Topoisomerase II beta expression level correlates with doxorubicin-induced apoptosis in peripheral blood cells

Kersting, Gisela; Tzvetkov, Mladen V.; Huse, Klaus; Kulle, Bettina; Hafner, Verena; Brockmöller, Jürgen; Wojnowski, Leszek

doi:10.1007/s00210-006-0091-0

Cited by 23 publications

(21 citation statements)

References 36 publications

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“…TOP2B expression is correlated with cellular sensitivity to doxorubicin [31] and the TOP2B protein is necessary for development of anthracycline-induced cardiotoxicity in mice [13]. Using bioinformatics tools we identified a SNP (rs2363520) that is highly associated with TOP2B expression (p = 9 × 10 -6 ) in lymphoblastoid cell lines [32].…”

Section: Resultsmentioning

confidence: 99%

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

et al. 2016

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with Aims: Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity. Patients & methods: A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis. Results: Previously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012). Conclusion: The associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.

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Section: Resultsmentioning

confidence: 99%

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

et al. 2016

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“…These results support the critical concept that doxorubicin-induced cardiotoxicity is mediated by Top2β in cardiomyocytes. 39 (Figure 1)…”

Section: Novel Mechanisms Of Anthracycline Cardiotoxicity Are Identifiedmentioning

confidence: 99%

“…It has been reported that Top2β levels in peripheral blood are correlated with the apoptotic response of leukocytes to doxorubicin in humans. 39 Hence, the Top2β level in peripheral blood may be useful as a surrogate marker for susceptibility to anthracycline-induced cardiomyopathy. However, this remains to be proven in clinical studies.…”

Section: Novel Mechanisms Of Anthracycline Cardiotoxicity Are Identifiedmentioning

confidence: 99%

Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Vejpongsa

Yeh

et al. 2013

Circulation Research

134

124

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The cardiovascular care of cancer patients (“Cardio-Oncology”) has emerged as a new discipline in clinical medicine given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies, such as anthracyclines and radiation, have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of “targeted” cancer therapies, which were initially felt to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, and/or over-expression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting Her2 (mutated or over-expressed in breast cancer), BCR-ABL (CML and some cases of ALL),and c-Kit (gastrointestinal stromal tumor).Other agents targeting more complex malignancies such as advanced solid tumors have had successes, but have not extended life to the degree seen with CML. Years before the first targeted therapeutic, Judah Folkman correctly proposed that to address solid tumors, one had to target the inherent neo-angiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the Catch 22. On the other hand, cardiomyopathies that arise unexpectedly from such targeted therapies can provide key insights into the normal function of the heart.

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“…top2a expression is elevated in solid tumors and predicts responsiveness to anthracycline-based chemotherapy in women with primary breast cancer (33,183,226). Similarly, top2b levels in hematological cells correlates with sensitivity to and apoptosis by doxorubicin (117). The relationship between top2a and top2b and drug sensitivity in cancer is complex due to the role of the drug resistance proteins p-glycoprotein and multidrug resistance protein, changes in subcellular localization of top2 proteins, shared homology and catalytic activity between top2a and top2b, and phosphorylation/mutations in top2 (185).…”

Section: Raomentioning

confidence: 99%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955.

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Topoisomerase II beta expression level correlates with doxorubicin-induced apoptosis in peripheral blood cells

Cited by 23 publications

References 36 publications

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

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