Functional Studies - SN 38, DNA topoisomerase I inhibitor (ab141108) ab2893 staining γH2A.X in HeLa cells treated with SN 38 (ab141108), by ICC/IF. Human DNA Topoisomerase II. DNA topoisomerase I inhibitor. Block the ligation step of the cell cycle, creating double and single strand breaks that effect the genome. DNA topoisomerases I and II are essential enzymes that manipulate the topological states of DNA in vivo by cleaving and religating DNA strands in a controlled manner .Their activity is critical to fundamental cellular processes such as transcription, replication, recombination, and DNA repair -.Mammalian cells express two isoforms of topoisomerase II (Top2) , : Top2α . They showed excellent inhibitory effects on several tumor cell lines with nanomolar IC 50 values. Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. DNA topoisomerases are enzymes that regulate DNA topology and are essential for the integrity of the genetic material during transcription, replication and recombination processes. The clinical . Idarubicin HCl (4-demethoxydaunorubicin, NSC256439, 4-DMDR) is a hydrochloride salt form of Idarubicin which is an anthracycline antibiotic and a DNA topoisomerase II (topo II) inhibitor for MCF-7 cells with IC50 of 3.3 ng/mL in a cell-free assay. Indirect immunofluorescence revealed that topo I was distributed throughout the nuclei but was concentrated in nucleoli of untreated K562 leukemia cells and A549 non-small cell lung cancer cells. Inhibitor. Some drugs, such as camptothecins, inhibit the dissociation of topoisomerase and DNA, leading to replication-mediated DNA damage, which can be repaired more efficiently in normal cells than in cancer cells (deficient for DNA repair). Beta dissociates more slowly from DNA. are active against several types of tumours. For example, induction therapies for adult acute myeloid leukemia (AML) include an anthracycline (eg, idarubicin or daunorubicin) in combination with cytosine arabinoside (araC), and consolidation protocols include other topo II poisons like mitoxantrone or etoposide. Histone deacetylase (HDAC) inhibitors, including MGCD0103 and vorinostat, have led to tumor growth inhibition and apoptosis in vivo. 1996 Jul;59(7):701-3. doi: 10.1021/np960336f. Most if not all Topoisomerase I inhibitors are derivatives of the plant extract camp-tothecin. All four agents are semisynthetic analogues of natural toxins that were initially identified in plants. Affiliation 1 Laboratoire de Chimie, URA 401 CNRS . DNA-intercalating drug topoisomerase II inhibitor oncolytic", abstract = "(Chemical Equation Presented) Voreloxin (SNS-595) is being developed by Sunesis Pharmaceuticals under license from Dainippon Sumitomo Pharma for the treatment of a variety of solid and hematological malignancies. Knocking out the orthologous gene in Drosophila melanogaster is also lethal. In contrast, TOP2 catalytic inhibitors induce limited DNA damage, have low cytotoxicity, and are effective in suppressing cancer cell proliferation. DNA topoisomerase I inhibitors: cytotoxic flavones from Lethedon tannaensis J Nat Prod. Topoisomerase inhibitors in current use in the United States include irinotecan and topotecan, inhibitors of topoisomerase I, and etoposide and teniposide, inhibitors of topoisomerase II. Mondal and Parvin (2001) demonstrated that DNA topoisomerase II-alpha is associated with the pol II holoenzyme and is a required component of chromatin-dependent coactivation. Differential Induction of Apoptosis in Undifferentiated and Differentiated HL-60 Cells by DNA Topoisomerase I and I1 Inhibitors By Eric Solary, Richard Bertrand, Kurt W. Kohn, and Yves Pommier The effects of monocytic/macrophage and granulocytic dif- promoter that does not induce differentiation, was not ac- ferentiation induced by phorbol myristate acetate (TPA) and tive. To overcome the limitations of known Top2 inhibitors, novel Top2 catalytic inhibitors with new scaffolds were identified by structure-based virtual screening. DNA topoisomerases are essential enzymes that control the topological state of DNA during cellular processes in both prokaryotic and eukaryotic cells. Dxd (Exatecan derivative for ADC) is a potent DNA topoisomerase I inhibitor, with an IC 50 of 0.31 μM, used as a conjugated drug of HER2-targeting ADC (DS-8201a). Their . 3135. The enzymes create and then repair single stranded nicks in cellular DNA. