Topoisomerase II (TOP2) is the target of several important classes of anticancer drugs, including the epipodophyllotoxin etoposide and the anthracycline doxorubicin.
Most clinically active drugs that target TOP2 kill cells by trapping an enzyme intermediate termed the covalent complex. Therefore, the principal action of the TOP2-targeting drugs that are currently used is to generate enzyme-mediated DNA damage.
A recent structure of the breakage reunion domain of TOP2 bound to DNA has been determined. This structure is likely to be useful for understanding the protein determinants of the action of drugs targeting TOP2. A drug–protein–DNA ternary complex would be valuable but has not yet been determined.
TOP2-mediated DNA damage is repaired by multiple pathways. This DNA damage includes DNA strand breaks and proteins that are covalently bound to DNA. Repair of TOP2-mediated damage requires double-strand break repair pathways and other pathways that are specific for the removal of protein–DNA adducts.
Sensitivity to TOP2-targeting drugs depends in part on the levels of TOP2. Cells overexpressing TOP2 are hypersensitive to TOP2 poisons and cells expressing low levels of TOP2 are drug resistant. TOP2A is frequently co-amplified with ERBB2, which can lead to the development of tumours with increased levels of TOP2α.
An important side effect of targeting TOP2 with TOP2 poisons is the formation of secondary malignancies that arise from drug-induced translocations. TOP2β might be the TOP2 isoform that is most responsible for the secondary malignancies caused by TOP2-targeting drugs.
Anthracycline use is limited by cardiotoxicity. Although the mechanism of the cardiotoxicity is poorly understood, recent results suggest that anthracyclines that target TOP2β might contribute to cardiotoxicity. There might be considerable benefit to developing TOP2-targeting drugs that are specific for the TOP2α isoform.
Catalytic inhibition of TOP2 could also be a useful anticancer strategy. New compounds are being developed to test this possibility.
Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Liu, L. F. DNA topoisomerase poisons as antitumor drugs. Annu. Rev. Biochem. 58, 351–375 (1989).
Chen, G. L. et al. Nonintercalative antitumor drugs interfere with the breakage–reunion reaction of mammalian DNA topoisomerase II. J. Biol. Chem. 259, 13560–13566 (1984).
Tewey, K. M., Rowe, T. C., Yang, L., Halligan, B. D. & Liu, L. F. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 226, 466–468 (1984).
Pommier, Y., Schwartz, R. E., Zwelling, L. A. & Kohn, K. W. Effects of DNA intercalating agents on topoisomerase II induced DNA strand cleavage in isolated mammalian cell nuclei. Biochemistry 24, 6406–6410 (1985).
Nitiss, J. L. & Beck, W. T. Antitopoisomerase drug action and resistance. Eur. J. Cancer 32A, 958–966 (1996).
Walker, J. V. & Nitiss, J. L. DNA topoisomerase II as a target for cancer chemotherapy. Cancer Invest. 20, 570–589 (2002).
Kaufmann, W. K. Human topoisomerase II function, tyrosine phosphorylation and cell cycle checkpoints. Proc. Soc. Exp. Biol. Med. 217, 327–334 (1998).
Fedier, A. et al. Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites. Ann. Oncol. 14, 938–945 (2003).
Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).
Kerrigan, D., Pommier, Y. & Kohn, K. W. Protein-linked DNA strand breaks produced by etoposide and teniposide in mouse L1210 and human VA-13 and HT-29 cell lines: relationship to cytotoxicity. NCI Monogr., 117–121 (1987).
Covey, J. M., Kohn, K. W., Kerrigan, D., Tilchen, E. J. & Pommier, Y. Topoisomerase II-mediated DNA damage produced by 4′-(9- acridinylamino methanesulfon-m-anisidide and related acridines in L1210 cells and isolated nuclei: relation to cytotoxicity. Cancer Res. 48, 860–865 (1988).
Kaufmann, S. H. Cell death induced by topoisomerase-targeted drugs: more questions than answers. Biochim. Biophys. Acta 1400, 195–211 (1998).
Wang, L. & Eastmond, D. A. Catalytic inhibitors of topoisomerase II are DNA-damaging agents: induction of chromosomal damage by merbarone and ICRF-187. Environ. Mol. Mutagen. 39, 348–356 (2002).
Haggarty, S. J. et al. Small molecule modulation of the human chromatid decatenation checkpoint. Chem. Biol. 10, 1267–1279 (2003).
Luo, K. T., Yuan, J., Chen, J. J. & Lou, Z. K. Topoisomerase IIα controls the decatenation checkpoint. Nature Cell Biol. 11, 204–210 (2009).
