Cellular response to etoposide treatment.

Etoposide is a potent anti-tumor drug that belongs to the class of topoisomerase poisons. Although its molecular target, i.e. DNA topoisomerase II, has been identified more than 20 years ago, the cellular response to etoposide is still poorly understood. The cytotoxicity of the drug stems from its ability to stabilize a covalent complex between DNA topoisomerase II and DNA that results in a high level of DNA damage. Here, we review the present knowledge about the strategy used by the cells to deal with the etoposide-induced DNA damage. New and unanticipated effects of topoisomerase II poisoning on cell metabolism are recently emerging, among which the ability to activate cell cycle checkpoint pathways and to affect gene expression at different levels, including chromatin remodeling and alternative splicing of gene transcripts. The elucidation of the effects of etoposide on cell metabolism will increase our ability to exploit this drug in cancer therapy and will expand our comprehension of the cancerous cell.

[1]  J. Champoux.  DNA topoisomerases: structure, function, and mechanism. , 2001, Annual review of biochemistry.

[2]  Jin H. Song,et al.  Role of death receptor and mitochondrial pathways in conventional chemotherapy drug induction of apoptosis. , 2006, Cellular signalling.

[3]  J. Gautier,et al.  An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. , 2003, Molecular cell.

[4]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[5]  M. Carroll,et al.  BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint. , 2004, Cancer cell.

[6]  Wen‐Ming Yang,et al.  Histone deacetylase interacts directly with DNA topoisomerase II , 2000, Nature Genetics.

[7]  J. Bissler,et al.  DNA Lesion-specific Co-localization of the Mre11/Rad50/Nbs1 (MRN) Complex and Replication Protein A (RPA) to Repair Foci* , 2005, Journal of Biological Chemistry.

[8]  T. Hirano.  At the heart of the chromosome: SMC proteins in action , 2006, Nature Reviews Molecular Cell Biology.

[9]  Jiri Bartek,et al.  Checking on DNA damage in S phase , 2004, Nature Reviews Molecular Cell Biology.

[10]  B. Nelms,et al.  hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks , 1997, Molecular and cellular biology.

[11]  N. Osheroff,et al.  Topoisomerase II·Etoposide Interactions Direct the Formation of Drug-induced Enzyme-DNA Cleavage Complexes* , 1996, The Journal of Biological Chemistry.

[12]  W. Earnshaw,et al.  Induction of apoptosis by cancer chemotherapy. , 2000, Experimental cell research.

[13]  A. Scovassi,et al.  Two-color fluorescence detection of Poly (ADP-Ribose) Polymerase-1 (PARP-1) cleavage and DNA strand breaks in etoposide-induced apoptotic cells. , 2009, European journal of histochemistry : EJH.

[14]  JAMES C. Wang,et al.  Cellular roles of DNA topoisomerases: a molecular perspective , 2002, Nature Reviews Molecular Cell Biology.

[15]  K. Kreuzer,et al.  Endonuclease cleavage of blocked replication forks: An indirect pathway of DNA damage from antitumor drug–topoisomerase complexes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  T. Ried,et al.  SMC1 involvement in fragile site expression. , 2005, Human molecular genetics.

[17]  M. Weitzman,et al.  Adenovirus oncoproteins inactivate the Mre11–Rad50–NBS1 DNA repair complex , 2002, Nature.

[18]  D. J. Clarke,et al.  A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells , 1994, Nature.

[19]  K. Nasmyth,et al.  Sister chromatid cohesion is required for postreplicative double-strand break repair in Saccharomyces cerevisiae , 2001, Current Biology.

[20]  Chun-Yuan Ting,et al.  26 S Proteasome-mediated Degradation of Topoisomerase II Cleavable Complexes* , 2001, The Journal of Biological Chemistry.

[21]  J. Gautier,et al.  Regulation of DNA replication by ATR: signaling in response to DNA intermediates. , 2004, DNA repair.

[22]  D. Leach,et al.  Repair of DNA covalently linked to protein. , 2004, Molecular cell.

[23]  P. Jeggo,et al.  DNA double-strand break repair pathways and cellular tolerance to inhibitors of topoisomerase II. , 1990, Cancer Research.

[24]  S. Kaufmann.  Cell death induced by topoisomerase-targeted drugs: more questions than answers. , 1998, Biochimica et biophysica acta.

[25]  J. Bartek,et al.  Differential impact of diverse anticancer chemotherapeutics on the Cdc25A-degradation checkpoint pathway. , 2005, Experimental cell research.

[26]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[27]  O. Cuvier,et al.  A role of topoisomerase II in linking DNA replication to chromosome condensation , 2003, The Journal of cell biology.

[28]  N. Osheroff,et al.  A Two-drug Model for Etoposide Action against Human Topoisomerase IIα* , 2003, The Journal of Biological Chemistry.

