Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy

Martin, Elke; Thougaard, Annemette; Grauslund, Morten; Jensen, Peter Buhl; Björkling, Fredrik; Hasinoff, Brian B.; Tjørnelund, Jette; Sehested, Maxwell; Jensen, Lars H.

doi:10.1016/j.tox.2008.10.011

Cited by 81 publications

(76 citation statements)

References 22 publications

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“…Despite significant toxicities associated with DXZ use, consideration of underlying principles behind its cardioprotective action is critical for the development of novel treatments for DOX toxicity. Thus, the Top-2β-inactive analog of DXZ, which retains its iron-chelating properties and does not induce myelosuppression, was shown to exhibit a similar degree of protection against DOX (44). This finding, together with our data on DXZ efficacy in chelating mitochondrial iron, provides an important foundation for the development of drugs that can access the mitochondrial iron pool, without side effects associated with DXZ use.…”

Section: Discussionsupporting

confidence: 63%

“…There may be a yet unidentified link between mitochondrial iron homeostasis and topoisomerases, as several iron chelators, including DXZ, were also shown to inhibit Top-2α/2β activities (43). However, the protective effects reported here are likely independent of the topoisomerase pathway, since a topoisomerase-inactive analog of DXZ that retains its iron-chelating properties confers a similar degree of protection to its parent compound (44), and also genetic overexpression of ABCB8 confers protection comparable to that of DXZ. Moreover, we show that reduction in mitochondrial iron levels through overexpression of ABCB8 in vitro and in vivo does not alter Top-2β protein levels and knockdown of Top-2β has no effect on ABCB8 protein expression or mitochondrial iron content in NRCMs.…”

Section: Methodsmentioning

confidence: 71%

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Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

715

559

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Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.

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Section: Discussionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 71%

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

715

559

View full text Add to dashboard Cite

show abstract

“…7) (176). Both compounds were found hydrolyzable to iron-chelating products, and they were comparable in their effectiveness to displace iron from its complex with DOX.…”

Section: Dex Derivatives As Cardioprotectantsmentioning

confidence: 97%

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Štěrba

Popelová

Vávrová

et al. 2013

Antioxidants & Redox Signaling

276

192

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“…Spectrophotometric Titration of Pixantrone with Fe 31 and Cu 21 . Spectrophotometric titration experiments, as we described (Martin et al, 2009), were carried out to determine whether pixantrone could bind either Fe 31 or Cu 21 . Spectral scanning (250-800 nm) of solutions containing FeCl 3 (5-250 mM final concentrations) and pixantrone (30 mM final concentration) added to Tris/KCl buffer (50 mM/150 mM, pH 7.4, 25°C) showed no significant spectral changes (data not shown).…”

Section: Mechanisms Of the Reduced Cardiotoxicity Of Pixantronementioning

confidence: 99%

Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

Hasinoff

Patel

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Pixantrone is a new noncardiotoxic aza-anthracenedione anticancer drug structurally related to anthracyclines and anthracenediones, such as doxorubicin and mitoxantrone. Pixantrone is approved in the European Union for the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphoma. This study was undertaken to investigate both the mechanism(s) of its anticancer activity and its relative lack of cardiotoxicity. Pixantrone targeted DNA topoisomerase IIa as evidenced by its ability to inhibit kinetoplast DNA decatenation; to produce linear double-strand DNA in a pBR322 DNA cleavage assay; to produce DNA double-strand breaks in a cellular phosphohistone gH2AX assay; to form covalent topoisomerase II-DNA complexes in a cellular immunodetection of complex of enzymeto-DNA assay; and to display cross-resistance in etoposideresistant K562 cells. Pixantrone produced semiquinone free radicals in an enzymatic reducing system, although not in a cellular system, most likely due to low cellular uptake. Pixantrone was 10-to 12-fold less damaging to neonatal rat myocytes than doxorubicin or mitoxantrone, as measured by lactate dehydrogenase release. Three factors potentially contribute to the reduced cardiotoxicity of pixantrone. First, its lack of binding to iron(III) makes it unable to induce iron-based oxidative stress. Second, its low cellular uptake may limit its ability to produce semiquinone free radicals and redox cycle. Finally, because the b isoform of topoisomerase II predominates in postmitotic cardiomyocytes, and pixantrone is demonstrated in this study to be selective for topoisomerase IIa in stabilizing enzyme-DNA covalent complexes, the attenuated cardiotoxicity of this agent may also be due to its selectivity for targeting topoisomerase IIa over topoisomerase IIb.

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Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy

Cited by 81 publications

References 22 publications

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection

Mechanisms of Action and Reduced Cardiotoxicity of Pixantrone; a Topoisomerase II Targeting Agent with Cellular Selectivity for the Topoisomerase II Isoform

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