Germe, T. & Hyrien, O. Topoisomerase II–DNA complexes trapped by ICRF-193 perturb chromatin structure. EMBO Rep. 6, 729–735 (2005).
Skoufias, D. A., Lacroix, F. B., Andreassen, P. R., Wilson, L. & Margolis, R. L. Inhibition of DNA decatenation, but not DNA damage, arrests cells at metaphase. Mol. Cell 15, 977–990 (2004).
Jensen, P. B. & Sehested, M. DNA topoisomerase II rescue by catalytic inhibitors - a new strategy to improve the antitumor selectivity of etoposide. Biochem. Pharmacol. 54, 755–759 (1997).
Marchand, C. et al. A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I–DNA covalent complex. Mol. Cancer Ther. 5, 287–295 (2006). A model for the action of TOP1-targeting drugs. This model might be more generally applicable to all topoisomerase poisons.
Staker, B. L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl Acad. Sci. USA 99, 15387–15392 (2002).
Chrencik, J. E. et al. Mechanisms of camptothecin resistance by human topoisomerase I mutations. J. Mol. Biol. 339, 773–784 (2004). This paper is mainly applicable to the study of TOP1-targeting drugs and shows how a relevant drug–DNA–enzyme ternary structure can be used to understand mutants that had unexplained effects.
Pommier, Y. & Cherfils, J. Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery. Trends Pharmacol. Sci. 26, 138–145 (2005).
Capranico, G., Kohn, K. W. & Pommier, Y. Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. Nucleic Acids Res. 18, 6611–6619 (1990).
Pommier, Y., Capranico, G., Orr, A. & Kohn, K. W. Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide. Nucleic Acids Res. 19, 5973–5980 (1991).
Freudenreich, C. H. & Kreuzer, K. N. Localization of an aminoacridine antitumor agent in a type II topoisomerase–DNA complex. Proc. Natl Acad. Sci. USA 91, 11007–11011 (1994).
Huff, A. C., Ward, R. E., Kreuzer, K. N. & Ward, R. E. Mutational alteration of the breakage/resealing subunit of bacteriophage T4 DNA topoisomerase confers resistance to antitumor agent m-AMSA. Mol. Gen. Genet. 221, 27–32 (1990).
Capranico, G. & Binaschi, M. DNA sequence selectivity of topoisomerases and topoisomerase poisons. Biochim. Biophys. Acta 1400, 185–194 (1998).
Fortune, J. M. & Osheroff, N. Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog. Nucleic Acid Res. Mol. Biol. 64, 221–253 (2000).
Kingma, P. S., Burden, D. A. & Osheroff, N. Binding of etoposide to topoisomerase II in the absence of DNA: decreased affinity as a mechanism of drug resistance. Biochemistry 38, 3457–3461 (1999).
Bandele, O. J. & Osheroff, N. The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells. Biochemistry 47, 11900–11908 (2008).
Bromberg, K. D., Burgin, A. B. & Osheroff, N. A two-drug model for etoposide action against human topoisomerase IIα. J. Biol. Chem. 278, 7406–7412 (2003).
Rogojina, A. T. & Nitiss, J. L. Isolation and Characterization of mAMSA-hypersensitive mutants. Cytotoxicity of Top2 covalent complexes containing DNA single strand breaks. J. Biol. Chem. 283, 29239–29250 (2008).
Robinson, M. J. et al. Effects of quinolone derivatives on eukaryotic topoisomerase II. A novel mechanism for enhancement of enzyme-mediated DNA cleavage. J. Biol. Chem. 266, 14585–14592 (1991).
Jiang, X. Random mutagenesis of the B′A′ core domain of yeast DNA topoisomerase II and large-scale screens of mutants resistant to the anticancer drug etoposide. Biochem. Biophys. Res. Commun. 327, 597–603 (2005).
Staker, B. L. et al. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl Acad. Sci. USA 99, 15387–15392 (2002).
Dong, K. C. & Berger, J. M. Structural basis for gate–DNA recognition and bending by type IIA topoisomerases. Nature 450, 1201–1205 (2007).
Drlica, K. & Malik, M. Fluoroquinolones: action and resistance. Curr. Top. Med. Chem. 3, 249–282 (2003).
Gruger, T. et al. A mutation in Escherichia coli DNA gyrase conferring quinolone resistance results in sensitivity to drugs targeting eukaryotic topoisomerase II. Antimicrob. Agents Chemother. 48, 4495–4504 (2004).
Dong, J., Walker, J. & Nitiss, J. L. A mutation in yeast topoisomerase II that confers hypersensitivity to multiple classes of topoisomerase II poisons. J. Biol. Chem. 275, 7980–7987 (2000).