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). Further investigations revealed that teniposide could induce DCs and T cell activation and protect against tumor growth when used in a vaccine setting. DNA topoisomerase inhibitor, 5 | C13H17IN4OS - PubChem compound Summary DNA topoisomerase inhibitor, 5 Contents 1 Structures 2 Names and Identifiers 3 Chemical and Physical Properties 4 Related Records 5 Information Sources 1 Structures 1.1 2D Structure Find Similar Structures Chemical Structure Depiction 1.2 3D Conformer 2 Names and Identifiers Top2 inhibitors stabilize the Top2 cleavage complexes and are potent anticancer drugs.1,3,4,134Topoisomerases III (Top3α and Top3β) bind as monomers to non-canonical DNA structures (single-stranded DNA)14in association with a RecQ helicase (BLM in humans, Sgs-1 in budding yeast, Rhq1 in fission yeast). Authors A Zahir 1 , A Jossang, B Bodo, J Provost, J P Cosson, T Sévenet. Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. inhibitors, so it appears that interacting with multiple kinases is a key feature of this successful class of anticancer drugs and is critical for their effectiveness.21,22 1.2. A large number of topoisomerase inhibitors are known to play a major role as anticancer, antiparasitic and antibacterial agents. The function of the topoisomerase II is cutting both strands of one DNA double helix and passes another unbroken DNA helix through it. 되여 결국 세포분열을 이루어지지 않는다. Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense . Camptothecins. ≥98.0%. Among the non-camptothecin inhibitors, the . DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. By combining 2 screening assay results, we showed that the DNA topoisomerase II (Top II) inhibitor teniposide was capable of eliciting tumor cell ICD and subsequent T cell activation. Camptothecin. Finally, the cut ends are relegated again. DNA topoisomerase inhibitor, 8 | C9H18N4OS - PubChem compound Summary DNA topoisomerase inhibitor, 8 Contents 1 Structures 2 Names and Identifiers 3 Chemical and Physical Properties 4 Related Records 5 Information Sources 1 Structures 1.1 2D Structure Find Similar Structures Chemical Structure Depiction 1.2 3D Conformer 2 Names and Identifiers We employed topoisomerase inhibitors, which block the unwinding of dsDNA leading to inhibition of fundamental biological processes including DNA replication, transcription, DNA repair and chromatin remodelling, by stabilizing the DNA-single or -double breaks (Hsiang et al, 1989; Gorczyca et al, 1993). Humans express another isoform of topoisomerase II which is known as DNA topoisomerase II β (TOP2B) [15, 16]. Although A549 Smad4 −/− cells did not exhibit increased DNA damage at baseline , when challenged with etoposide (a DNA topoisomerase II inhibitor) for 4 h and then allowed to recover for 24 h . Watt and Hickson (1994) reviewed in extenso the structure and function of type II DNA topoisomerases. A second category of topoisomerase II inhibitors are referred to as catalytic inhibitors. Topoisomerase inhibitors are agents with anticancer activity. Topoisomerase II inhibitor; immunosuppressive and antineoplastic agent. 2,6-Diaminopyridine-3,5-bis(thiocyanate) (PR-619) is a broad-spectrum deubiquitinating enzyme (DUB) inhibitor that has been employed in cell-based studies as a tool to investigate the role of ubiquitination in various cellular processes. The acute effect of RNA and DNA synthesis inhibitors on DNA topoisomerase (topo) I localization within cells was examined. Topoisomerase Inhibitors Topoisomerase Inhibitors Excerpt Topoisomerase I and II are normal host enzymes that are found in the nucleus of mammalian cells and are required for normal DNA replication and cellular division. The DXd-ADC technology has a linker stable in plasma, a payload with a short systemic half-life, and an ADC in which the average drug-to-antibody ratio (DAR) can be optimized to up to 8 for each target . In this article, we discuss the characteristics of topoisomerase (DNA) I (TOP1) and its inhibitors, as well as the underlying DNA repair pathways and the use of TOP1 inhibitors in . OPM-2 cells were left untreated (0) or treated for 24 h with increasing concentrations of doxorubicin (A), etoposide (B) topotecan (C), bortezomib (D) and vincristine (E). Amrubicin (SM-5887) is a DNA topoisomerase II inhibitor, used for the research of cancer. Besides identifying a number of genes known to be important in HR, we also identified that loss of DNA topoisomerase 1 (TOP1), an enzyme that relieves the