All the drugs shown in Figure 3 (panel CF) inhibit Top2 by targeting Top2cc and inhibiting their religation,1,5,7,11,74 most likely through interfacial inhibition (see section 3 and Fig. Topoisomerases facilitate transcription of long genes linked to autism Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese,. Under normal conditions, Top1 and Top2 cleave and religate DNA very rapidly (AB and EF). This supercoiling increases with the progression of the replication fork. 1 and and2).2). Type I enzymes cleave one strand to process DNA entanglements whereas type II cleave both strands by concerted action of each Top2 monomer (see Table 1). The .gov means its official. Lin CP, Ban Y, Lyu YL, Desai SD, Liu LF. 2C & G).29,30. Quinolones target the GyrA subunit of gyrase and the ParC subunit of Topo IV5 by interfacial inhibition3941 (see section 36). Camptothecin-stabilised topoisomerase I-DNA complexes in leukaemia cells visualised and quantified in situ by the TARDIS assay (trapped in agarose DNA immunostaining). Viard T, de la Tour CB. Makeyev Y, Muggia FM, Rajan A, Giaccone G, Furuta T, Rougier P. In: Vo TT, Ryan J, Carrasco R, Neuberg D, Rossi DJ, Stone RM, Deangelo DJ, Frattini MG, Letai A. Willmore E, Frank AJ, Padget K, Tilby MJ, Austin CA. The second part of the review focuses on the challenges for discovery and precise use of topoisomerase inhibitors, including targeting topoisomerase inhibitors using chemical coupling and encapsulation for selective tumor delivery, use of pharmacodynamic biomarkers to follow drug activity, complexity of the response determinants for anticancer activity and patient selection, prospects of rational combinations with DNA repair inhibitors targeting tyrosyl-DNA-phosphodiesterases 1 and 2 (TDP1 and TDP2) and PARP, and the unmeet need to develop inhibitors for type IA enzymes. DNA topoisomerase II is required for RNA polymerase II transcription Topoisomerase: Overview & Applications - Excedr Hawtin RE, Stockett DE, Byl JA, McDowell RS, Nguyen T, Arkin MR, Conroy A, Yang W, Osheroff N, Fox JA. 2G).3942 The interfacial inhibition principle extends beyond topoisomerase inhibitors. The therapeutic mechanism of action of topoisomerase inhibitors revealed another new paradigm for drug action (in addition to interfacial inhibition detailed above): enzyme poisoning rather than catalytic inhibition drives drug activity. Azarova AM, Lyu YL, Lin CP, Tsai YC, Lau JY, Wang JC, Liu LF. A special thank to C. Marchand for figure 2. There are two classes of topoisomerases: type I enzymes introduce single strand breaks in DNA and type II topoisomerases introduce double strand breaks 1, 2. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF. 1B),2023 whereas type IA and type IIA enzymes work by passing one strand or one duplex, respectively, from the same DNA molecule through the single- or double-strand break generated by the topoisomerase in another duplex (Fig. A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity. Drugging Topoisomerases: Lessons and Challenges - PMC 5068, NIH, Bethesda, MD 20892, USA. Teicher BA. A comparable approach is to encapsulate topoisomerase inhibitors into nanoparticles, which are preferentially sequestered in tumors with uneven blood flow and taken up by tumor cells. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Stewart L, Redinbo MR, Qiu X, Hol WG, Champoux JJ. Nitiss JL. Reactions are represented from left to right. Etirinotean pegol (NKTR-102) couples the active metabolite of irinotecan (SN-38) to polyethylene glycol, limiting the release of SN-38 to normal tissues with tight vasculature, whereas the drug is released into tumors by their intrinsically leaky blood vessels. PARP inhibitors are highly synergistic with Top1 inhibitors but not with Top2 inhibitors, which fits with PARP activation by Top1 but not by Top2 inhibitors.120,148,149 PARP activation by Top1cc is both transcription- and replication-dependent120 and tightly coupled with TDP1 activity (our unpublished data). 