Hsiung, Y., Elsea, S. H., Osheroff, N. & Nitiss, J. L. A mutation in yeast TOP2 homologous to a quinolone-resistant mutation in bacteria. Mutation of the amino acid homologous to Ser83 of Escherichia coli gyrA alters sensitivity to eukaryotic topoisomerase inhibitors. J. Biol. Chem. 270, 20359–20364 (1995).
Avemann, K., Knippers, R., Koller, T. & Sogo, J. M. Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks. Mol. Cell. Biol. 8, 3026–3034 (1988).
D'Arpa, P., Beardmore, C. & Liu, L. F. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 50, 6919–6924 (1990).
Tennyson, R. B. & Lindsley, J. E. Type II DNA topoisomerase from Saccharomyces cerevisiae is a stable dimer. Biochemistry 36, 6107–6114 (1997).
Connelly, J. C. & Leach, D. R. Repair of DNA covalently linked to protein. Mol. Cell 13, 307–316 (2004).
Liu, C., Pouliot, J. J. & Nash, H. A. The role of TDP1 from budding yeast in the repair of DNA damage. DNA Repair 3, 593–601 (2004).
Pouliot, J. J., Yao, K. C., Robertson, C. A. & Nash, H. A. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286, 552–555 (1999). A description of a unique protein that repairs protein covalently bound to DNA.
Vance, J. R. & Wilson, T. E. Yeast Tdp1 and Rad1–Rad10 function as redundant pathways for repairing Top1 replicative damage. Proc. Natl Acad. Sci. USA 99, 13669–13674 (2002). This study showed that multiple nucleases function in the repair of Top1 damage.
Pouliot, J. J., Robertson, C. A. & Nash, H. A. Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae. Genes Cells 6, 677–687 (2001).
Deng, C., Brown, J. A., You, D. & Brown, J. M. Multiple endonucleases function to repair covalent topoisomerase I complexes in Saccharomyces cerevisiae. Genetics 170, 591–600 (2005).
Yang, S. W. et al. A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc. Natl Acad. Sci. USA 93, 11534–11539 (1996).
Nitiss, K. C., Malik, M., He, X., White, S. W. & Nitiss, J. L. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Proc. Natl Acad. Sci. USA 103, 8953–8958 (2006).
He, X. et al. Mutation of a conserved active site residue converts tyrosyl-DNA phosphodiesterase I into a DNA topoisomerase I-dependent poison. J. Mol. Biol. 372, 1070–1081 (2007).
Davies, D. R., Interthal, H., Champoux, J. J. & Hol, W. G. The crystal structure of human tyrosyl-DNA phosphodiesterase, TDP1. Structure 10, 237–248 (2002).
Keeney, S., Giroux, C. N. & Kleckner, N. Meiosis-specific DNA double-strand breaks are catalyzed by Spo11, a member of a widely conserved protein family. Cell 88, 375–384 (1997).
Keeney, S. & Kleckner, N. Covalent protein–DNA complexes at the 5′ strand termini of meiosis- specific double-strand breaks in yeast. Proc. Natl Acad. Sci. USA 92, 11274–11278 (1995).
Cao, L., Alani, E. & Kleckner, N. A pathway for generation and processing of double-strand breaks during meiotic recombination in S. cerevisiae. Cell 61, 1089–1101 (1990).
Prinz, S., Amon, A. & Klein, F. Isolation of COM1, a new gene required to complete meiotic double-strand break-induced recombination in Saccharomyces cerevisiae. Genetics 146, 781–795 (1997).
Keeney, S. & Kleckner, N. Covalent protein–DNA complexes at the 5′-strand termini of meiosis-specific double-strand breaks in yeast. Proc. Natl Acad. Sci. USA 92, 11274–11278 (1995).
Lengsfeld, B. M., Rattray, A. J., Bhaskara, V., Ghirlando, R. & Paull, T. T. Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol. Cell 28, 638–651 (2007).
Limbo, O. et al. Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol. Cell 28, 134–146 (2007).
Sartori, A. A. et al. Human CtIP promotes DNA end resection. Nature 450, 509–514 (2007).
Neale, M. J., Pan, J. & Keeney, S. Endonucleolytic processing of covalent protein-linked DNA double-strand breaks. Nature 436, 1053–1057 (2005). This paper describes a unique approach for assessing the repair of protein–DNA covalent complexes in vivo.
Connelly, J. C., de Leau, E. S. & Leach, D. R. F. Nucleolytic processing of a protein-bound DNA end by the E.coli SbcCD (MR) complex. DNA Repair 2, 795–807 (2003).
