The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Matias-Barrios, Victor M.; Dong, Xuesen

doi:10.3390/ph16010094

Cited by 6 publications

(7 citation statements)

References 139 publications

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“…The Z-DNA related properties of topoII described in this publication, potentially shared with some of its interactome partners [ 140 ], offer the prospect of new antiproliferative compounds, pharmacologically complementary to the numerous existing anticancer drugs targeting the isomerase mechanism of the protein. Current strategies for topoII-based drug discovery [ 56 , 57 , 58 , 141 , 142 ] lend themselves to this goal. GTP-binding site-specific compounds based on non-hydrolyzable nucleotides, isomerase inhibitory purine scaffolds [ 143 ] or suitably adapted ATP-competitors [ 144 ] would introduce a new dimension of target selectivity.…”

Section: Resultsmentioning

confidence: 99%

Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Bartas

Slychko

Červeň

et al. 2023

IJMS

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The dynamic processes operating on genomic DNA, such as gene expression and cellular division, lead inexorably to topological challenges in the form of entanglements, catenanes, knots, “bubbles”, R-loops, and other outcomes of supercoiling and helical disruption. The resolution of toxic topological stress is the function attributed to DNA topoisomerases. A prominent example is the negative supercoiling (nsc) trailing processive enzymes such as DNA and RNA polymerases. The multiple equilibrium states that nscDNA can adopt by redistribution of helical twist and writhe include the left-handed double-helical conformation known as Z-DNA. Thirty years ago, one of our labs isolated a protein from Drosophila cells and embryos with a 100-fold greater affinity for Z-DNA than for B-DNA, and identified it as topoisomerase II (gene Top2, orthologous to the human UniProt proteins TOP2A and TOP2B). GTP increased the affinity and selectivity for Z-DNA even further and also led to inhibition of the isomerase enzymatic activity. An allosteric mechanism was proposed, in which topoII acts as a Z-DNA-binding protein (ZBP) to stabilize given states of topological (sub)domains and associated multiprotein complexes. We have now explored this possibility by comprehensive bioinformatic analyses of the available protein sequences of topoII representing organisms covering the whole tree of life. Multiple alignment of these sequences revealed an extremely high level of evolutionary conservation, including a winged-helix protein segment, here denoted as Zτ, constituting the putative structural homolog of Zα, the canonical Z-DNA/Z-RNA binding domain previously identified in the interferon-inducible RNA Adenosine-to-Inosine-editing deaminase, ADAR1p150. In contrast to Zα, which is separate from the protein segment responsible for catalysis, Zτ encompasses the active site tyrosine of topoII; a GTP-binding site and a GxxG sequence motif are in close proximity. Quantitative Zτ-Zα similarity comparisons and molecular docking with interaction scoring further supported the “B-Z-topoII hypothesis” and has led to an expanded mechanism for topoII function incorporating the recognition of Z-DNA segments (“Z-flipons”) as an inherent and essential element. We further propose that the two Zτ domains of the topoII homodimer exhibit a single-turnover “conformase” activity on given G(ate) B-DNA segments (“Z-flipins”), inducing their transition to the left-handed Z-conformation. Inasmuch as the topoII-Z-DNA complexes are isomerase inactive, we infer that they fulfill important structural roles in key processes such as mitosis. Topoisomerases are preeminent targets of anti-cancer drug discovery, and we anticipate that detailed elucidation of their structural–functional interactions with Z-DNA and GTP will facilitate the design of novel, more potent and selective anti-cancer chemotherapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Bartas

Slychko

Červeň

et al. 2023

IJMS

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“…TOP2A is an enzyme involved in DNA replication and transcription, and its overexpression has been associated with a poor prognosis in NSCLC patients 39,40 . In addition, several TOP2A inhibitors, such as etoposide and doxorubicin, have shown promising results in preclinical studies for cancer treatment 41 . TYMS is an important enzyme for making DNA.…”

Section: Discussionmentioning

confidence: 99%

“… 39 , 40 In addition, several TOP2A inhibitors, such as etoposide and doxorubicin, have shown promising results in preclinical studies for cancer treatment. 41 TYMS is an important enzyme for making DNA. It has been found to be upregulated in NSCLC and could be a target for chemotherapy drugs like 5‐fluorouracil.…”

Section: Discussionmentioning

confidence: 99%

Network‐based identification of key proteins and repositioning of drugs for non‐small cell lung cancer

Adeyemo,

Ashimiyu‐Abdusalam,

Adewunmi

et al. 2024

Cancer Reports

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BackgroundNSCLC is a lethal cancer that is highly prevalent and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation, frequently exhibit limited efficacy and notable adverse reactions. Therefore, a drug repurposing method is proposed for effective NSCLC treatment.AimsThis study aims to evaluate candidate drugs that are effective for NSCLC at the clinical level using a systems biology and network analysis approach.MethodsDifferentially expressed genes in transcriptomics data were identified using the systems biology and network analysis approaches. A network of gene co‐expression was developed with the aim of detecting two modules of gene co‐expression. Following that, the Drug–Gene Interaction Database was used to find possible drugs that target important genes within two gene co‐expression modules linked to non‐small cell lung cancer (NSCLC). The use of Cytoscape facilitated the creation of a drug–gene interaction network. Finally, gene set enrichment analysis was done to validate candidate drugs.ResultsUnlike previous research on repositioning drugs for NSCLC, which uses a gene co‐expression network, this project is the first to research both gene co‐expression and co‐occurrence networks. And the co‐occurrence network also accounts for differentially expressed genes in cancer cells and their adjacent normal cells. For effective management of non‐small cell lung cancer (NSCLC), drugs that show higher gene regulation and gene affinity within the drug–gene interaction network are thought to be important. According to the discourse, NSCLC genes have a lot of control over medicines like vincristine, fluorouracil, methotrexate, clotrimazole, etoposide, tamoxifen, sorafenib, doxorubicin, and pazopanib.ConclusionHence, there is a possibility of repurposing these drugs for the treatment of non‐small‐cell lung cancer.

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“…Inhibiting topoisomerase II can lead to DNA damage and cell death in cancer cells. This is a mechanism used by several chemotherapeutic drugs [ 48 , 49 ]. Trans-syringin exhibits a high affinity for topoisomerase II, indicating its potential to effectively inhibit the activity of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the therapeutic potential: Evaluation of anti-inflammatory and antineoplastic activity of Magnolia champaca Linn’s stem bark isolate through molecular docking insights

Hasan,

Islam,

Hossain

et al. 2024

Heliyon

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The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Cited by 6 publications

References 139 publications

Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

Network‐based identification of key proteins and repositioning of drugs for non‐small cell lung cancer

Unveiling the therapeutic potential: Evaluation of anti-inflammatory and antineoplastic activity of Magnolia champaca Linn’s stem bark isolate through molecular docking insights

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