4): precise cleavage of the tyrosyl-DNA bond by phosphodiesterases or endonuclease cleavage and elimination of the DNA strand attached to the topoisomerase. Formation and resealing of intercalator-induced DNA strand breaks in permeabilized L1210 cells without the stimulated synthesis of poly(ADP-ribose). Introduction DNA topoisomerases are present in all domains of life to resolve a wide variety of topological problems arising from the length of the human double-helix DNA polymer (about 3 10 9. Trapping protein-DNA complexes extends to a novel mechanism of action of PARP inhibitors and could be applied to the targeting of transcription factors. 4 and section 8.4 above). Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae. Quinolones (Fig. Champoux JJ. Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Topoisomerases are ubiquitous enzymes that control DNA supercoiling and entanglements. Debethune L, Kohlhagen G, Grandas A, Pommier Y. The site is secure. Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS. Formation and rejoining of deoxyribonucleic acid double-strand breaks induced in isolated cell nuclei by antineoplastic intercalating agents. Crystal structure of a transition state mimic for tdp1 assembled from vanadate, DNA, and a topoisomerase I-derived Peptide. Mir O, Dahut W, Goldwasser F, Heery C. In: Tewey KM, Chen GL, Nelson EM, Liu LF. DNA topoisomerases: Advances in understanding of cellular roles and The enzyme poisoning mechanism of action first identified for topoisomerase inhibitors has recently been extended to poly(adenosine diphosphoribose) polymerase (PARP) inhibitors. Topoisomerases are enzymes that relax DNA supercoiling during replication and transcription. Targeting DNA topoisomerase II in cancer chemotherapy. Type II enzymes are homodimeric (humans) or heterotetrameric (bacteria), and cleave both strands of duplex DNA with a 5-four-base overhang (see Fig. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2,. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Huang SY, Pommier Y, Marchand C. Tyrosyl-DNA Phosphodiesterase 1 (Tdp1) inhibitors. If the supercoiling is not relieved, it will physically prevent the movement of helicase. In vitro epsilon RNA-dependent protein priming activity of human hepatitis B virus polymerase. The fourth Top2-targeted drug in clinical trials is the quinoxaline R(+)-XK469 (Fig. 1 and Table 1).15,24,25, Replication of circular DNA molecules and chromatin loops produces interlinked DNA products (catenanes)5 that need to be removed by the strand passing activities of topoisomerases. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro. Topoisomerases bind to DNA in a noncovalent fashion followed by the formation of transient cleavage complexes. Zhang HF, Tomida A, Koshimizu R, Ogiso Y, Lei S, Tsuruo T. Cullin 3 promotes proteasomal degradation of the topoisomerase I-DNA covalent complex. To avoid the dose-limiting toxicity of camptothecins and their short half lives and to reduce normal tissue toxicity while increasing drug delivery to tumors, camptothecins have been conjugated to a macromolecular core as in etirinotecan pegols (NKTR-102). Nature reviews. Takeshita T, Wu W, Koike A, Fukuda M, Ohta T. Perturbation of DNA repair pathways by proteasome inhibitors corresponds to enhanced chemosensitivity of cells to DNA damage-inducing agents. 2).23, Interfacial inhibition for Top1 (left) and Top2 inhibitors (right). Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, Robey R, Pommier Y, Fojo T, Bates SE. Novel indenoisoquinolines NSC 725776 and NSC 724998 produce persistent topoisomerase I cleavage complexes and overcome multidrug resistance. It remains used today primarily for the treatment of acute leukemia.78 Doxorubicin (adriamycin), another bacterial toxin, was discovered soon after daunorubicin and is more widely used.78 It is active in first line therapy for breast cancers, bone and soft tissue sarcomas, bladder cancers, anaplastic thyroid cancer, Hodgkins and non-Hodgkins lymphomas and multiple myeloma.79 Epirubicin (4-epi-doxorubicin), an active isomer of doxorubicin (Fig. Structure of anticancer and antibacterial topoisomerase inhibitors. 