Skip to main content
Erschienen in: Investigational New Drugs 3/2014

01.06.2014 | PRECLINICAL STUDIES

Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair

verfasst von: Suraj Radhamani, Christopher Bradley, Terri Meehan-Andrews, Saleh K. Ihmaid, Jasim Al-Rawi

Erschienen in: Investigational New Drugs | Ausgabe 3/2014

Einloggen, um Zugang zu erhalten

Summary

The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present a novel benzoxazine, 8-methyl-2-(morpholine-4yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one (LTU27) and analyse its ability to cause sensitization of lung cancer and colon cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them concomitantly with both radiation and LTU27. The mechanism of action appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis.
Literatur
1.
Zurück zum Zitat De Schutter H, Nuyts S (2009) Radiosensitizing Potential of Epigenetic Anticancer Drugs. Anti-Cancer Agent Me 9(1):99–108CrossRef De Schutter H, Nuyts S (2009) Radiosensitizing Potential of Epigenetic Anticancer Drugs. Anti-Cancer Agent Me 9(1):99–108CrossRef
2.
Zurück zum Zitat Willner J, Flentje M (1999) Radiochemotherapy with Taxol for locally advanced non-small-cell lung cancer. Strahlenther Onkol 175:14–19CrossRefPubMed Willner J, Flentje M (1999) Radiochemotherapy with Taxol for locally advanced non-small-cell lung cancer. Strahlenther Onkol 175:14–19CrossRefPubMed
3.
Zurück zum Zitat Bogdanov KV, Chukhlovin AB, Zaritskey AY, Frolova OI, Afanasiev BV (1997) Ultraviolet irradiation induces multiple DNA double-strand breaks and apoptosis in normal granulocytes and chronic myeloid leukaemia blasts. Brit J Haematol 98(4):869–872CrossRef Bogdanov KV, Chukhlovin AB, Zaritskey AY, Frolova OI, Afanasiev BV (1997) Ultraviolet irradiation induces multiple DNA double-strand breaks and apoptosis in normal granulocytes and chronic myeloid leukaemia blasts. Brit J Haematol 98(4):869–872CrossRef
5.
Zurück zum Zitat Quanz M, Chassoux D, Berthault N, Agrario C, Sun JS, Dutreix M (2009) Hyperactivation of DNA-PK by Double-Strand Break Mimicking Molecules Disorganizes DNA Damage Response. PLoS One 4 (7). doi:Artn E6298 Doi 10.1371/Journal.Pone.0006298 Quanz M, Chassoux D, Berthault N, Agrario C, Sun JS, Dutreix M (2009) Hyperactivation of DNA-PK by Double-Strand Break Mimicking Molecules Disorganizes DNA Damage Response. PLoS One 4 (7). doi:Artn E6298 Doi 10.​1371/​Journal.​Pone.​0006298
7.
Zurück zum Zitat Shimura T, Kakuda S, Ochiai Y, Nakagawa H, Kuwahara Y, Takai Y, Kobayashi J, Komatsu K, Fukumoto M (2010) Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression. Oncogene 29(34):4826–4837. doi:10.1038/onc.2010.238 CrossRefPubMed Shimura T, Kakuda S, Ochiai Y, Nakagawa H, Kuwahara Y, Takai Y, Kobayashi J, Komatsu K, Fukumoto M (2010) Acquired radioresistance of human tumor cells by DNA-PK/AKT/GSK3beta-mediated cyclin D1 overexpression. Oncogene 29(34):4826–4837. doi:10.​1038/​onc.​2010.​238 CrossRefPubMed
10.
Zurück zum Zitat Hartley KO, Gell D, Smith GCM, Zhang H, Divecha N, Connelly MA, Admon A, Leesmiller SP, Anderson CW, Jackson SP (1995) DNA-Dependent Protein-Kinase Catalytic Subunit - a Relative of Phosphatidylinositol 3-Kinase and the Ataxia-Telangiectasia Gene-Product. Cell 82(5):849–856. doi:10.1016/0092-8674(95)90482-4 CrossRefPubMed Hartley KO, Gell D, Smith GCM, Zhang H, Divecha N, Connelly MA, Admon A, Leesmiller SP, Anderson CW, Jackson SP (1995) DNA-Dependent Protein-Kinase Catalytic Subunit - a Relative of Phosphatidylinositol 3-Kinase and the Ataxia-Telangiectasia Gene-Product. Cell 82(5):849–856. doi:10.​1016/​0092-8674(95)90482-4 CrossRefPubMed
14.