strain generated by the DNA double helix's twisting during DNA replication and transcription, could cooperate with CX-5461 in inhibiting ovarian cancer cell proliferation. Specific inhibitors of topoisomerase II blocked transcription on chromatin templates, but did not affect transcription . An antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical cancer. Exatecan mesylate. However, with limited single-agent activity demonstrated in solid tumor trials, we examined the potential for enhanced effects in combination with topoisomerase I and II inhibitors, a staple for treatment in refractory small cell lung cancer (SCLC). DXd is a more potent DNA topoisomerase I (TOP1) inhibitor than SN-38, an active metabolite of irinotecan . Decreased expression of γH2A.X (phospho S139) in HeLa cells correlates with an increase camptothecin concentration, as described in literature. Topoisomerase inhibitors block the ligation step of the cell cycle, which generates DNA single- and double-strand breaks, leading to apoptotic cell death. We used the transwell chamber assay to test effects of Topoisomerase inhibitors . DNA topoiso-merases are nuclear enzymes that catalyze the introduction of topological changes to the DNA molecule. Abstract. 7 Type I topoisomerases change the DNA linking . Topoisomerase inhibitors (TI) can inhibit cell proliferation by preventing DNA replication, stimulating DNA damage and inducing cell cycle arrest. Topoisomerase inhibitors are chemical compounds used to stop the action of topoisomerase I and II, an enzyme that controls the changes in DNA structure. of topoisomerase II inhibitors acts by stabilizing the covalently bound form of topoisomerase II with DNA, resulting in increased topoisomerase II-cross-linked DNA strand breaks. 3863. Although these agents have been commonly used in the chemotherapy for the anti-proliferative effect, their impacts on the metastasis of cancer cells remain obscure. Replication and Topoisomerase I inhibitors are a new class of anti-cancer agents with a mechanism of action aimed at inter-rupting DNA replication in cancer cells, the result of which is cell death. Topoisomerase inhibitors block the ligation step of the cell cycle, which generates DNA single- and double-strand breaks, leading to apoptotic cell death. There is an DS-7300a, a novel B7-H3-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd, exhibits potent anti-tumor effects in nonclinical models European Journal of Cancer 10.1016/s0959-8049(20)31102-3 A methanol extract of Zanthoxylum nitidum found to inhibit topoisomerase I-mediated DNA relaxation and stabilize the covalent binary complex between the enzyme and DNA was subjected to bioassay-guided fractionation; three strongly inhibitory principles were identified including nitidine, chelerythrine, and a new alkaloid for which the name isofagaridine is suggested. Bacterial type IIA topoisomerase inhibitors, such as fluoroquinolones and novel bacterial topoisomerase inhibitors, can trap DNA cleavage complexes with double- or single-stranded cleaved DNA. DNA topoisomerase I (TOP1) is ubiquitous and essential in mammals; Top1 knockout mice die early during embryogenesis 1. DNA topoisomerase inhibitor, 1 BDBM246599 4-benzoyl-1- (4-methyl-imidazol-5-ylcarbonyl)-thiosemicarbazide 3 Chemical and Physical Properties 3.1 Computed Properties 5 Literature 5.1 Springer Nature References Springer Nature 5.2 Depositor Provided PubMed Citations 6 Information Sources Filter by Source ALL SOURCES Springer Nature The nuclear enzymes topoisomerase I and II are critical for DNA function and cell survival, and recent studies have identified these enzymes as cellular targets for several clinically active anticancer drugs. TAS-103 is a dual topoisomerase I and II inhibitor that has marked efficacy against various lung metastatic cancers and a broad antitumor spectrum in human xeno-grafts, and it has reached clinical trials for the treatment of solid tumors.21 DNA I Pentapeptide I Chromophore — NH2 PO2 Intercalation Chromophore — NH2 PO2 Intercalation b-ring Irinotecan. While fluoroquinolones target the type II enzymes, seconeolitsine, a new antimicrobial agent, targets topoisomerase I. Also inhibits cdk1 and cdk2. However, treatment with these drugs often results in the development . Media in category "Topoisomerase inhibitors" The following 3 files are in this category, out of 3 total. Increase of γH2A.X nuclear expression correlates with increased concentration of SN 38, as described in literature. