Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Six 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin were examined for inhibitory activity against human DNA topoisomerase II and tubulin polymerization, their ability to generate protein-linked DNA breaks in cells, and their cytotoxicity toward the KB cell line and its VP-16- and vincristine-resistant variants. Five of these derivatives were 5- to 10-fold more potent than VP-16 as inhibitors of DNA topoisomerase II in vitro, and all of these derivatives could generate the same amount of or more protein-linked DNA breaks in cells than VP-16 at 1-20 microMs. Tubulin polymerization was inhibited by these compounds to different degrees in the order: podophyllotoxin greater than W73 greater than W87 greater than NPF greater than NPC greater than W68 greater than W38 greater than VP-16. These analogues were cytotoxic not only to KB cells but also to their VP-16-resistant and vincristine-resistant variants which showed decreased cellular uptake of VP-16 and a decrease in DNA topoisomerase II content or overexpression of MDR1 phenotype. These characteristics may cause these derivatives to have different spectrums of antitumor activity.
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PMID:Effect of 4 beta-arylamino derivatives of 4'-O-demethylepipodophyllotoxin on human DNA topoisomerase II, tubulin polymerization, KB cells, and their resistant variants. 184 78

Combination of selecting agents that act on different cellular mechanisms is a common strategy in cancer chemotherapy. GL331 is a new potent topoisomerase II (Topo II) poison; distinctly, paclitaxel is a microtubule-interfering cancer chemotherapeutic agent. In this study, we intended to evaluate the efficacy of combining GL331 with paclitaxel in cell killing and apoptotic induction in nasopharyngeal carcinoma NPC-TW01 cells. By MTT and internucleosomal DNA cleavage assays, we found that pretreatment or simultaneous treatment of NPC-TW01 cells with GL331 could significantly interfere with paclitaxel's cell killing and apoptosis-inducing activity. When the administration schedule was reversed, the cytotoxicity of GL331 was attenuated by paclitaxel pretreatment. The anti-cancer activity produced by combining GL331 with paclitaxel was obviously lower than the addition of the activities of two individual agents. NPC-TW01 cells were treated with GL331 and 3H-labeled paclitaxel simultaneously or with GL331 before 3H-labeled paclitaxel. In both conditions, GL331 did not reduce the [3H]paclitaxel level in the cells, suggesting that GL331's interference with paclitaxel's cell-killing and apoptosis-inducing efficacy did not result from any inhibition of cellular uptake or retention of paclitaxel. In addition, we found that GL331-induced perturbation of cell cycle progression dramatically over-rode the patterns of mitotic arrest induced by paclitaxel, and the mechanism could be the inhibition of cyclin B1/CDC2 kinase and MAD2 checkprotein activities.
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PMID:Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle perturbation and apoptosis. 1129 Aug 73

From the surrounding shell to the inner machinery, nuclear proteins provide the functional plasticity of the nucleus. This study highlights the nuclear association of Pore membrane (POM) protein NDC1 and Werner protein (WRN), a RecQ helicase responsible for the DNA instability progeria disorder, Werner Syndrome. In our previous publication, we connected the DNA damage sensor Werner's Helicase Interacting Protein (WHIP), a binding partner of WRN, to the NPC. Here, we confirm the association of the WRN/WHIP complex and NDC1. In established WRN/WHIP knockout cell lines, we further demonstrate the interdependence of WRN/WHIP and Nucleoporins (Nups). These changes do not completely abrogate the barrier of the Nuclear Envelope (NE) but do affect the distribution of FG Nups and the RAN gradient, which are necessary for nuclear transport. Evidence from WRN/WHIP knockout cell lines demonstrates changes in the processing and nucleolar localization of lamin B1. The appearance of "RAN holes" void of RAN corresponds to regions within the nucleolus filled with condensed pools of lamin B1. From WRN/WHIP knockout cell line extracts, we found three forms of lamin B1 that correspond to mature holoprotein and two potential post-translationally modified forms of the protein. Upon treatment with topoisomerase inhibitors lamin B1 cleavage occurs only in WRN/WHIP knockout cells. Our data suggest the link of the NDC1 and WRN as one facet of the network between the nuclear periphery and genome stability. Loss of WRN complex leads to multiple alterations at the NPC and the nucleolus.
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PMID:Werner complex deficiency in cells disrupts the Nuclear Pore Complex and the distribution of lamin B1. 2405 Sep 18