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DNA-PK in CLL Chemotherapy

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Advances in DNA Repair in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 72))

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Abstract

DNA is the principal target of many conventional anticancer agents, and inhibition of DNA repair is one of the most promising strategies in novel cancer therapy. Many studies demonstrated that nonhomologous end-joining (NHEJ) repair pathway proteins, and especially DNA-dependent protein kinase (DNA-PK), is an attractive and effective target for the sensitization of cancer cells, including the most common type of leukemia in western countries, chronic lymphocytic leukemia (CLL), to DNA double-strand break (DSB)-inducing agents used in conventional cancer therapy. Nevertheless, promising results obtained in vitro cannot be translated to the clinic yet due to the nature of the DNA-PK inhibitors which are either nonspecific, for the first class of inhibitors, or degraded/eliminated from the human body before reaching the tumor site for the newer specific DNA-PK inhibitors.

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References

  1. Schmid C, Isaacson PG (1994) Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. Histopathology 24(5):445–451

    Article  PubMed  CAS  Google Scholar 

  2. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D et al (2005) In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest 115(3):755–764

    PubMed  CAS  Google Scholar 

  3. Hamblin TJ, Oscier DG (1997) Chronic lymphocytic leukaemia: the nature of the leukaemic cell. Blood Rev 11(3):119–128

    Article  PubMed  CAS  Google Scholar 

  4. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236

    Article  PubMed  Google Scholar 

  5. Chiorazzi N, Rai KR, Ferrarini M (2005) Chronic lymphocytic leukemia. N Engl J Med 352(8):804–815

    Article  PubMed  CAS  Google Scholar 

  6. Vroblova V, Smolej L, Vrbacky F, Jankovicova K, Hrudkova M, Maly J et al (2009) Biological prognostic markers in chronic lymphocytic leukemia. Acta Medica (Hradec Kralove) 52(1):3–8

    CAS  Google Scholar 

  7. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al (2005) Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23(18):4079–4088

    Article  PubMed  CAS  Google Scholar 

  8. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376(9747):1164–1174

    Article  PubMed  CAS  Google Scholar 

  9. Smith MR, Neuberg D, Flinn IW, Grever MR, Lazarus HM, Rowe JM et al (2011) Incidence of Therapy-related Myeloid Neoplasia after Initial Therapy for CLL with Fludarabine-Cyclophosphamide versus Fludarabine: Long-Term Follow-up of US Intergroup Study E2997. Blood 118(13):3525–3527

    Article  PubMed  CAS  Google Scholar 

  10. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M et al (2009) First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114(16):3382–3391

    Article  PubMed  CAS  Google Scholar 

  11. Byrd JC, Stilgenbauer S, Flinn IW (2004) Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Prog) 1:163–183

    Article  Google Scholar 

  12. Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23(5):687–696

    Article  PubMed  CAS  Google Scholar 

  13. De Silva IU, McHugh PJ, Clingen PH, Hartley JA (2000) Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol Cell Biol 20(21):7980–7990

    Article  PubMed  Google Scholar 

  14. McHugh PJ, Spanswick VJ, Hartley JA (2001) Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol 2(8):483–490

    Article  PubMed  CAS  Google Scholar 

  15. Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H et al (1998) Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J 17(18):5497–5508

    Article  PubMed  CAS  Google Scholar 

  16. Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23(16):5706–5715

    Article  PubMed  CAS  Google Scholar 

  17. Finnie NJ, Gottlieb TM, Blunt T, Jeggo PA, Jackson SP (1996) DNA-dependent protein kinase defects are linked to deficiencies in DNA repair and V(D)J recombination. Philos Trans R Soc Lond B Biol Sci 351(1336):173–179

    Article  PubMed  CAS  Google Scholar 

  18. Jeggo PA, Taccioli GE, Jackson SP (1995) Menage a trois: double strand break repair, V(D)J recombination and DNA-PK. Bioessays 17(11):949–957