15.
Zurück zum Zitat Fraser M, Leung BM, Yan XJ, Dan HC, Cheng JQ, Tsang BK (2003) p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res 63(21):7081–7088PubMed Fraser M, Leung BM, Yan XJ, Dan HC, Cheng JQ, Tsang BK (2003) p53 is a determinant of X-linked inhibitor of apoptosis protein/Akt-mediated chemoresistance in human ovarian cancer cells. Cancer Res 63(21):7081–7088PubMed
20.
Zurück zum Zitat Kim CH, Park SJ, Lee SH (2002) A targeted inhibition of DNA-dependent protein kinase sensitizes breast cancer cells following ionizing radiation. Journal of Pharmacology and Experimental Therapeutics 303(2):753–759. doi:10.1124/jpet.102.038505 CrossRefPubMed Kim CH, Park SJ, Lee SH (2002) A targeted inhibition of DNA-dependent protein kinase sensitizes breast cancer cells following ionizing radiation. Journal of Pharmacology and Experimental Therapeutics 303(2):753–759. doi:10.​1124/​jpet.​102.​038505 CrossRefPubMed
22.
Zurück zum Zitat Martin NMB (2001) DNA repair inhibition and cancer therapy. J Photoch Photobio B 63(1–3):162–170CrossRef Martin NMB (2001) DNA repair inhibition and cancer therapy. J Photoch Photobio B 63(1–3):162–170CrossRef
23.
Zurück zum Zitat Murr MDE, Cano C, Golding BT, Hardcastle IR, Hummersome M, Frigerio M, Curtin NJ, Menear K, Richardson C, Smith GCM, Griffin RJ (2008) 8-biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK). Bioorg Med Chem Lett 18(17):4885–4890. doi:10.1016/j.bmcl.2008.07.066 CrossRef Murr MDE, Cano C, Golding BT, Hardcastle IR, Hummersome M, Frigerio M, Curtin NJ, Menear K, Richardson C, Smith GCM, Griffin RJ (2008) 8-biarylchromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK). Bioorg Med Chem Lett 18(17):4885–4890. doi:10.​1016/​j.​bmcl.​2008.​07.​066 CrossRef
24.
Zurück zum Zitat Yano H, Agatsuma T, Nakanishi S, Saitoh Y, Fukui Y, Nonomura Y, Matsuda Y (1995) Biochemical and Pharmacological Studies with Kt7692 and Ly294002 on the Rare of Phosphatidylinositol 3-Kinase in Fc-Epsilon-Ri-Mediated Signal-Transduction. Biochem J 312:145–150PubMedCentralCrossRefPubMed Yano H, Agatsuma T, Nakanishi S, Saitoh Y, Fukui Y, Nonomura Y, Matsuda Y (1995) Biochemical and Pharmacological Studies with Kt7692 and Ly294002 on the Rare of Phosphatidylinositol 3-Kinase in Fc-Epsilon-Ri-Mediated Signal-Transduction. Biochem J 312:145–150PubMedCentralCrossRefPubMed
25.
Zurück zum Zitat Poh TW, Pervaiz S (2005) LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-akt pathway. Cancer Res 65(14):6264–6274. doi:10.1158/0008-5472.Can-05-0152 CrossRefPubMed Poh TW, Pervaiz S (2005) LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-akt pathway. Cancer Res 65(14):6264–6274. doi:10.​1158/​0008-5472.​Can-05-0152 CrossRefPubMed
26.
Zurück zum Zitat Dibiase SJ, Zeng ZC, Chen R, Hyslop T, Curran WJ, Iliakis G (2000) DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 60(5):1245–1253PubMed Dibiase SJ, Zeng ZC, Chen R, Hyslop T, Curran WJ, Iliakis G (2000) DNA-dependent protein kinase stimulates an independently active, nonhomologous, end-joining apparatus. Cancer Res 60(5):1245–1253PubMed
27.