Hartsuiker, E., Neale, M. J. & Carr, A. M. Distinct requirements for the Rad32Mre11 nuclease and Ctp1CtIP in the removal of covalently bound topoisomerase I and II from DNA. Mol. Cell 33, 117–123 (2009). This paper directly showed that Mre11 and Ctp1 from S. pombe can process trapped Top2 covalent complexes. It also provides the best direct proof for the existence of a nucleolytic processing pathway that is distinct from the proteolytic pathway.
Pommier, Y. et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 81, 179–229 (2006).
Mao, Y., Desai, S. D., Ting, C. Y., Hwang, J. & Liu, L. F. 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J. Biol. Chem. 276, 40652–40658 (2001). This study showed that there is a proteolysis pathway for repairing TOP2-mediated DNA damage.
Zhang, A. L. et al. A protease pathway for the repair of topoisomerase II–DNA covalent complexes. J. Biol. Chem. 281, 35997–36003 (2006).
Fan, J. R. et al. Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses. DNA Repair 7, 452–463 (2008). This paper showed that the protease pathway can be expanded to repair TOP2α covalent complexes. It also contains an interesting explanation of the importance of processing pathways in cell survival.
Holm, C., Covey, J. M., Kerrigan, D. & Pommier, Y. Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res. 49, 6365–6368 (1989).
Powell, S. N. & Kachnic, L. A. Therapeutic exploitation of tumor cell defects in homologous recombination. Anticancer Agents Med. Chem. 8, 448–460 (2008).
Treszezamsky, A. D. et al. BRCA1- and BRCA2-deficient cells are sensitive to etoposide-induced DNA double-strand breaks via topoisomerase II. Cancer Res. 67, 7078–7081 (2007).
Aratani, Y., Andoh, T. & Koyama, H. Effects of DNA topoisomerase inhibitors on nonhomologous and homologous recombination in mammalian cells. Mutat. Res. 362, 181–191 (1996).
Kantidze, O. L. & Razin, S. V. Chemotherapy-related secondary leukemias: a role for DNA repair by error-prone non-homologous end joining in topoisomerase II-induced chromosomal rearrangements. Gene 391, 76–79 (2007).
Roca, J., Ishida, R., Berger, J. M., Andoh, T. & Wang, J. C. Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp. Proc. Natl Acad. Sci. USA 91, 1781–1785 (1994). This paper biochemically showed the mechanism of action of a catalytic Top2 inhibitor.
Andoh, T. & Ishida, R. Catalytic inhibitors of DNA topoisomerase II. Biochim. Biophys. Acta 1400, 155–171 (1998).
Roca, J. & Wang, J. C. The capture of a DNA double helix by an ATP-dependent protein clamp: a key step in DNA transport by type II DNA topoisomerases. Cell 71, 833–840 (1992).
Jensen, L. H. et al. A novel mechanism of cell killing by anti-topoisomerase II bisdioxopiperazines. J. Biol. Chem. 275, 2137–2146 (2000).
Huang, K. C. et al. Topoisomerase II poisoning by ICRF-193. J. Biol. Chem. 276, 44488–44494 (2001).
Xiao, H. et al. The topoisomerase IIβ circular clamp arrests transcription and signals a 26S proteasome pathway. Proc. Natl Acad. Sci. USA 100, 3239–3244 (2003).
Chene, P. et al. Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue. BMC Chem. Biol. 9, 1 (2009).
Beck, W. T., Danks, M. K., Wolverton, J. S., Kim, R. & Chen, M. Drug resistance associated with altered DNA topoisomerase II. Adv. Enzyme Regul. 33, 113–127 (1993).
Gudkov, A. V. et al. Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. Proc. Natl Acad. Sci. USA 90, 3231–3235 (1993).
Burgess, D. J. et al. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc. Natl Acad. Sci. USA 105, 9053–9058 (2008). This study directly showed the 'poison hypothesis' in mammalian cells – that TOP2-mediated DNA damage is responsible for the cytotoxicity of TOP2-targeting drugs.
Coutts, J., Plumb, J. A., Brown, R. & Keith, W. N. Expression of topoisomerase IIα and topoisomerase IIβ in an adenocarcinoma cell line carrying amplified topoisomerase IIα and retinoic acid receptor-α genes. Br. J. Cancer 68, 793–800 (1993).
Keith, W. N. et al. Coamplification of erbB2, topoisomerase IIα and retinoic acid receptor-α genes in breast cancer and allelic loss at topoisomerase I on chromosome 20. Eur. J. Cancer 29A, 1469–1475 (1993).
