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Category: TopoGEN Blog

Study: Geminin Silencing Inhibits Topo II Function

Study: Geminin Silencing Inhibits Topo II Function

The Topo II Assay Kit is arguably our most simple and tractable diagnostic, making it one of our most popular products for novel chemo-therapuetics research.  Referenced here is a study that utilized the assay to monitor topoisomerase II enzyme in relation to the presence of geminin in human breast cancer cells.  The findings indicate that targeting geminin has therapeutic potential in the study of cancer cells and drug resistance.  This work opens up the prospect of using geminin as a…

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Emodin: Topo II Inhibitor and Poison

Emodin: Topo II Inhibitor and Poison

In this work, the authors demonstrate very nicely the mode of action of emodin, an active anthraquinone natural product from plants and fungi (and used as a laxative).  This widely used drug is genotoxic and is a carcinogen.  Its mode of action is unclear and this work defines it as a topo II inhibitor and poison.  They propose a mechanism involving both cleavage stabilization and inhibition of ATP hydrolysis.  The key experiments involved using the ICE bioassay to examine in…

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Genomic Instability and Topo II

Genomic Instability and Topo II

For those looking for background about the  human topoisomerase II alpha protein and its role as a decatenating check-point during mitosis, an informative article originally published in Oncogene is available here.  Nuclear extracts were assayed for decatenation using the Human Topoisomerase II Assay Kit.  Human Topoisomerase II is available from TopoGEN. Article Source: NIH Public Access Website

Topotecan and its Effects on Human Topoisomerase I

Topotecan and its Effects on Human Topoisomerase I

A very nice paper has been recently published in the free access journal PLoS One.  These investigators are starting to ask important structural questions about how Topotecan, a clinically useful topoisomerase I poison, interacts with the enzyme to create a stable complex.  The authors go on to examine the molecular details on DNA deformation with drug/specific residue contacts.  By focusing on the ternary complex between topo/topotecan/DNA they have gained key insight to our understanding of the dynamics of the process….

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Topoisomerase II Drug Sensitivity May Be Individually Determined

Topoisomerase II Drug Sensitivity May Be Individually Determined

Effect of a Single Nucleotide Polymorphism in the Murine Double Minute 2 Promoter (SNP309) on the Sensitivity to Topoisomerase II-Targeting Drugs Abstract A single nucleotide polymorphism (SNP) SNP309 (T–>G) in the murine double minute 2 (MDM2) promoter creates a high-affinity Sp1 binding site and increases the expression of MDM2 mRNA and protein. Approximately 40% of the populations harbor at least one variant allele and 12% to 17% are homozygous G/G at codon 309. This MDM2 SNP increases susceptibility to cancer…

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Topoisomerase I Not Simply Adjusting Genome Topology

Topoisomerase I Not Simply Adjusting Genome Topology

Topoisomerases are well known to be essential for all aspects of DNA function, from replication to repair and particularly in transcription. For this reason, they have for many years been excellent DNA damaging agents that display selectively for tumor cells. A relatively recent finding has come to light that involves topoisomerase I and induction of cellular senescence. Cellular senescence is a form of tumor suppression that puts cells in a more or less permanent proliferative arrest. It is induced by…

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Doxorubicin: A Preclinical Study

Doxorubicin: A Preclinical Study

Sequencing of Type I Insulin-Like Growth Factor Receptor Inhibition Affects Chemotherapy Response In vitro and In vivo Xianke Zeng,1,2 Deepali Sachdev,2 Hua Zhang,2 Martine Gaillard-Kelly,3 and DouglasYee1,2 Abstract Purpose: The aim of this study was to determine the optimal sequence of combining anti-type I insulin-like growth factor receptor (IGF1R) antibodies with chemotherapeutic drugs in cancer cells in vitro and in vivo. Experimental Design: MCF-7 and LCC6 cells were treated with subcytotoxic concentrations of doxorubicin with or without anti-IGF1R antibodies (scFv-Fc…

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Gyrase B Inhibitor Potential HIV Treatment

Gyrase B Inhibitor Potential HIV Treatment

Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein Chemical genetics is an emerging approach to investigate the biology of host-pathogen interactions. We screened several inhibitors of ATP-dependent DNA motors and detected the gyrase B inhibitor coumermycin A1 (C-A1) as a potent antiretroviral. C-A1 inhibited HIV-1 integration and gene expression from acutely infected cell, but the two activities mapped to distinct targets. Target discovery identified Hsp90 as the C-A1 target affecting viral gene expression. Chromatin immunoprecipitation…

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Findings of PARP Inhibitors Study at NIH

Findings of PARP Inhibitors Study at NIH

Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. Zhang YW, Regairaz M, Seiler JA, Agama KK, Doroshow JH, Pommier Y. Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA. Abstract Poly(ADP-Ribose) (PAR) polymerase (PARP) inhibitors represent a promising class of novel anticancer agents. The present study explores the molecular rationale for combining veliparib (ABT-888) with camptothecin (CPT) and its…

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Topoiosomerase Inhibition: A Study

Topoiosomerase Inhibition: A Study

Cytotoxicity and topoisomerase I/II inhibition of glycosylated 2-phenyl-indoles, 2-phenyl-benzo[b]thiophenes and 2-phenyl-benzo[b]furans Wei Shia, Sandra L. Marcusa and Todd L. Lowary Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB T6G 2G2 Canada Abstract A panel of glycosylated DNA binding agents (1–12) designed as functional anthracycline mimics was screened against three solid-tumor cell lines (MCF-7, HT 29 and HepG2/C3A) and three non-tumor cell lines by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) cell viability assay….

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