[29]  D L Spector,et al.  Dynamic organization of DNA replication in mammalian cell nuclei: spatially and temporally defined replication of chromosome-specific alpha-satellite DNA sequences , 1992, The Journal of cell biology.

[30]  H. Hiasa,et al.  DNA gyrase and topoisomerase IV: biochemical activities, physiological roles during chromosome replication, and drug sensitivities. , 1998, Biochimica et biophysica acta.

[31]  L. Corcos,et al.  Differential influence of etoposide on two caspase-2 mRNA isoforms in leukemic cells. , 2002, Cancer letters.

[32]  Yigong Shi,et al.  Molecular mechanisms of caspase regulation during apoptosis , 2004, Nature Reviews Molecular Cell Biology.

[33]  D. Gilbert,et al.  Temporally coordinated assembly and disassembly of replication factories in the absence of DNA synthesis , 2000, Nature Cell Biology.

[34]  M. J. Neale,et al.  Endonucleolytic processing of covalent protein-linked DNA double-strand breaks , 2005, Nature.

[35]  F. Palitti,et al.  Hypersensitivity of lymphoblastoid lines derived from ataxia telangiectasia patients to the induction of chromosomal aberrations by etoposide (VP-16). , 1993, Mutation research.

[36]  M. Giacca,et al.  DNA loop anchorage region colocalizes with the replication origin located downstream to the human gene encoding lamin B2 , 1998, Journal of cellular biochemistry.

[37]  Monika Tsai-Pflugfelder,et al.  Modulation of drug sensitivity in yeast cells by the ATP-binding domain of human DNA topoisomerase IIalpha. , 2003, Nucleic acids research.

[38]  G. Biamonti,et al.  DNA ligase I is dephosphorylated during the execution step of etoposide-induced apoptosis , 2002, Cell Death and Differentiation.

[39]  Anindya Dutta,et al.  DNA replication in eukaryotic cells. , 2002, Annual review of biochemistry.

[40]  K. Hande,et al.  Etoposide: four decades of development of a topoisomerase II inhibitor. , 1998, European journal of cancer.

[41]  T. Pandita,et al.  Initial chromosome damage but not DNA damage is greater in ataxia telangiectasia cells. , 1992, Radiation research.

[42]  B. Turner,et al.  Deacetylase Activity Associates with Topoisomerase II and Is Necessary for Etoposide-induced Apoptosis* , 2001, The Journal of Biological Chemistry.

[43]  N. Osheroff,et al.  Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. , 2005, Journal of Biological Chemistry.

[44]  L. Liu,et al.  Tumor cell death induced by topoisomerase-targeting drugs. , 2001, Annual review of pharmacology and toxicology.

[45]  D. Loegering,et al.  Rad9 Protects Cells from Topoisomerase Poison-induced Cell Death* , 2004, Journal of Biological Chemistry.

[46]  G. Maga,et al.  DNA replication: a complex matter , 2003, EMBO reports.

[47]  A. Eastman,et al.  The Involvement of Protein Phosphatases in the Activation of ICE/CED-3 Protease, Intracellular Acidification, DNA Digestion, and Apoptosis* , 1996, The Journal of Biological Chemistry.

[48]  G. Biamonti,et al.  The dispersal of replication proteins after Etoposide treatment requires the cooperation of Nbs1 with the ataxia telangiectasia Rad3-related/Chk1 pathway. , 2006, Cancer research.

[49]  Jun Qin,et al.  SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. , 2002, Genes & development.

[50]  G. Biamonti,et al.  Etoposide induces the dispersal of DNA ligase I from replication factories. , 2001, Molecular biology of the cell.

[51]  D. Stacey,et al.  Influence of Cell Cycle and Oncogene Activity upon Topoisomerase IIα Expression and Drug Toxicity , 2000, Molecular and Cellular Biology.

[52]  T. Helleday,et al.  DNA repair rate and etoposide (VP16) resistance of tumor cell subpopulations derived from a single human small cell lung cancer. , 2003, Lung cancer.

[53]  M. Kastan,et al.  Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. , 2002, Genes & development.

[54]  M. Donzelli,et al.  Multiparametric staining to identify apoptotic human cells. , 1997, Experimental cell research.

[55]  L. Corcos,et al.  Topoisomerase I and II inhibitors control caspase-2 pre-messenger RNA splicing in human cells. , 2004, Molecular cancer research : MCR.

[56]  M. Giacca,et al.  Modular Structure of the Human Lamin B2 Replicator , 2004, Molecular and Cellular Biology.

[57]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[58]  O. Hyrien,et al.  Topoisomerase II can unlink replicating DNA by precatenane removal , 2001, The EMBO journal.

[59]  T. Misteli,et al.  E2F-dependent repression of topoisomerase II regulates heterochromatin formation and apoptosis in cells with melanoma-prone mutation. , 2005, Cancer research.