Smith, K., Houlbrook, S., Greenall, M., Carmichael, J. & Harris, A. L. Topoisomerase IIα coamplification with erbB2 in human primary breast cancer and breast cancer cell lines —relationship to m-AMSA and mitoxantrone sensitivity. Oncogene 8, 933–938 (1993).
Mano, M. S., Rosa, D. D., De Azambuja, E., Ismael, G. F. & Durbecq, V. The 17q12–q21 amplicon: Her2 and topoisomerase-IIα and their importance to the biology of solid tumours. Cancer Treat. Rev. 33, 64–77 (2007). A comprehensive review of TOP2A and ERBB2 co-amplification.
Jarvinen, T. A., Tanner, M., Barlund, M., Borg, A. & Isola, J. Characterization of topoisomerase IIα gene amplification and deletion in breast cancer. Genes Chromosom. Cancer 26, 142–150 (1999).
Arriola, E. et al. Predictive value of HER-2 and topoisomerase IIα in response to primary doxorubicin in breast cancer. Eur. J. Cancer 42, 2954–2960 (2006).
Roulston, D. et al. Therapy-related acute leukemia associated with t(11q23) after primary acute myeloid leukemia with t(8;21) — a report of two cases. Blood 86, 3613–3614 (1995).
Ratain, M. J. & Rowley, J. D. Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II — from the bedside to the target genes. Ann. Oncol. 3, 107–111 (1992).
Kudo, K. et al. Etoposide-related acute promyelocytic leukemia. Leukemia 12, 1171–1175 (1998).
Pedersen-Bjergaard, J. et al. Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series. Leukemia 7, 1975–1986 (1993). An early paper that was particularly convincing in showing that targeting TOP2 could lead to secondary malignancies.
Felix, C. A. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim. Biophys. Acta 1400, 233–255 (1998).
Mistry, A. R. et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N. Engl. J. Med. 352, 1529–1538 (2005).
Stanulla, M., Wang, J. J., Chervinsky, D. S., Thandla, S. & Aplan, P. D. DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. Mol. Cell. Biol. 17, 4070–4079 (1997).
Azarova, A. M. et al. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc. Natl Acad. Sci. USA 107, 11014–11019. (2007).
Tebbi, C. K. et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J. Clin. Oncol. 25, 493–500 (2007).
Hellmann, K. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without evidence. J. Clin. Oncol. 25, 4689–4690 (2007).
Schwartz, C. L. et al. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin's disease: a claim without evidence — reply. J. Clin. Oncol. 25, 4690–4691 (2007).
Barry, E. V. et al. Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J. Clin. Oncol. 26, 1106–1111 (2008).
Menna, P., Salvatorelli, E. & Minotti, G. Cardiotoxicity of antitumor drugs. Chem. Res. Toxicol. 21, 978–989 (2008).
Lyu, Y. L. et al. Topoisomerase IIβ-mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 67, 8839–8846 (2007). This paper describes provocative experiments that suggested that TOP2β plays an important part in anthracycline-induced cardiomyopathy.
Willmore, E. et al. A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood 103, 4659–4665 (2004).
Palumbo, A. et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann. Oncol. 19, 1160–1165 (2008).
Braccalenti, G. et al. Antitumour activity of bortezomib-pegylated liposomal doxorubicine association as salvage therapy in multiple myeloma patients. Blood 110, 4832 (2007).
Errington, F. et al. Murine transgenic cells lacking DNA topoisomerase IIβ are resistant to acridines and mitoxantrone: analysis of cytotoxicity and cleavable complex formation. Mol. Pharmacol. 56, 1309–1316 (1999).
Onda, T. et al. NK314, a novel topoisomerase II inhibitor, induces rapid DNA double-strand breaks and exhibits superior antitumor effects against tumors resistant to other topoisomerase II inhibitors. Cancer Lett. 259, 99–110 (2008).
Toyoda, E. et al. NK314, a topoisomerase II inhibitor that specifically targets the α isoform. J. Biol. Chem. 283, 23711–23720 (2008). A description of a potent TOP2-targeting drug that is specific for the TOP2α isoform.
Classen, S., Olland, S. & Berger, J. M. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc. Natl Acad. Sci. USA 100, 10629–10634 (2003). The only structure available of a TOP2-targeting drug bound to TOP2. This structure will be key to designing new agents that target the ATPase domain of TOP2.
Schneider, E. et al. Cell line selectivity and DNA breakage properties of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide: role of DNA topoisomerase II. Eur. J. Cancer Clin. Oncol. 24, 1783–1790 (1988). A review that discusses the mechanism of action of anthracyclines in careful detail.
Gewirtz, D. A. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem. Pharmacol. 57, 727–741 (1999).