Zurück zum Zitat Rosenzweig KE, Youmell MB, Palayoor ST, Price BD (1997) Radiosensitization of human tumor cells by the phosphatidylinositol 3-kinase inhibitors Wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G(2)-M delay. Clinical Cancer Research 3(7):1149–1156PubMed Rosenzweig KE, Youmell MB, Palayoor ST, Price BD (1997) Radiosensitization of human tumor cells by the phosphatidylinositol 3-kinase inhibitors Wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G(2)-M delay. Clinical Cancer Research 3(7):1149–1156PubMed
28.
Zurück zum Zitat Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJ, Smith GC, Griffin RJ (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):3083–3086CrossRefPubMed Hollick JJ, Golding BT, Hardcastle IR, Martin N, Richardson C, Rigoreau LJ, Smith GC, Griffin RJ (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):3083–3086CrossRefPubMed
29.
Zurück zum Zitat Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, Calvert AH, Newell DR, Smith GCM, Curtin NJ (2006) Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 66(10):5354–5362. doi:10.1158/0008-5472.Can-05-4275 CrossRefPubMed Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, Calvert AH, Newell DR, Smith GCM, Curtin NJ (2006) Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 66(10):5354–5362. doi:10.​1158/​0008-5472.​Can-05-4275 CrossRefPubMed
30.
31.
Zurück zum Zitat Ihmaid SK, Al-Rawi JMA, Bradley CJ, Angove MJ, Robertson MN (2012) Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines. Eur J Med Chem 57:85–101. doi:10.1016/j.ejmech.2012.08.035 CrossRefPubMed Ihmaid SK, Al-Rawi JMA, Bradley CJ, Angove MJ, Robertson MN (2012) Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines. Eur J Med Chem 57:85–101. doi:10.​1016/​j.​ejmech.​2012.​08.​035 CrossRefPubMed
32.
Zurück zum Zitat Lee CM, Fuhrman CB, Planelles V, Peltier MR, Gaffney DK, Soisson AP, Dodson MK, Tolley HD, Green CL, Zempolich KA (2006) Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines. Clin Cancer Res 12(1):250–256. doi:10.1158/1078-0432.Ccr-05-1084 CrossRefPubMed Lee CM, Fuhrman CB, Planelles V, Peltier MR, Gaffney DK, Soisson AP, Dodson MK, Tolley HD, Green CL, Zempolich KA (2006) Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines. Clin Cancer Res 12(1):250–256. doi:10.​1158/​1078-0432.​Ccr-05-1084 CrossRefPubMed
33.
Zurück zum Zitat Izzard RA, Jackson SP, Smith GCM (1999) Competitive and noncompetitive inhibition of the DNA-dependent protein kinase. Cancer Res 59(11):2581–2586PubMed Izzard RA, Jackson SP, Smith GCM (1999) Competitive and noncompetitive inhibition of the DNA-dependent protein kinase. Cancer Res 59(11):2581–2586PubMed
34.
Zurück zum Zitat Chaussade C, Rewcastle GW, Kendall JD, Denny WA, Cho K, Gronning LM, Chong ML, Anagnostou SH, Jackson SP, Daniele N, Shepherd PR (2007) Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J 404:449–458. doi:10.1042/Bj20070003 PubMedCentralCrossRefPubMed Chaussade C, Rewcastle GW, Kendall JD, Denny WA, Cho K, Gronning LM, Chong ML, Anagnostou SH, Jackson SP, Daniele N, Shepherd PR (2007) Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J 404:449–458. doi:10.​1042/​Bj20070003 PubMedCentralCrossRefPubMed
35.
Zurück zum Zitat Veuger SJ, Curtin NJ, Richardson CJ, Smith GCM, Durkacz BW (2003) Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res 63(18):6008–6015PubMed Veuger SJ, Curtin NJ, Richardson CJ, Smith GCM, Durkacz BW (2003) Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res 63(18):6008–6015PubMed
38.
Zurück zum Zitat Buch K, Peters T, Nawroth T, Sanger M, Schmidberger H, Langguth P (2012) Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay - A comparative study. Radiat Oncol 7. doi:Artn 1 Doi 10.1186/1748-717x-7-1 Buch K, Peters T, Nawroth T, Sanger M, Schmidberger H, Langguth P (2012) Determination of cell survival after irradiation via clonogenic assay versus multiple MTT Assay - A comparative study. Radiat Oncol 7. doi:Artn 1 Doi 10.​1186/​1748-717x-7-1
39.