2C & G). Davies DR, Interthal H, Champoux JJ, Hol WG. 3D) drives the update of the drug to cells overexpressing the polyamine transport system (PTS). Bacterial cell killing mediated by topoisomerase I DNA cleavage activity. 1 & 2). Global fluoroquinolone resistance epidemiology and implictions for clinical use. Zeng Z, Sharma A, Ju L, Murai J, Umans L, Vermeire L, Pommier Y, Takeda S, Huylebroeck D, Caldecott KW, El-Khamisy SF. Burgess DJ, Doles J, Zender L, Xue W, Ma B, McCombie WR, Hannon GJ, Lowe SW, Hemann MT. Protein-associated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic acid intercalating agents 4'-(9-acridinylamino) methanesulfon-m-anisidide and adriamycin. 3A). Topoisomerases are required,34,4446,5254 yet there is no simple linear correlation between topoisomerase levels and drug response.60,61 Two main approaches are should define cancer-related defects predicting drug response (or lack of). Proteasome-dependent processing of topoisomerase I-DNA adducts into DNA double-strand breaks at arrested replication forks. DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Voreloxin is an intercalative quinolone derivative in Phase IIIII clinical development in combination with cytarabine for relapsing and refractory acute myeloblastic leukemia.95 DNA intercalation is important for its activity. Simultaneous amplification of HER-2 (ERBB2) and topoisomerase IIalpha (TOP2A) genes--molecular basis for combination chemotherapy in cancer. Camptothecin induction of a time- and concentration-dependent decrease of topoisomerase I and its implication in camptothecin activity. Clinically relevant Top1 inhibitors (Fig. First, it is the most selective Top2cc-targeted drug currently in the clinic. Tanizawa A, Fujimori A, Fujimori Y, Pommier Y. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Before Careers, Unable to load your collection due to an error. Accessibility One possible model is that conversion of Top1cc into DNA damage by transcription and replication collisions recruits the proteasome, which prepares the DNA ends for processing by the TDP1-PARP complex, in which PARP acts as a cofactor of TDP1 to facilitate its stability and recruitment to the DNA damage sites along with XRCC1, PNK and ligase III. Finally, etoposide traps both Top2 and very effectively,59,90 whereas doxorubicin tends to target more selectively cellular Top2 over Top2.91 The trapping of Top2 has been related to the induction of secondary leukemia in patient previously treated with etoposide,92 and linked to Top2-mediated DNA translocations (see section 8.2).93,94, The anthracenedione mitoxantrone (Novantrone) (Fig. Reinhold WC, Sunshine M, Liu H, Varma S, Kohn KW, Morris J, Doroshow J, Pommier Y. CellMiner: A Web-Based Suite of Genomic and Pharmacologic Tools to Explore Transcript and Drug Patterns in the NCI-60 Cell Line Set. The first part of this assay summarizes the known mechanisms by which drugs target topoisomerases, complementing and updating more detailed reviews.112 The relatively unknown mechanism of action of topoisomerase inhibitors can be traced to the complexity of the topic with 6 different genes in humans cells and bacteria, drugs acting as interfacial inhibitors that trap ternary complexes, and drug cytotoxic mechanisms mediated by the trapping of topoisomerases on DNA rather than by classical enzymatic inhibition. 3A). Several approaches are being implemented to target topoisomerase inhibitors to tumors while sparing normal tissues. Differential catalytic mechanisms of topoisomerases. Medical Definition of Topoisomerase - MedicineNet Topoisomerases are ubiquitous enzymes, found in all living . The other non-camptothecin in clinical trials is 8,9-dimethoxy-5-(2-N-methylaminoethyl)-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (Genz-644282; SAR402674) (Fig.