Comparison of the effect of three different topoisomerase II inhibitors combined with cisplatin in human glioblastoma cells sensitized with double strand break repair inhibitors

Macieja, Anna; Kopa, Paulina; Galita, Grzegorz; Pastwa, Elżbieta; Majsterek, Ireneusz; Popławski, Tomasz

doi:10.1007/s11033-019-04605-0

Cited by 20 publications

(9 citation statements)

References 44 publications

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“…The combination index (CI) may be used to determine if a drug combination may have synergistic effect [18]. To assess whether the combined effect of Top2 α and β inhibitors represented additive or synergistic effects we calculated the CI values based on the median-effect equation.…”

Section: The Combination Of Top2 α and β Inhibitors (Nk314 And Vp-16)mentioning

confidence: 99%

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

et al. 2019

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Etoposide (VP-16) is the topoisomerase 2 (Top2) inhibitor used for treating of glioma patients however at high dose with serious side effects. It induces DNA double-strand breaks (DSBs). These DNA lesions are repaired by non-homologous DNA end joining (NHEJ) mediated by DNA-dependent protein kinase (DNA-PK). One possible approach to decrease the toxicity of etoposide is to reduce the dose while maintaining the anticancer potential. It could be achieved through combined therapy with other anticancer drugs. We have assumed that this objective can be obtained by (1) a parallel topo2 α inhibition and (2) sensitization of cancer cells to DSBs. In this work we investigated the effect of two Top2 inhibitors NK314 and VP-16 in glioma cell lines (MO59 K and MO59 J) sensitized by DNA-PK inhibitor, NU7441. Cytotoxic effect of VP-16, NK314 alone and in combination on human glioblastoma cell lines, was assessed by a colorimetric assay. Genotoxic effect of anticancer drugs in combination with NU7441 was assessed by comet assay. Cell cycle distribution and apoptosis were analysed by flow cytometry. Compared with VP-16 or NK314 alone, the combined treatment significantly inhibited cell proliferation. Combination treatment was associated with a strong accumulation of DSBs, modulated cell cycle phases distribution and apoptotic cell death. NU7441 potentiated these effects and additionally postponed DNA repair. Our findings suggest that NK314 could overcome resistance of MO59 cells to VP-16 and NU7441 could serve as sensitizer to VP-16/ NK314 combined treatment. The combined tripartite approach of chemotherapy could reduce the overall toxicity associated with each individual therapy, while concomitantly enhancing the anticancer effect to treat human glioma cells. Thus, the use of a tripartite combinatorial approach could be promising and more efficacious than mono therapy or dual therapy to treat and increase the survival of the glioblastoma patients.

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Section: The Combination Of Top2 α and β Inhibitors (Nk314 And Vp-16)mentioning

confidence: 99%

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

et al. 2019

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“…17 While NK314 is being tested with clinically approved agents, neither of these approaches has reached the clinic. 18 TOP2A and TOP2B are homodimeric enzymes with multiple folded protein domains. 1,19 While much of the enzyme is very similar between the two human isoforms, the C-terminal domain (CTD) amino acid sequence diverges significantly.…”

Section: ■ Introductionmentioning

confidence: 99%

Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity

et al. 2021

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Human topoisomerase IIα (TOP2A) is a vital nuclear enzyme involved in resolving knots and tangles in DNA during replication and cell division. TOP2A is a homodimer with a symmetrical, multidomain structure. While the N-terminal and core regions of the protein are well-studied, the C-terminal domain is poorly understood but is involved in enzyme regulation and is predicted to be intrinsically disordered. In addition, it appears to be a major region of post-translational modification and includes several Ser and Thr residues, many of which have not been studied for biochemical effects. Therefore, we generated a series of human TOP2A mutants where we changed specific Ser and Thr residues in the C-terminal domain to Ala, Gly, or Ile residues. We designed, purified, and examined 11 mutant TOP2A enzymes. The amino acid changes were made between positions 1272 and 1525 with 1−7 residues changed per mutant. Several mutants displayed increased levels of DNA cleavage without displaying any change in plasmid DNA relaxation or DNA binding. For example, mutations in the regions 1272−1279, 1324−1343, 1351−1365, and 1374− 1377 produced 2−3 times more DNA cleavage in the presence of etoposide than wild-type TOP2A. Further, several mutants displayed changes in relaxation and/or decatenation activity. Together, these results support previous findings that the C-terminal domain of TOP2A influences catalytic activity and interacts with the substrate DNA. Furthermore, we hypothesize that it may be possible to regulate the enzyme by targeting positions in the C-terminal domain. Because the C-terminal domain differs between the two human TOP2 isoforms, this strategy may provide a means for selectively targeting TOP2A for therapeutic inhibition. Additional studies are warranted to explore these results in more detail.

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“…Its enzymatic activity mediates the unwinding of DNA double strands for replication. Certain studies have indicated that Top II in patients with recurrent gliomas is prone to mutation, which frequently leads to the loss of drug targeting and the development of drug resistance ( 15 , 20 ). In addition, a study by Santangelo et al ( 21 ) demonstrated that metallothionein is highly expressed in gliomas, another important cause of chemoresistance and poor prognosis.…”

Section: Mechanisms Of Chemotherapy Resistance In Gliomasmentioning

confidence: 99%

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

et al. 2022

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As the most common primary tumour of the central nervous system, gliomas have a high recurrence rate after surgical resection and are resistant to chemotherapy, particularly high-grade gliomas dominated by glioblastoma multiforme (GBM). The prognosis of GBM remains poor despite improvements in treatment modalities, posing a serious threat to human health. At present, although drugs such as temozolomide, cisplatin and bevacizumab, are effective in improving the overall survival of patients with GBM, most patients eventually develop drug resistance, leading to poor clinical prognosis. The development of multidrug resistance has therefore become a major obstacle to improving the effectiveness of chemotherapy for GBM. The ability to fully understand the underlying mechanisms of chemotherapy resistance and to develop novel therapeutic targets to overcome resistance is critical to improving the prognosis of patients with GBM. Of note, growing evidence indicates that a large number of abnormally expressed noncoding RNAs (ncRNAs) have a central role in glioma chemoresistance and may target various mechanisms to modulate chemosensitivity. In the present review, the roles and molecular mechanisms of ncRNAs in glioma drug resistance were systematically summarized, the potential of ncRNAs as drug resistance markers and novel therapeutic targets of glioma were discussed and prospects for glioma treatment were outlined. ncRNAs are a research direction for tumor drug resistance mechanisms and targeted therapies, which not only provides novel perspectives for reversing glioma drug resistance but may also promote the development of precision medicine for clinical diagnosis and treatment.

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Comparison of the effect of three different topoisomerase II inhibitors combined with cisplatin in human glioblastoma cells sensitized with double strand break repair inhibitors

Cited by 20 publications

References 44 publications

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

Inhibition of DNA-PK potentiates the synergistic effect of NK314 and etoposide combination on human glioblastoma cells

Exploration of the Role of the C-Terminal Domain of Human DNA Topoisomerase IIα in Catalytic Activity

NcRNAs: Multi‑angle participation in the regulation of glioma chemotherapy resistance (Review)

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