Zurück zum Zitat Pauwels B, Korst AEC, de Pooter CMJ, Pattyn GGO, Lambrechts HAJ, Baay MFD, Lardon F, Vermorken JB (2003) Comparison of the sulforhodamine B assay and the clonogenic assay for in vitro chemoradiation studies. Cancer Chemoth Pharm 51(3):221–226. doi:10.1007/s00280-002-0557-9 Pauwels B, Korst AEC, de Pooter CMJ, Pattyn GGO, Lambrechts HAJ, Baay MFD, Lardon F, Vermorken JB (2003) Comparison of the sulforhodamine B assay and the clonogenic assay for in vitro chemoradiation studies. Cancer Chemoth Pharm 51(3):221–226. doi:10.​1007/​s00280-002-0557-9
40.
Zurück zum Zitat Zhou Y, Gwadry FG, Reinhold WC, Miller LD, Smith LH, Scherf U, Liu ET, Kohn KW, Pommier Y, Weinstein JN (2002) Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: Microarray analysis of dose- and time-dependent effects. Cancer Res 62(6):1688–1695PubMed Zhou Y, Gwadry FG, Reinhold WC, Miller LD, Smith LH, Scherf U, Liu ET, Kohn KW, Pommier Y, Weinstein JN (2002) Transcriptional regulation of mitotic genes by camptothecin-induced DNA damage: Microarray analysis of dose- and time-dependent effects. Cancer Res 62(6):1688–1695PubMed
41.
Zurück zum Zitat Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). The Journal of biological chemistry 269(7):5241–5248PubMed Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). The Journal of biological chemistry 269(7):5241–5248PubMed
43.
Zurück zum Zitat Yuan XL, Shan YJ, Zhao ZH, Chen JP, Cong YW (2005) G0/G1 arrest and apoptosis induced by SARS-CoV 3b protein in transfected cells. Virol J 2. doi:Artn 66 Doi 10.1186/1743-422x-2-66 Yuan XL, Shan YJ, Zhao ZH, Chen JP, Cong YW (2005) G0/G1 arrest and apoptosis induced by SARS-CoV 3b protein in transfected cells. Virol J 2. doi:Artn 66 Doi 10.​1186/​1743-422x-2-66
44.
45.
Zurück zum Zitat Liang K, Lu Y, Jin WD, Ang KK, Milas L, Fan Z (2003) Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2(11):1113–1120PubMed Liang K, Lu Y, Jin WD, Ang KK, Milas L, Fan Z (2003) Sensitization of breast cancer cells to radiation by trastuzumab. Mol Cancer Ther 2(11):1113–1120PubMed
46.
Zurück zum Zitat Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GCM, Martin NMB, Workman P, Raynaud FI (2005) Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Brit J Cancer 93(9):1011–1018. doi:10.1038/sj.bjc.6602823 PubMedCentralPubMed Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GCM, Martin NMB, Workman P, Raynaud FI (2005) Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026. Brit J Cancer 93(9):1011–1018. doi:10.​1038/​sj.​bjc.​6602823 PubMedCentralPubMed
47.
Zurück zum Zitat Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin NMB, Newell DR, Smith GCM, Curtin NJ (2012) Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3K. Mol Cancer Ther 11(8):1789–1798. doi:10.1158/1535-7163.Mct-11-0535 PubMedCentralCrossRefPubMed Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin NMB, Newell DR, Smith GCM, Curtin NJ (2012) Chemosensitization of Cancer Cells by KU-0060648, a Dual Inhibitor of DNA-PK and PI-3K. Mol Cancer Ther 11(8):1789–1798. doi:10.​1158/​1535-7163.​Mct-11-0535 PubMedCentralCrossRefPubMed
48.
Zurück zum Zitat Redon C, Boon C, Johnson K, Bonner WM, Rogakou EP (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. Mol Biol Cell 10:282a–282a Redon C, Boon C, Johnson K, Bonner WM, Rogakou EP (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. Mol Biol Cell 10:282a–282a
49.
50.
Zurück zum Zitat Ismail IH, Wadhra TI, Hammarsten O (2007) An optimized method for detecting gamma-H2AX in blood cells reveals a significant interindividual variation in the gamma-H2AX response among humans. Nucleic Acids Res 35 (5). doi:Artn E36 Doi 10.1093/Nar/Gkl1169 Ismail IH, Wadhra TI, Hammarsten O (2007) An optimized method for detecting gamma-H2AX in blood cells reveals a significant interindividual variation in the gamma-H2AX response among humans. Nucleic Acids Res 35 (5). doi:Artn E36 Doi 10.​1093/​Nar/​Gkl1169
51.