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms: Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents. Topoisomerases are enzymes that resolve winding problem of DNA during cellular processes. DNA topoisomerase II (topo II) is the target of some of the most important chemotherapeutic drugs used to treat leukemia. Compounds that inhibit the activity of DNA TOPOISOMERASE I. Irinotecan (CPT-11), a semi-synthetic deriva- This work investigates sub-5 nm ultrafine iron oxide nanoparticles (uIONP) with 3.5 nm core diameter as a carrier for delivering DNA topoisomerase inhibitor 7-ethyl-10-hydroxyl camptothecin (SN38) to treat GBM. E) Etoposide stabilizes the cleavable complex of DNA and topoisomerase. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Trovafloxacin mesylate. 6 DNA topoisomerase I is a ubiquitous enzyme responsible for the relaxation of DNA supercoils arising as a consequence of processes such as transcription and replication. Introduction. Background: The MLL 11q23 translocation arises in utero and is present in 75% of infant leukemias. In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. Introduction. 1, 2 In addition, the enzyme catenates- decatenates double-stranded DNA circles, resolves knots in DNA and also relaxes negatively supercoiled DNA in the absence of ATP. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. 4250. Etoposide is 3-4 times less active against the beta form than the alpha. Topoisomerase II α (Top2-α), a subclass of . Because of essential roles of these enzymes in maintenance of cell function, topoisomerases are important targets for cancer chemotherapy. Indirect immunofluorescence revealed that topo I was distributed throughout the nuclei but was concentrated in nucleoli of untreated K562 leukemia cells and A549 non-small cell lung cancer cells. Inhibitors in this category prevent topoisomerase II from carrying out Here, we demonstrate that in addition to its action as a DUB inhibitor, PR-619 is a potent DNA topoisomerase II (TOP2) poison, inducing both DNA topoisomerase . Topoisomerases are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. Topoisomerase II inhibitor. Functional Studies - Camptothecin, DNA topoisomerase inhibitor (ab120115) HeLa cells were incubated at 37°C for 3h with vehicle control (0 µM) and different concentrations of camptothecin (ab120115). The acute effect of RNA and DNA synthesis inhibitors on DNA topoisomerase (topo) I localization within cells was examined. 결국 t-inhibitor들을 암세포의 분열을 막는 용도로 사용할수 있는 것이다. Studies have shown that ARC-111 (dibenzo [ c, h ]- [1,6]naphthyridin-6-one) is one of the effective topoisomerase I (top I) targeting agents and its analogs exhibit antitumor activities [25]. DNA minor groove-binding ligands: A different class of mammalian DNA topoisomerase I inhibitors ALLAN Y. CHEN, CHIANG Yu, BARBARA GATTO, AND LEROY F. LIu* Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635 Communicated by James C. Wang, May . Topoisomerase inhibitors are chemotherapeutic agents that interfere with the topoisomerase enzymes (topoisomerase I and II), which control changes in DNA structure [91]. Poison inhibitors of DNA topoisomerase II (TOP2) are clinically used drugs that cause cancer cell death by inducing DNA damage, which mechanism of action is also associated with serious side effects such as secondary malignancy and cardiotoxicity. Dxd is cytotoxic to human cancer cell lines of KPL-4, NCI-N87, SK-BR-3, and MDA-MB-468 with IC 50 s of 1.43 nM-4.07 nM, but the control IgG-ADC (Dxd is the payload) shows no inhibition on the four cell lines (with HER2 expression). The cellular processes include DNA replication, transcription, recombination and chromatin segregation, to control the synthesis of proteins and to facilitate DNA replication during mitosis 2). Antibiotic; inhibits bacterial DNA topoisomerase IV and DNA gyrase. DNA topoisomerases are enzymes responsible for the relaxation of DNA torsional strain, as well as for the untangling of DNA duplexes after replication, and are important cancer drug targets. 