molecule, deferiprone is able to enter cardiac myocytes rapidly [13] and is capable of efficiently preventing free radicalbased cardiotoxicity by quickly displacing iron from the complex with DOX [13] . Moreover, deferiprone and its complex with Fe 3+ have antioxidant properties.…”

Section: Introductionmentioning

confidence: 99%

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Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Jin

Pan

et al. 2006

Acta Pharmacologica Sinica

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Aim: To investigate the effects of deferiprone on doxorubicin-induced cardiotoxicity and determine its protection on cardiac contractility in vivo at tissue level. Methods: Spontaneously-beating isolated atria from rats were pretreated with deferiprone for 10 min at 1.2 mmol/L or 0.3 mmol/L, respectively before co-incubation with doxorubicin (DOX) at 0.03 mmol/L for 60 min. Contractility (dF/dt) was assessed every 10 min during the incubation. After that, the tissues around the sinuatrial nodes were fixed for ultrastructural study; succinate dehydrogenase (SDH) and Cu, Zn superoxide dismutase (Cu, Zn-SOD) activity, as well as malondialdehyde (MDA) level of the atria were assayed. Results: Treatment with DOX alone resulted in a 49.34% reduction of the contractility, mitochondria swelling, disruption of mitochondrial crista and decreased electron density of the matrices. Conversely, with the presence of deferiprone, the negative inotropic effect and lesions in the cardiac mitochondria structure induced by DOX were attenuated. Cu, Zn-SOD activity increased by 12.97%-12.11%, the MDA level decreased by 29.12%-39.82% and succinate dehydrogenase (SDH) activity was ameliorated by 25.15%-34.76%. Conclusion : Deferiprone can efficiently preserve cardiac contractility. Moreover, the results of this study indicate that deferiprone is able to protect mitochondrial function and structure form damage induced by DOX. This cardiac protective potential of deferiprone could be due to its defense capability against oxidative damage.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Jin

Pan

et al. 2006

Acta Pharmacologica Sinica

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“…A freshly prepared 15 μl aliquot of kinamycin F in the reaction systems indicated was injected into an 8-cm length of gas-permeable Teflon tubing (Zeus Industrial Products, Raritan, NJ) which was then folded at both ends and inserted into a quartz EPR tube open at both ends, and placed in the EPR cavity as described [25]. The EPR spectra were recorded with a Bruker (Milton, Canada) EMX EPR spectrometer.…”

Section: Electron Paramagnetic Resonance Spectroscopymentioning

confidence: 99%

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group as well as a paraquinone and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and by catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen peroxideand hydroxyl radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

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“…In severe cases, doxorubicin side effects may include cardiac toxicity [2,3]. The mechanism of doxorubicin action has been linked to DNA damage, topoisomerase inhibition, and iron sequestration with subsequent free radical generation [4][5][6][7]. Although the DNA damaging aspects of doxorubicin are the most widely accepted explanation of the drug's effects, both therapeutic and detrimental, the free radical hypothesis has been revisited recently by several groups.…”

Section: Introductionmentioning

confidence: 99%

Doxorubicin generates a proapoptotic phenotype by phosphorylation of elongation factor 2

White

Kasman

Kelly

et al. 2007

Free Radical Biology and Medicine

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We have previously shown that doxorubicin sensitizes prostate cancer cells to TNF-Related Apoptosis Inducing Ligand (TRAIL). Sensitization correlated with decreased expression of the antiapoptotic protein cFLIP S . The decrease in cFLIP S could not be explained by transcriptional regulation or increased degradation, leading us to focus on translational mechanisms. In this study, we found that doxorubicin caused strong and sustained phosphorylation of elongation factor 2 (EF-2), which interferes with protein elongation. Phosphorylation of EF-2 appeared to occur in a kinaseindependent manner. Treatment with hydrogen peroxide recapitulated the events observed after doxorubicin treatment. In addition, cells treated with hydrogen peroxide expressed less XIAP and survivin which, like cFLIP S , are short half-life proteins with an anti-apoptotic function while expression levels of DR5, caspases-8, -9, -3, and Bax are maintained. The doxorubicin-mediated decrease in cFLIP S and XIAP as well as TRAIL-induced apoptosis was prevented by pretreatment with an iron chelator, indicating that expression of these proteins was affected by free radical generation upon interaction of iron with doxorubicin. In conclusion, our data suggest that free radicals can affect the phosphorylation of EF-2 resulting in a net loss of short half-life proteins such as cFLIP S and XIAP, leaving a cell more vulnerable to apoptotic stimuli.

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Deferiprone protects against doxorubicin-induced myocyte cytotoxicity

Cited by 79 publications

References 33 publications

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Deferiprone protects the isolated atria from cardiotoxicity induced by doxorubicin

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Doxorubicin generates a proapoptotic phenotype by phosphorylation of elongation factor 2

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