Jensen, B. V. Cardiotoxic consequences of anthracycline-containing therapy in patients with breast cancer. Semin. Oncol. 33, S15–S21 (2006).
Injac, R. & Strukelj, B. Recent advances in protection against doxorubicin-induced toxicity. Technol. Cancer Res. Treat. 7, 497–516 (2008).
Ferreira, A. L. A., Matsubara, L. S. & Matsubara, B. B. Anthracycline-induced cardiotoxicity. Cardiovasc. Hematol. Agents Medic. Chem. 6, 278–281 (2008).
Bender, R. P. et al. Substituents on etoposide that interact with human topoisomerase IIα in the binary enzyme–drug complex: contributions to etoposide binding and activity. Biochemistry 47, 4501–4509 (2008).
Wilstermann, A. M. et al. Topoisomerase II-drug interaction domains: identification of substituents on etoposide that interact with the enzyme. Biochemistry 46, 8217–8225 (2007).
Ishida, R. et al. Inhibition of intracellular topoisomerase II by antitumor bis(2,6- dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors. Cancer Res. 51, 4909–4916 (1991).
Tanabe, K., Ikegami, Y., Ishida, R. & Andoh, T. Inhibition of topoisomerase II by antitumor agents bis(2,6- dioxopiperazine) derivatives. Cancer Res. 51, 4903–4908 (1991).
Sugino, A., Higgins, N. P., Brown, P. O., Peebles, C. L. & Cozzarelli, N. R. Energy coupling in DNA gyrase and the mechanism of action of novobiocin. Proc. Natl Acad. Sci. USA 75, 4838–4842 (1978).
Cotten, M., Bresnahan, D., Thompson, S., Sealy, L. & Chalkley, R. Novobiocin precipitates histones at concentrations normally used to inhibit eukaryotic type II topoisomerase. Nucleic Acids Res. 14, 3671–3686 (1986).
Collins, A. Topoisomerase II can relax; novobiocin is a mitochondrial poison after all. Bioessays 12, 493–494 (1990).
Drake, F. H. et al. In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone. Cancer Res. 49, 2578–2583 (1989).
Jensen, P. B. et al. Antagonistic effect of aclarubicin on the cytotoxicity of etoposide and 4′-(9-acridinylamino)methanesulfon-m-anisidide in human small cell lung cancer cell lines and on topoisomerase II-mediated DNA cleavage. Cancer Res. 50, 3311–3316 (1990).
Nitiss, J. L., Pourquier, P. & Pommier, Y. Aclacinomycin A stabilizes topoisomerase I covalent complexes. Cancer Res. 57, 4564–4569 (1997).
Clifford, B., Beljin, M., Stark, G. R. & Taylor, W. R. G2 arrest in response to topoisomerase II inhibitors: the role of p53. Cancer Res. 63, 4074–4081 (2003).
Fortune, J. M. & Osheroff, N. Merbarone inhibits the catalytic activity of human topoisomerase IIα by blocking DNA cleavage. J. Biol. Chem. 273, 17643–17650 (1998). A rationally designed catalytic inhibitor of mammalian TOP2.
Verborg, W. A., Campbell, L. R., Highley, M. S. & Rankin, E. M. Weekly cisplatin with oral etoposide: a well-tolerated and highly effective regimen in relapsed ovarian cancer. Int. J. Gynecol. Cancer 18, 228–234 (2008).
Puhalla, S. et al. Randomized phase II adjuvant trial of dose-dense docetaxel before or after doxorubicin plus cyclophosphamide in axillary node-positive breast cancer. J. Clin. Oncol. 26, 1691–1697 (2008).
Navid, F. et al. Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas — The St. Jude Children's Research Hospital experience. Cancer 106, 1846–1856 (2006).
Eder, J. P. et al. Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo. Cancer Chemother. Pharmacol. 42, 327–335 (1998).
Houghton, J. A. et al. Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma. Clin. Cancer Res. 2, 107–118 (1996).
Crump, M. et al. Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. Leukemia 13, 343–347 (1999).
Vey, N. et al. Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study. Invest. New Drugs 17, 89–95 (1999).
Simon, T., Langler, A., Berthold, F., Klingebiel, T. & Hero, B. Topotecan and etoposide in the treatment of relapsed high-risk neuroblastoma — results of a phase 2 trial. J. Pediatr. Hematol. Oncol. 29, 101–106 (2007).
Choi, H. J. et al. Combination of topotecan and etoposide as a salvage treatment for patients with recurrent small cell lung cancer following irinotecan and platinum first-line chemotherapy. Cancer Chemother. Pharmacol. 61, 309–313 (2008).
Saraiya, B. et al. Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia. Anticancer Drugs 19, 411–420 (2008).