Zurück zum Zitat Prendergast AM, Cruet-Hennequart S, Shaw G, Barry FP, Carty MP (2011) Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or gamma-irradiation. Cell Cycle 10(21):3768–3777. doi:10.4161/cc.10.21.17972 CrossRefPubMed Prendergast AM, Cruet-Hennequart S, Shaw G, Barry FP, Carty MP (2011) Activation of DNA damage response pathways in human mesenchymal stem cells exposed to cisplatin or gamma-irradiation. Cell Cycle 10(21):3768–3777. doi:10.​4161/​cc.​10.​21.​17972 CrossRefPubMed
52.
Zurück zum Zitat Wang JH, Pluth JM, Cooper PK, Cowan MJ, Chen DJ, Yannone SM (2005) Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair (Amst) 4(5):556–570. doi:10.1016/j.dnarep.2005.02.001 CrossRef Wang JH, Pluth JM, Cooper PK, Cowan MJ, Chen DJ, Yannone SM (2005) Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair (Amst) 4(5):556–570. doi:10.​1016/​j.​dnarep.​2005.​02.​001 CrossRef
53.
Zurück zum Zitat Francisco DC, Peddi P, Hair JM, Flood BA, Cecil AM, Kalogerinis PT, Sigounas G, Georgakilas AG (2008) Induction and processing of complex DNA damage in human breast cancer cells MCF-7 and nonmalignant MCF-10A cells. Free Radical Bio Med 44(4):558–569. doi:10.1016/j.freeradbiomed.2007.10.045 CrossRef Francisco DC, Peddi P, Hair JM, Flood BA, Cecil AM, Kalogerinis PT, Sigounas G, Georgakilas AG (2008) Induction and processing of complex DNA damage in human breast cancer cells MCF-7 and nonmalignant MCF-10A cells. Free Radical Bio Med 44(4):558–569. doi:10.​1016/​j.​freeradbiomed.​2007.​10.​045 CrossRef
55.
Zurück zum Zitat Langland GT, Yannone SM, Langland RA, Nakao A, Guan Y, Long SB, Vonguyen L, Chen DJ, Gray JW, Chen F (2010) Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities. Oncol Rep 23(4):1021–1026PubMedCentralCrossRefPubMed Langland GT, Yannone SM, Langland RA, Nakao A, Guan Y, Long SB, Vonguyen L, Chen DJ, Gray JW, Chen F (2010) Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities. Oncol Rep 23(4):1021–1026PubMedCentralCrossRefPubMed
56.
Zurück zum Zitat Urushihara Y, Kobayashi J, Matsumoto Y, Komatsu K, Oda S, Mitani H (2012) DNA-PK inhibition causes a low level of H2AX phosphorylation and homologous recombination repair in Medaka (Oryzias latipes) cells. Biochem Biophys Res Commun 429(3–4):131–136. doi:10.1016/j.bbrc.2012.10.128 CrossRefPubMed Urushihara Y, Kobayashi J, Matsumoto Y, Komatsu K, Oda S, Mitani H (2012) DNA-PK inhibition causes a low level of H2AX phosphorylation and homologous recombination repair in Medaka (Oryzias latipes) cells. Biochem Biophys Res Commun 429(3–4):131–136. doi:10.​1016/​j.​bbrc.​2012.​10.​128 CrossRefPubMed
57.
Zurück zum Zitat Yu M, Dai J, Huang WW, Jiao Y, Liu L, Wu M, Tan DY (2011) hMTERF4 knockdown in HeLa cells results in sub-G1 cell accumulation and cell death. Acta Bioch Bioph Sin 43(5):372–379. doi:10.1093/Abbs/Gmr020 CrossRef Yu M, Dai J, Huang WW, Jiao Y, Liu L, Wu M, Tan DY (2011) hMTERF4 knockdown in HeLa cells results in sub-G1 cell accumulation and cell death. Acta Bioch Bioph Sin 43(5):372–379. doi:10.​1093/​Abbs/​Gmr020 CrossRef
58.
