Etoposide-mediated glioblastoma cell death: dependent or independent on the expression of its target, topoisomerase II alpha?

Sevim, Handan; Parkinson, Jonathan; McDonald, K. L.

doi:10.1007/s00432-011-1046-5

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…A number of studies have thus far shown an association between levels of topoisomerase expression and cellular susceptibility to TOP2 poisons ( 48 , 49 ). TOP2A suppression is thought to result in resistance by decreasing the amount of enzyme-DNA complex, in turn decreasing the amount of DNA damage ( 42 ).…”

Section: Topoisomerase Poison Susceptibility: Biomarkers To Personalimentioning

confidence: 99%

Topoisomerase II Poisons for Glioblastoma; Existing Challenges and Opportunities to Personalize Therapy

2018

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Despite advances in surgery, radiotherapy, and chemotherapy, glioblastoma (GBM) remains a malignancy with poor prognosis. The molecular profile of GBM is diverse across patients, and individual responses to therapy are highly variable. Yet, patients diagnosed with GBM are treated with a rather uniform paradigm. Exploiting these molecular differences and inter-individual responses to therapy may present an opportunity to improve the otherwise bleak prognosis of patients with GBM. This review aims to examine one group of chemotherapeutics: Topoisomerase 2 (TOP2) poisons, a class of drugs that enables TOP2 to induce DNA damage, but interferes with its ability to repair it. These potent chemotherapeutic agents are currently used for a number of malignancies and have shown promise in the treatment of GBM. Despite their robust efficacy in vitro, some of these agents have fallen short of achieving similar results in clinical trials for this tumor. In this review, we explore reasons for this discrepancy, focusing on drug delivery and individual susceptibility differences as challenges for effective TOP2-targeting for GBM. We critically review the evidence implicating genes in susceptibility to TOP2 poisons and categorize this evidence as experimental, correlative or both. This is important as mere experimental evidence does not necessarily lead to identification of genes that serve as good biomarkers of susceptibility for personalizing the use of these drugs.

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Section: Topoisomerase Poison Susceptibility: Biomarkers To Personalimentioning

confidence: 99%

Topoisomerase II Poisons for Glioblastoma; Existing Challenges and Opportunities to Personalize Therapy

2018

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“…TOP2 protein level is known to correlate with susceptibility to etoposide treatment in cancer 19 and specifically in glioma cell lines, 20 yet it is not known whether TOP2 expression defined by Sonabend et al: Convection-enhanced delivery of etoposide its transcript levels also correlates with susceptibility to etoposide. This is important given that the characteristic expression of this gene in PN glioblastoma in the database of TCGA was determined based on RNA expression array.…”

Section: Topoisomerase Iib Transcript Levels Correlate With Susceptibmentioning

confidence: 99%

Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma

et al. 2014

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“…With higher TOP levels being potentially accountable for enhanced drug sensitivity (Burgess et al , ; MacGrogan et al , ; Sevim et al , ), we determined whether differential expression of TOP2A and TOP2B, the two major isoforms of human TOP2, might be regulated by HMGA2 and thus could be responsible for the Etop treatment outcome. Western blot analysis revealed that the observed protective effect was not due to changes in TOP2A/B expression levels that consistently correlated with HMGA2 levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

Ahmed

Dröge

2019

Molecular Oncology

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Rapidly dividing cells maintain chromatin supercoiling homeostasis via two specialized classes of enzymes, DNA topoisomerase type 1 and 2 (TOP1/2). Several important anticancer drugs perturb this homeostasis by targeting TOP1/2, thereby generating genotoxic DNA damage. Our recent studies indicated that the oncofetal chromatin structuring high‐mobility group AT‐hook 2 (HMGA2) protein plays an important role as a DNA replication fork chaperone in coping with DNA topological ramifications that occur during replication stress, both genomewide and at fragile sites such as subtelomeres. Intriguingly, a recent large‐scale clinical study identified HMGA2 expression as a sole predicting marker for relapse and poor clinical outcomes in 350 acute myeloid leukemia (AML) patients receiving combinatorial treatments that targeted TOP2 and replicative DNA synthesis. Here, we demonstrate that HMGA2 significantly enhanced the DNA supercoil relaxation activity of the drug target TOP2A and that this activator function is mechanistically linked to HMGA2's known ability to constrain DNA supercoils within highly compacted ternary complexes. Furthermore, we show that HMGA2 significantly reduced genotoxic DNA damage in each tested cancer cell model during treatment with the TOP2A poison etoposide or the catalytic TOP2A inhibitor merbarone. Taken together with the recent clinical data obtained with AML patients targeted with TOP2 poisons, our study suggests a novel mechanism of cancer chemoresistance toward combination therapies administering TOP2 poisons or inhibitors. We therefore strongly argue for the future implementation of trials of HMGA2 expression profiling to stratify patients before finalizing clinical treatment regimes.

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Etoposide-mediated glioblastoma cell death: dependent or independent on the expression of its target, topoisomerase II alpha?

Cited by 10 publications

References 29 publications

Topoisomerase II Poisons for Glioblastoma; Existing Challenges and Opportunities to Personalize Therapy

Topoisomerase II Poisons for Glioblastoma; Existing Challenges and Opportunities to Personalize Therapy

Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma

Oncofetal HMGA2 attenuates genotoxic damage induced by topoisomerase II target compounds through the regulation of local DNA topology

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