    Article  PubMed  CAS  Google Scholar 

  19. Weaver DT (1995) What to do at an end: DNA double-strand-break repair. Trends Genet 11(10):388–392

    Article  PubMed  CAS  Google Scholar 

  20. Smith GC, Jackson SP (1999) The DNA-dependent protein kinase. Genes Dev 13(8):916–934

    Article  PubMed  CAS  Google Scholar 

  21. Hartley KO, Gell D, Smith GC, Zhang H, Divecha N, Connelly MA et al (1995) DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product. Cell 82(5):849–856

    Article  PubMed  CAS  Google Scholar 

  22. Durocher D, Jackson SP (2001) DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr Opin Cell Biol 13(2):225–231

    Article  PubMed  CAS  Google Scholar 

  23. Mimori T, Hardin JA (1986) Mechanism of interaction between Ku protein and DNA. J Biol Chem 261(22):10375–10379

    PubMed  CAS  Google Scholar 

  24. Gottlieb TM, Jackson SP (1993) The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell 72(1):131–142

    Article  PubMed  CAS  Google Scholar 

  25. Blier PR, Griffith AJ, Craft J, Hardin JA (1993) Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks. J Biol Chem 268(10):7594–7601

    PubMed  CAS  Google Scholar 

  26. Lees-Miller SP, Chen YR, Anderson CW (1990) Human cells contain a DNA-activated protein kinase that phosphorylates simian virus 40 T antigen, mouse p53, and the human Ku autoantigen. Mol Cell Biol 10(12):6472–6481

    PubMed  CAS  Google Scholar 

  27. Bannister AJ, Gottlieb TM, Kouzarides T, Jackson SP (1993) c-Jun is phosphorylated by the DNA-dependent protein kinase in vitro; definition of the minimal kinase recognition motif. Nucleic Acids Res 21(5):1289–1295

    Article  PubMed  CAS  Google Scholar 

  28. Anderson CW, Connelley MA, Zhang H, Sipley JD, Lees-Miller SP, Sakaguchi K et al (1994) The human DNA-activated protein kinase, DNA-PK, is activated by DNA breaks and phosphorylates nuclear DNA-binding substrates on serines and threonines following glutamine. J Prot Chem 13:500–501

    Google Scholar 

  29. Calsou P, Delteil C, Frit P, Drouet J, Salles B (2003) Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment. J Mol Biol 326(1):93–103

    Article  PubMed  CAS  Google Scholar 

  30. Mahaney BL, Meek K, Lees-Miller SP (2009) Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 417(3):639–650

    Article  PubMed  CAS  Google Scholar 

  31. Peterson SR, Kurimasa A, Oshimura M, Dynan WS, Bradbury EM, Chen DJ (1995) Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci USA 92(8):3171–3174

    Article  PubMed  CAS  Google Scholar 

  32. Taccioli GE, Rathbun G, Oltz E, Stamato T, Jeggo PA, Alt FW (1993) Impairment of V(D)J recombination in double-strand break repair mutants. Science 260(5105):207–210

    Article  PubMed  CAS  Google Scholar 

  33. Caldecott K, Jeggo P (1991) Cross-sensitivity of gamma-ray-sensitive hamster mutants to cross-linking agents. Mutat Res 255(2):111–121

    Article  PubMed  CAS  Google Scholar 

  34. Tanaka T, Yamagami T, Oka Y, Nomura T, Sugiyama H (1993) The scid mutation in mice causes defects in the repair system for both double-strand DNA breaks and DNA cross-links. Mutat Res 288(2):277–280

    Article  PubMed  CAS  Google Scholar 

  35. Chan DW, Chen BP, Prithivirajsingh S, Kurimasa A, Story MD, Qin J et al (2002) Autophosphorylation of the DNA-dependent protein kinase catalytic subunit is required for rejoining of DNA double-strand breaks. Genes Dev 16(18):2333–2338

