The Novel Anthracenedione, Pixantrone, Lacks Redox Activity and Inhibits Doxorubicinol Formation in Human Myocardium: Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

Salvatorelli, Emanuela; Menna, Pierantonio; Paz, Odalys Gonzalez; Chello, Massimo; Covino, Elvio; Singer, Jack W.; Minotti, Giorgio

doi:10.1124/jpet.112.200568

Cited by 51 publications

(57 citation statements)

References 53 publications

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“…These results are consistent with the much decreased uptake of dicationic pixantrone into cells compared with monocationic doxorubicin. Our EPR results, which were obtained under hypoxic conditions, to enhance our ability to observe EPR semiquinone signals, are at odds with a study in a more complex human myocardial strip model in which it was concluded that pixantrone was virtually resistant to oneelectron reduction (Salvatorelli et al, 2013). Our EPR results in cells are also consistent with our previous study of the comparative semiquinone formation of doxorubicin, epirubicin, idarubicin, and daunorubicin in CHO cell suspensions, and their fluorescence-determined uptake in CHO cells, in which we showed that anthracycline uptake paralleled formation of the semiquinone signal (Malisza and Hasinoff, 1996).…”

Section: Discussioncontrasting

confidence: 67%

“…In human myocardial strips, pixantrone lacked redox synergism with doxorubicin and formed neither O ×-2 nor H 2 O 2 (Salvatorelli et al, 2013). However, because pixantrone contains a quinone moiety, it can potentially be reductively activated to a semiquinone free radical like doxorubicin (Malisza and Hasinoff, 1996), which, in turn, could undergo aerobic oxidation and further redox cycling to induce cardiotoxic oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 67%

Section: Introductionmentioning

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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“…Moreover, recent biochemical studies in human cardiac myocytes demonstrated that PIX does not generate reactive oxygen species, probably due to its inability to interact with mitochondrial iron. 3,4 Despite the favorable preclinical and clinical findings regarding both efficacy and toxicity, a definitive mechanism of action for PIX-induced cell killing is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions

Beeharry

Rorà

Smith

et al. 2015

Cancer Biology & Therapy

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Pixantrone is a novel aza-anthracenedione active against aggressive lymphoma and is being evaluated for use against various hematologic and solid tumors. The drug is an analog of mitoxantrone, but displays less cardiotoxicity than mitoxantrone or the more commonly used doxorubicin. Although pixantrone is purported to inhibit topoisomerase II activity and intercalate with DNA, exact mechanisms of how it induces cell death remain obscure. Here we evaluated the effect of pixantrone on a panel of solid tumor cell lines to understand its mechanism of cell killing. Initial experiments with pixantrone showed an apparent discrepancy between its anti-proliferative effects in MTS assays (short-term) compared with clonogenic assays (long-term). Using live cell videomicroscopy to track the fates of cells, we found that cells treated with pixantrone underwent multiple rounds of aberrant cell division before eventually dying after approximately 5 d post-treatment. Cells underwent abnormal mitosis in which chromosome segregation was impaired, generating chromatin bridges between cells or within cells containing micronuclei. While pixantrone-treated cells did not display gH2AX foci, a marker of DNA damage, in the main nuclei, such foci were often detected in the micronuclei. Using DNA content analysis, we found that pixantrone concentrations that induced cell death in a clonogenic assay did not impede cell cycle progression, further supporting the lack of canonical DNA damage signaling. These findings suggest pixantrone induces a latent type of DNA damage that impairs the fidelity of mitosis, without triggering DNA damage response or mitotic checkpoint activation, but is lethal after successive rounds of aberrant division.

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“…Cardiotoxicity is an issue with anthracyclines, via iron-dependent formation of reactive oxygen species, and topoisomerase IIβ-mediated DNA damage response [25]. Pixantrone is believed to be less cardiotoxic because it does not bind iron and thus, has less potential for generation of reactive oxygen species [21,23,28,29], and because it is only a weak inhibitor of topoisomerase II versus similar agents and has a greater affinity for topoisomerase IIα than topoisomerase IIβ [21,23,25,27].…”

Section: • Pixantronementioning

confidence: 99%

The Servier oncology pipeline in 2017

et al. 2017

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Cancer is a complex, multifactorial disease that for years has been the focus of intensive research efforts to explore both the molecular and biological mechanisms involved and the development of novel agents to target these pathways. Servier is an independent French pharmaceutical company with a focus on oncology. Currently, Servier's commercial portfolio includes agents used to treat non-Hodgkin's lymphoma and metastatic colorectal cancer; Servier's oncology pipeline involves agents for the treatment of both solid and hematological tumors. The main areas of future research focus on the development of therapeutics targeting apoptosis or the active immune components involved in tumour development/maintenance. Servier intends to continue its focus on cutting-edge oncology innovation by collaborating with both industry and academia, and maintaining its strong patient-centered approach.

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The Novel Anthracenedione, Pixantrone, Lacks Redox Activity and Inhibits Doxorubicinol Formation in Human Myocardium: Insight to Explain the Cardiac Safety of Pixantrone in Doxorubicin-Treated Patients

Cited by 51 publications

References 53 publications

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

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

Pixantrone induces cell death through mitotic perturbations and subsequent aberrant cell divisions

The Servier oncology pipeline in 2017

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