Fanale, M. A. et al. Safety and efficacy of bortezomib plus ICE (BICE) for the treatment of relapsed/refractory classical Hodgkin's lymphoma. Blood 110, 4506 (2007).
Armstrong, M. B. et al. Bortezomib as a therapeutic candidate for neuroblastoma. J. Exp. Ther. Oncol. 7, 135–145 (2008).
Lieu, C. et al. A phase I study of bortezomib, etoposide and carboplatin in patients with advanced solid tumors refractory to standard therapy. Invest. New Drugs 27, 53–62 (2009).
Zhao, Y. et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 66, 5354–5362 (2006).
Hardcastle, I. R. et al. Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach. J. Med. Chem. 48, 7829–7846 (2005).
Andoh, T. & Ishida, R. Catalytic inhibitors of DNA topoisomerase II. Biochim. Biophys. Acta 1400, 155–171 (1998).
Zechiedrich, E. L., Christiansen, K., Andersen, A. H., Westergaard, O. & Osheroff, N. Double-stranded DNA cleavage/religation reaction of eukaryotic topoisomerase II: evidence for a nicked DNA intermediate. Biochemistry 28, 6229–6236 (1989).
Kurosawa, A. et al. The requirement of Artemis in double-strand break repair depends on the type of DNA damage. DNA Cell Biol. 27, 55–61 (2008).
Adachi, N., Iiizumi, S., So, S. & Koyama, H. Genetic evidence for involvement of two distinct nonhomologous end-joining pathways in repair of topoisomerase II-mediated DNA damage. Biochem. Biophys. Res. Commun. 318, 856–861 (2004).
Darroudi, F. et al. Role of Artemis in DSB repair and guarding chromosomal stability following exposure to ionizing radiation at different stages of cell cycle. Mutat. Res. 615, 111–124 (2007).
Zhao, H. & Piwnica-Worms, H. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human CHK1. Mol. Cell. Biol. 21, 4129–4139 (2001).
Jamil, S., Mojtabavi, S., Hojabrpour, P., Cheah, S. & Duronio, V. An essential role for MCL-1 in ATR-mediated CHK1 phosphorylation. Mol. Biol. Cell 19, 3212–3220 (2008).
Fan, J. R. et al. Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses. DNA Repair 7, 452–463 (2008).
Theard, D., Coisy, M., Ducommun, B., Concannon, P. & Darbon, J. M. Etoposide and adriamycin but not genistein can activate the checkpoint kinase CHK2 independently of ATM/ATR. Biochem. Biophys. Res. Commun. 289, 1199–1204 (2001).
Chen, L. C., Nievera, C. J., Lee, A. Y. L. & Wu, X. H. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J. Biol. Chem. 283, 7713–7720 (2008).
Jin, S., Inoue, S. & Weaver, D. T. Differential etoposide sensitivity of cells deficient in the Ku and DNA-PKcs components of the DNA-dependent protein kinase. Carcinogenesis 19, 965–971 (1998).
Biard, D. S. Untangling the relationships between DNA repair pathways by silencing more than 20 DNA repair genes in human stable clones. Nucleic Acids Res. 35, 3535–3550 (2007).
Dona, F. et al. Loss of histone H2AX increases sensitivity of immortalized mouse fibroblasts to the topoisomerase II inhibitor etoposide. Int. J. Oncol. 33, 613–621 (2008).
Adachi, N., Suzuki, H., Iiizumi, S. & Koyama, H. Hypersensitivity of nonhomologous DNA end-joining mutants to VP-16 and ICRF-193: implications for the repair of topoisomerase II-mediated DNA damage. J. Biol. Chem. 278, 35897–35902 (2003).
Malik, M., Nitiss, K. C., Enriquez-Rios, V. & Nitiss, J. L. Roles of nonhomologous end-joining pathways in surviving topoisomerase II-mediated DNA damage. Mol. Cancer Ther. 5, 1405–1414 (2006).
Ayene, I. S., Ford, L. P. & Koch, C. J. Ku protein targeting by Ku70 small interfering RNA enhances human cancer cell response to topoisomerase II inhibitor and gamma radiation. Mol. Cancer Ther. 4, 529–536 (2005).
Malik, M. & Nitiss, J. L. DNA repair functions that control sensitivity to topoisomerase-targeting drugs. Eukaryot. Cell 3, 82–90 (2004).
Liu, L. B. et al. hMRE11 plays an important role in U937 cellular response to DNA double-strand breaks following etoposide. Zhongguo Shi Yan Xue Ye Xue Za Zhi 15, 10–15 (2007).