    Article  PubMed  CAS  Google Scholar 

  36. Meek K, Douglas P, Cui X, Ding Q, Lees-Miller SP (2007) Trans Autophosphorylation at DNA-dependent protein kinase’s two major autophosphorylation site clusters facilitates end processing but not end joining. Mol Cell Biol 27(10):3881–3890

    Article  PubMed  CAS  Google Scholar 

  37. Douglas P, Cui X, Block WD, Yu Y, Gupta S, Ding Q et al (2007) The DNA-dependent protein kinase catalytic subunit is phosphorylated in vivo on threonine 3950, a highly conserved amino acid in the protein kinase domain. Mol Cell Biol 27(5):1581–1591

    Article  PubMed  CAS  Google Scholar 

  38. Hammel M, Yu Y, Mahaney BL, Cai B, Ye R, Phipps BM et al (2010) Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex. J Biol Chem 285(2):1414–1423

    Article  PubMed  CAS  Google Scholar 

  39. Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C et al (1994) Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54(9):2419–2423

    PubMed  CAS  Google Scholar 

  40. Durant S, Karran P (2003) Vanillins–a novel family of DNA-PK inhibitors. Nucleic Acids Res 31(19):5501–5512

    Article  PubMed  CAS  Google Scholar 

  41. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, Waterfield MD et al (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16(4):1722–1733

    PubMed  CAS  Google Scholar 

  42. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4 H-1-benzopyran-4-one (LY294002). J Biol Chem 269(7):5241–5248

    PubMed  CAS  Google Scholar 

  43. Kashishian A, Douangpanya H, Clark D, Schlachter ST, Eary CT, Schiro JG et al (2003) DNA-dependent protein kinase inhibitors as drug candidates for the treatment of cancer. Mol Cancer Ther 2(12):1257–1264

    PubMed  CAS  Google Scholar 

  44. Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJ et al (2003) 2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK). Bioorg Med Chem Lett 13(18):3083–3086

    Article  PubMed  CAS  Google Scholar 

  45. Willmore E, de Caux S, Sunter NJ, Tilby MJ, Jackson GH, Austin CA et al (2004) A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood 103(12):4659–4665

    Article  PubMed  CAS  Google Scholar 

  46. Leahy JJ, Golding BT, Griffin RJ, Hardcastle IR, Richardson C, Rigoreau L et al (2004) Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg Med Chem Lett 14(24):6083–6087

    Article  PubMed  CAS  Google Scholar 

  47. Bramson J, McQuillan A, Aubin R, Alaoui-Jamali M, Batist G, Christodoulopoulos G et al (1995) Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance. Mutat Res 336(3):269–278

    Article  PubMed  CAS  Google Scholar 

  48. Deriano L, Guipaud O, Merle-Beral H, Binet JL, Ricoul M, Potocki-Veronese G et al (2005) Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway. Blood 105(12):4776–4783

    Article  PubMed  CAS  Google Scholar 

  49. Aloyz R, Grzywacz K, Xu ZY, Loignon M, Alaoui-Jamali MA, Panasci L (2004) Imatinib sensitizes CLL lymphocytes to chlorambucil. Leukemia 18(3):409–414

    Article  PubMed  CAS  Google Scholar 

  50. Amrein L, Hernandez TA, Ferrario C, Johnston J, Gibson SB, Panasci L et al (2008) Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol 143(5):698–706

    Article  PubMed  CAS  Google Scholar 

  51. Amrein L, Rachid Z, Jean-Claude B, Soulieres D, Aloyz R, Panasci L (2011) ZRF4, a combi-molecule with increased efficacy as compared with the individual components in chronic lymphocytic leukemia lymphocytes in vitro. Leukemia 25(9):1512–1516

    Article  PubMed  CAS  Google Scholar 

  52. Hebb J, Assouline S, Rousseau C, Desjardins P, Caplan S, Egorin MJ et al (2011) A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol 68(3):643–651