그런데 topoisomerase inhibitor에 의해서 DNA twisting이 잘림이 일어나지 못하면 polymerase들은 일을 하지 못하고 stalling. Topoisomerase inhibitors are chemotherapeutic agents that interfere with the topoisomerase enzymes (topoisomerase I and II), which control changes in DNA structure [91]. Platinum complexes as inhibitors of DNA repair protein Ku70 and topoisomerase IIα in cancer cells† Hongmei Zhang , ab Ying Wang , a Yanqing Wang , b Qianqian Han , b Honghao Yan , b Tao Yang , a Zijian Guo cd and Xiaoyong Wang * ad One class of topoisomerase inhibitors, "poisons", binds to the transient enzyme-DNA complex which occurs during the mechanism of action, and inhibits the religation of DNA. The two isoforms of topoisomerase II are 68% identical and their catalytic portion share ~78% similarity. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Exatecan mesylate (DX8951f) is a DNA topoisomerase I inhibitor, with an IC50 of 2.2 μM (0.975 μg/mL). β -Lapachone. A new class of pyridobenzophenoxazine compounds has been developed as topoisomerase II inhibitors for anticancer chemotherapy. Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Journal of Medicinal Chemistry 2018, 61 (22) , 9908-9930. https://doi.org/10.1021/acs.jmedchem.8b00639 Exatecan mesylate can be used in cancer research. The discovery of novel noncamptothecin inhibitors is facilitated by the availability of biochemical and cellular assays for testing topoisomerase I activity. During DNA replication, TOP2A plays a key role and its main functions are chromosome segregation and chromosome condensation . These enzymes maintain the DNA topology, which is essential for replication and transcription. The DNA topoisomerase complement of Streptococcus pneumoniae is constituted by two type II enzymes (topoisomerase IV and gyrase), and a single type I enzyme (topoisomerase I). Mitoxantrone dihydrochloride. Human DNA topoisomerase II (Top2) is a promising target for cancer treatment. Inhibitors of the mammalian enzymes are widely used antitumor drugs. In particular, compound 8 showed good in vitro antiproliferative activit HY-13631A. To date, several topoisomerase inhibitors have been introduced and applied as drugs in the treatment of cancer. That MLL+ acute myeloid leukemia (AML) can arise following chemotherapy with DNA topoisomerase II (DNAt2) inhibitors suggests that these substances, which also occur naturally in foods, may contribute toward infant leukemia. As a result, the enzyme is vital for almost all cellular processes that involve duplex . Topotecan. Topoisomerase inhibitors are chemical compounds used to stop the action of topoisomerase I and II, an enzyme that controls the changes in DNA structure. Topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins, etc.) Topoisomerase I inhibitors induce single-strand breaks into DNA, and can work by a variety of mechanisms. The 5' end of the nicked DNA is realigned with the 3' end which enables religation. DNA topoisomerase 1 (Top1), which belongs to type IB and was the focus of Pommier's talk, is found in the nuclear genome and is not transported into the mitochondria, at least in mammals. Common problems such as overwinding (positive supercoiling), knots and tangles are . 1 . We hypothesized that maternal consumption of dietary DNAt2 . Drug Description. D) Topoisomerase II exists in two forms, alpha and beta. Studies have shown that ARC-111 (dibenzo [ c, h ]- [1,6]naphthyridin-6-one) is one of the effective topoisomerase I (top . DNA gyrase, a type II DNA topoisomerase, is the only known enzyme that negatively supercoils DNA in the presence of ATP. NU 2058. 7"-O-Methyl-agathisflavone (I) and amentoflavone (II) are biflavonoids and were isolated from the Brazilian plants Ouratea hexasperma . They stabilize topoisomerase-DNA cleavable complex … Idarubicin induces mTOR-dependent cytotoxic autophagy. Along these lines, DNA topoisomerase inhibitors are of great interest because they help to maintain strand breaks generated by topoisomerases during replication. DNA topoisomerases, also known as the vertebrate DNA untwisting enzymes, are found in a variety of organisms and act to regulate DNA supercoiling. Topovale, also known as ARC-111, is a potent topoisomerase I inhibitor. A nice clip i found on the mechanisms of action of topoisomerase 1 and 2 The cells were incubated at 37°C for 6 hours in media containing different . Drugs. Depending upon the affected step of the TOP2A activity cycle, these so-called catalytic inhibitors are thought to prevent binding between DNA and TOP2A (aclarubicin and suramin), to stabilize non-covalent DNA-TOP2A complexes (merbarone and bisdioxopiperazines) or to inhibit ATP binding (novobiocin) (Larsen et al., 2003). What is thought to be the process of topoisomerase inhibitors? 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