Baldwin, E. L., Berger, A. C., Corbett, A. H. & Osheroff, N. Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II. Nucleic Acids Res. 33, 1021–1030 (2005).
Rossi, R., Lidonnici, M. R., Soza, S., Biamonti, G. & Montecucco, A. The dispersal of replication proteins after etoposide treatment requires the cooperation of Nbs1 with the ataxia telangiectasia Rad3-related/Chk1 pathway. Cancer Res. 66, 1675–1683 (2006).
Robison, J. G., Bissler, J. J. & Dixon, K. Replication protein A is required for etoposide-induced assembly of MRE11/RAD50/NBS1 complex repair foci. Cell Cycle 6, 2408–2416 (2007).
Trenz, K., Errico, A. & Costanzo, V. Plx1 is required for chromosomal DNA replication under stressful conditions. EMBO J. 27, 876–885 (2008).
Nitiss, J. L., Rose, A., Sykes, K. C., Harris, J. & Zhou, J. Using yeast to understand drugs that target topoisomerases. Ann. NY Acad. Sci. 803, 32–43 (1996).
Adachi, N., Iiizumi, S. & Koyama, H. Evidence for a role of vertebrate Rad52 in the repair of topoisomerase II-mediated DNA damage. DNA Cell Biol. 24, 388–393 (2005).
Nitiss, J. L. et al. Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II. Cancer Res. 52, 4467–4472 (1992).
Xiao, H. & Goodrich, D. W. The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Oncogene 24, 8105–8113 (2005).
Interthal, H. et al. SCAN1 mutant Tdp1 accumulates the enzyme–DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 24, 2224–2233 (2005).
Despras, E. et al. Long-term XPC silencing reduces DNA double-strand break repair. Cancer Res. 67, 2526–2534 (2007).
Huang, R. Y., Kowalski, D., Minderman, H., Gandhi, N. & Johnson, E. S. Small ubiquitin-related modifier pathway is a major determinant of doxorubicin cytotoxicity in Saccharomyces cerevisiae. Cancer Res. 67, 765–772 (2007).
Rogojina, A. T., Li, Z., Nitiss, K. C. & Nitiss, J. L. in Yeast as a Tool in Cancer Research Ch. 16 (eds Nitiss, J. L. & Heitman, J.) 409–427 (Springer, Heidelberg, 2007).
Berger, J. M., Gamblin, S. J., Harrison, S. C. & Wang, J. C. Structure and mechanism of DNA topoisomerase II. Nature 379, 225–232 (1996).
The author thanks J. Berger, University of California, Berkeley, USA, who kindly provided figures and also provided useful discussions, and also Y. Pommier, National Cancer Institute, Bethesda, for encouragement. Work in the author's laboratory is supported by grants from the National Cancer Institute (CA82313 and CA21765) and the American Lebanese Syrian Associated Charities (ALSAC).
A class of small molecules, including ICRF-159, ICRF-187 and MST-16, that inhibit the catalytic activity of TOP2 and do not stabilize the TOP2 cleaved complex. Bisdioxopiperazines are the most commonly used catalytic inhibitors of type II topoisomerases.
- TOPRIM domain
A conserved domain found in topoisomerases, primases and other DNA metabolic enzymes. The TOPRIM domain adopts a Rossman fold, and is involved in divalent cation binding.
- MRN complex
A protein complex consisting of MRE11, RAD50 and nibrin (NBN), which is required for checkpoint signalling and double strand break repair. In yeast, the NBN component is replaced by a protein called Xrs2 and the yeast complex is termed the MRX complex. The yeast complex is required for removing Spo11 from DNA during meiotic recombination.
- TOP2β isozyme
In lower eukaryotes for example, yeast, insects and vertebrates such as Xenopus laevis – there is a single Top2 isoform. Mammals have two TOP2 isoforms termed α and β. The α isoform is preferentially expressed in proliferating cells and is essential for all growing cells. The β isoform is expressed in quiescent cells and is required for viability in mice.
About this article
Cite this article
Nitiss, J. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9, 338–350 (2009). https://doi.org/10.1038/nrc2607
RSC Chemical Biology (2021)
Cell Cycle (2021)
Aquaporin 1 promotes sensitivity of anthracycline chemotherapy in breast cancer by inhibiting β-catenin degradation to enhance TopoIIα activity
Cell Death & Differentiation (2021)
Nanoporous Gold Monolith for High Loading of Unmodified Doxorubicin and Sustained Co-Release of Doxorubicin-Rapamycin
Biomimetic carrier-free nanoparticle delivers digoxin and doxorubicin to exhibit synergetic antitumor activity in vitro and in vivo
Chemical Engineering Journal (2021)