    Article  PubMed  CAS  Google Scholar 

  53. Muller C, Salles B (1997) Regulation of DNA-dependent protein kinase activity in leukemic cells. Oncogene 15(19):2343–2348

    Article  PubMed  CAS  Google Scholar 

  54. Muller C, Christodoulopoulos G, Salles B, Panasci L (1998) DNA-Dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood 92(7):2213–2219

    PubMed  CAS  Google Scholar 

  55. Christodoulopoulos G, Muller C, Salles B, Kazmi R, Panasci L (1998) Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic leukemia by inhibition of DNA-dependent protein kinase activity using wortmannin. Cancer Res 58(9):1789–1792

    PubMed  CAS  Google Scholar 

  56. Torres-Garcia SJ, Cousineau L, Caplan S, Panasci L (1989) Correlation of resistance to nitrogen mustards in chronic lymphocytic leukemia with enhanced removal of melphalan-induced DNA cross-links. Biochem Pharmacol 38(18):3122–3123

    Article  PubMed  CAS  Google Scholar 

  57. Eriksson A, Lewensoh R, Larsson R, Nilsson A (2002) DNA-dependent protein kinase in leukaemia cells and correlation with drug sensitivity. Anticancer Res 22(3):1787–1793

    PubMed  CAS  Google Scholar 

  58. Willmore E, Elliott SL, Mainou-Fowler T, Summerfield GP, Jackson GH, O’Neill F et al (2008) DNA-dependent protein kinase is a therapeutic target and an indicator of poor prognosis in B-cell chronic lymphocytic leukemia. Clin Cancer Res 14(12):3984–3992

    Article  PubMed  CAS  Google Scholar 

  59. Boulton S, Kyle S, Yalcintepe L, Durkacz BW (1996) Wortmannin is a potent inhibitor of DNA double strand break but not single strand break repair in Chinese hamster ovary cells. Carcinogenesis 17(11):2285–2290

    Article  PubMed  CAS  Google Scholar 

  60. Svirnovski AI, Serhiyenka TF, Kustanovich AM, Khlebko PV, Fedosenko VV, Taras IB et al (2010) DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells. Exp Oncol 32(4):258–262

    PubMed  CAS  Google Scholar 

  61. Amrein L, Loignon M, Goulet AC, Dunn M, Jean-Claude B, Aloyz R et al (2007) Chlorambucil cytotoxicity in malignant B lymphocytes is synergistically increased by 2-(morpholin-4-yl)-benzo[h]chomen-4-one (NU7026)-mediated inhibition of DNA double-strand break repair via inhibition of DNA-dependent protein kinase. J Pharmacol Exp Ther 321(3):848–855

    Article  PubMed  CAS  Google Scholar 

  62. Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT et al (2005) Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Br J Cancer 93(9):1011–1018

    PubMed  CAS  Google Scholar 

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  1. Lady Davis Institute, 3755 Cote ste Catherine, Montreal, QC, Canada

    L. Amrein, D. Davidson, R. Aloyz & L. Panasci

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  1. L. Amrein
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  2. D. Davidson
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  3. R. Aloyz
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  4. L. Panasci
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Correspondence to R. Aloyz .

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Editors and Affiliations

  1. Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, Canada

    Lawrence Panasci

  2. , Department of Oncology, McGill University, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Raquel Aloyz

  3. McGill University, Department of Medicine and Oncology, Faculty of Medicine, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Moulay Alaoui-Jamali

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Amrein, L., Davidson, D., Aloyz, R., Panasci, L. (2013). DNA-PK in CLL Chemotherapy. In: Panasci, L., Aloyz, R., Alaoui-Jamali, M. (eds) Advances in DNA Repair in Cancer Therapy. Cancer Drug Discovery and Development, vol 72. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4741-2_7

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  • DOI: https://doi.org/10.1007/978-1-4614-4741-2_7

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