Zurück zum Zitat Sun PC, Tzao C, Chen BH, Liu CW, Yu CP, Jin JS (2010) Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. J Biomed Sci 17. doi:Artn 76 Doi 10.1186/1423-0127-17-76 Sun PC, Tzao C, Chen BH, Liu CW, Yu CP, Jin JS (2010) Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. J Biomed Sci 17. doi:Artn 76 Doi 10.​1186/​1423-0127-17-76
60.
Zurück zum Zitat Bressenot A, Pooya S, Bossenmeyer-Pourie C, Gauchotte G, Germain A, Chevaux JB, Coste F, Vignaud JM, Gueant JL, Peyrin-Biroulet L (2013) Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats. Brit J Nutr 109(4):667–677. doi:10.1017/S0007114512001869 CrossRefPubMed Bressenot A, Pooya S, Bossenmeyer-Pourie C, Gauchotte G, Germain A, Chevaux JB, Coste F, Vignaud JM, Gueant JL, Peyrin-Biroulet L (2013) Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats. Brit J Nutr 109(4):667–677. doi:10.​1017/​S000711451200186​9 CrossRefPubMed
61.
Zurück zum Zitat Shawi M, Chu TW, Martinez-Marignac V, Yu Y, Gryaznov SM, Johnston JB, Lees-Miller SP, Assouline SE, Autexier C, Aloyz R (2013) Telomerase Contributes to Fludarabine Resistance in Primary Human Leukemic Lymphocytes. Plos One 8 (7). doi:ARTN e70428 DOI 10.1371/journal.pone.0070428 Shawi M, Chu TW, Martinez-Marignac V, Yu Y, Gryaznov SM, Johnston JB, Lees-Miller SP, Assouline SE, Autexier C, Aloyz R (2013) Telomerase Contributes to Fludarabine Resistance in Primary Human Leukemic Lymphocytes. Plos One 8 (7). doi:ARTN e70428 DOI 10.​1371/​journal.​pone.​0070428
62.
Zurück zum Zitat Amrein L, Loignon M, Goulet AC, Dunn M, Jean-Claude B, Aloyz R, Panasci L (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. doi:10.1124/jpet.106.118356 CrossRefPubMed Amrein L, Loignon M, Goulet AC, Dunn M, Jean-Claude B, Aloyz R, Panasci L (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. doi:10.​1124/​jpet.​106.​118356 CrossRefPubMed
64.
Zurück zum Zitat Chen BPC, Chan DW, Kobayashi J, Burma S, Asaithamby A, Morotomi-Yano K, Botvinick E, Qin J, Chen DJ (2005) Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J Biol Chem 280(15):14709–14715. doi:10.1074/jbc.M408827200 CrossRefPubMed Chen BPC, Chan DW, Kobayashi J, Burma S, Asaithamby A, Morotomi-Yano K, Botvinick E, Qin J, Chen DJ (2005) Cell cycle dependence of DNA-dependent protein kinase phosphorylation in response to DNA double strand breaks. J Biol Chem 280(15):14709–14715. doi:10.​1074/​jbc.​M408827200 CrossRefPubMed
65.
Zurück zum Zitat Chen BPC, Uematsu N, Kobayashi J, Lerenthal Y, Krempler A, Yajima H, Lobrich M, Shiloh Y, Chen DJ (2007) Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J Biol Chem 282(9):6582–6587. doi:10.1074/jbc.M611605200 CrossRefPubMed Chen BPC, Uematsu N, Kobayashi J, Lerenthal Y, Krempler A, Yajima H, Lobrich M, Shiloh Y, Chen DJ (2007) Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J Biol Chem 282(9):6582–6587. doi:10.​1074/​jbc.​M611605200 CrossRefPubMed
67.
Zurück zum Zitat Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664CrossRefPubMed Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664CrossRefPubMed
68.
Zurück zum Zitat Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC alpha but not S6K1. Dev Cell 11(6):859–871. doi:10.1016/j.devcel.2006.10.007 CrossRefPubMed Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC alpha but not S6K1. Dev Cell 11(6):859–871. doi:10.​1016/​j.​devcel.​2006.​10.​007 CrossRefPubMed
Metadaten
Titel
Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair
verfasst von
Suraj Radhamani
Christopher Bradley
Terri Meehan-Andrews
Saleh K. Ihmaid
Jasim Al-Rawi
Publikationsdatum
01.06.2014
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 3/2014
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-014-0079-4

Weitere Artikel der Ausgabe 3/2014

Investigational New Drugs 3/2014 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.