Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

Mariani, Angelica; Bartoli, Alexandra; Atwal, Mandeep; Lee, Ka C.; Austin, Caroline A.; Rodriguez, Raphaël

doi:10.1021/acs.jmedchem.5b00473

Cited by 19 publications

(17 citation statements)

References 41 publications

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“…4, A and B), which express similar levels of both topoisomerase IIa and topoisomerase IIb (Padget et al, 2000), showed that pixantrone, mitoxantrone, and etoposide all increased topoisomerase IIa and topoisomerase IIb covalently bound to DNA. Consistent with these results, etoposide and mitoxantrone have been shown to target both topoisomerase IIa and topoisomerase IIb (Willmore et al, 1998;Errington et al, 2004;Mariani et al, 2015). An earlier study had suggested topoisomerase IIb as an important target for mitoxantrone (Errington et al, 1999).…”

Section: Discussionmentioning

confidence: 78%

“…It has also been suggested that targeting of topoisomerase IIb is responsible for induction of anticancer drug-induced secondary malignancies produced by topoisomerase II-targeted anticancer drugs Cowell et al, 2012). Development of drugs such as NK314 (Toyoda et al, 2008) and etoposide analogs (Mariani et al, 2015) that specifically target the topoisomerase IIa isoform to reduce topoisomerase IIb-mediated toxicity/carcinogenicity is being actively pursued (Vejpongsa and Yeh, 2014). Because preclinical studies with pixantrone showed little or no cardiotoxicity, this result suggested that pixantrone, unlike the anthracyclines, may be specifically targeting the topoisomerase IIa isoform.…”

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: Discussionmentioning

confidence: 78%

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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“…Therefore, optimal topoisomerase II poisons will maximize interactions with hTOPOIIα to inhibit proliferating cells and minimize hTOPOIIβ interactions to reduce side effects. With this goal in mind, others have identified etoposide analogues with different isoform specificities but have not determined the mechanism of specificity [45]. Our study functionally validates a key residue determining isoform specificity and is critical to the improvement of this widely administered drug class.…”

Section: Discussionmentioning

confidence: 88%

Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons

et al. 2017

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Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue. The residue affected by this substitution is conserved from yeast to humans and is one of the few differences between the two human topoisomerase II isoforms (methionine in hTOPIIα and glutamine in hTOPIIβ). We go on to show that this amino acid difference between the two human topoisomerase isoforms influences cytotoxicity of topoisomerase II poisons in human cell lines. These results explain why hTOPIIα and hTOPIIβ are differentially affected by various poisons and demonstrate the utility of C. elegans in understanding the genetics of drug responses.

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“…K562 cells (1x10 7 ) were washed with PBS and then treated with lysis buffer containing 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM phenylmethane sulfonyl fluoride, 1 mM aprotitin and 1% NP40 for 30 min at 4˚C. Following centrifugation at 11,000 x g for 20 min, the protein concentration of the supernatant was determined; equal amounts (30 µg) of protein were separated by 10% SDS-polyacrylamide gel electrophoresis and then electro-transferred onto nitrocellulose membranes in transfer buffer.…”

Section: Antitumor Effects In Vivomentioning

confidence: 99%

“…DNA topoisomerases are a class of enzymes involved in the regulation of DNA supercoiling. Topoisomerase overexpression has been linked to a number of human malignancies and is the target for numerous chemotherapeutic agents (7). In the event that topoisomerases are blocked, the cell encounters problems during transcription of the DNA and during cell division.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

Chen

Li³

et al. 2016

Oncology Letters

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Abstract. Ganoderma lucidum is a popular herbal medicine used in China to promote health. Modern studies have disclosed that the active ingredients of Ganoderma can exhibit several effects, including antitumor effects and immunomodulation. The present study evaluated the antitumor effects of self-prepared Ganoderma extracts and spores oil, and investigated the possible underlying mechanisms by observing the effects of the extracts and oil on topoisomerases and the cell cycle. The results showed that Ganoderma extracts and spores oil presented dose-dependent inhibitory effects on tumor cells. The half maximal inhibitory concentration (IC 50 ) values of Ganoderma extracts on HL60, K562 and SGC-7901 cells for 24 h were 0.44, 0.39 and 0.90 mg/ml, respectively; for Ganoderma spores oil, the IC 50 values were 1.13, 2.27 and 6.29 mg/ml, respectively. In the in vivo study, the inhibitory rates of Ganoderma extracts (4 g/kg/d, intragastrically) on S180 and H22 cells were 39.1 and 44.6%, respectively, and for Ganoderma spores oil (1.2 g/kg/d, intragastrically) the inhibitory rates were 30.9 and 44.9%, respectively. Ganoderma extracts and spores oil inhibited the activities of topoisomerase I and II. Ganoderma spores oil was shown block the cell cycle at the transition between the G1 and S phases and induce a marked decrease in cyclin D1 levels in K562 cells, with no significant change in cyclin E level. These results suggest that the Ganoderma extracts and spores oil possessed antitumor effects in the in vitro and in vivo studies. The antitumor mechanisms of the extracts and spores oil were associated with inhibitory effects on topoisomerase I and II activities, and for Ganoderma spores oil, the antitumor effects may also be associated with decreased cyclin D1 levels, thus inducing G1 arrest in the cell cycle.

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Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules

Cited by 19 publications

References 41 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

Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons

Antitumor effects and mechanisms of Ganoderma extracts and spores oil

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