Advertisement

Apoptosis

, Volume 14, Issue 5, pp 641–654 | Cite as

Cell cycle arrest in early mitosis and induction of caspase-dependent apoptosis in U937 cells by diallyltetrasulfide (Al2S4)

  • Claudia Cerella
  • Christiane Scherer
  • Silvia Cristofanon
  • Estelle Henry
  • Awais Anwar
  • Corinna Busch
  • Mathias Montenarh
  • Mario Dicato
  • Claus Jacob
  • Marc Diederich
Original Paper

Abstract

Naturally occurring organic sulfur compounds (OSCs), such as linear allylsulfides from Allium species, are attracting attention in cancer research, since several OSCs were shown to act beneficially both in chemoprevention and in chemotherapy, while hardly exerting any harmful side effects. Hence, we investigated the possible role of different OSCs in the treatment of leukemia. Thereby, we found that the compounds tested in this study induced apoptosis in U937 cells, with an efficiency depending on the number of sulfides, and selected the most promising candidate, diallyltetrasulfide (Al2S4), for detailed mechanistic studies. Here we show that Al2S4 induced an accumulation of cells in early mitosis (G2/M phase), followed by the activation of caspase-dependent apoptosis. The compound counteracted different anti-apoptotic Bcl-2 family members (Bcl-xL, phospho-Bad and Bcl-2), promoted activation of Bax and Bak and induced the release of cytochrome c into the cytoplasm. Treatment by Al2S4 let to the identification of early apoptotic events including Bcl-xL degradation, Bak activation and release of cytochrome c followed by late events including Bcl-2 proteolysis, Bax activation, Bad dephosphorylation, caspase activation, nuclear fragmentation and phosphatidylserine exposure.

Keywords

Diallyltetrasulfide Apoptosis Cell cycle Mitosis Leukemia Bax/Bak activation 

Notes

Acknowledgments

CC is a recipient of a postdoctoral Télévie-Luxembourg grant. CS and SC are recipients of a postdoctoral grant from the “Ministère de la Culture, de l’Enseignement supérieur et de la Recherche of Luxembourg”. Additionally the authors are indebted to several institutions for their support: Télévie Luxembourg, the ‘‘Fondation de Recherche Cancer et Sang’’ and ‘‘Recherches Scientifiques Luxembourg association”. Besides the authors thank “Een Häerz fir Kriibskrank Kanner” association, the Action Lions “Vaincre le Cancer”, the Foundation for Scientific Cooperation between Germany and Luxembourg, the Saarland University and the “Ministry of Economics and Science of Saarland” for additional support. Moreover, AA thanks the Saarland University for financial support.

References

  1. 1.
    Delhalle S, Duvoix A, Schnekenburger M, Morceau F, Dicato M, Diederich M (2003) An introduction to the molecular mechanisms of apoptosis. Ann N Y Acad Sci 1010:1–8. doi: 10.1196/annals.1299.001 CrossRefPubMedGoogle Scholar
  2. 2.
    Bremer E, van Dam G, Kroesen BJ, de Leij L, Helfrich W (2006) Targeted induction of apoptosis for cancer therapy: current progress and prospects. Trends Mol Med 12:382–393. doi: 10.1016/j.molmed.2006.06.002 CrossRefPubMedGoogle Scholar
  3. 3.
    Hsu S, Singh B, Schuster G (2004) Induction of apoptosis in oral cancer cells: agents and mechanisms for potential therapy and prevention. Oral Oncol 40:461–473. doi: 10.1016/j.oraloncology.2003.09.012 CrossRefPubMedGoogle Scholar
  4. 4.
    Fernandez-Luna JL (2007) Apoptosis regulators as targets for cancer therapy. Clin Transl Oncol 9:555–562. doi: 10.1007/s12094-007-0103-7 CrossRefPubMedGoogle Scholar
  5. 5.
    Stan SD, Kar S, Stoner GD, Singh SV (2008) Bioactive food components and cancer risk reduction. J Cell Biochem 104:339–356. doi: 10.1002/jcb.21623 CrossRefPubMedGoogle Scholar
  6. 6.
    Meiler J, Schuler M (2006) Therapeutic targeting of apoptotic pathways in cancer. Curr Drug Targets 7:1361–1369. doi: 10.2174/138945006778559175 CrossRefPubMedGoogle Scholar
  7. 7.
    Herman-Antosiewicz A, Powolny AA, Singh SV (2007) Molecular targets of cancer chemoprevention by garlic-derived organosulfides. Acta Pharmacol Sin 28:1355–1364. doi: 10.1111/j.1745-7254.2007.00682.x CrossRefPubMedGoogle Scholar
  8. 8.
    Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF et al (2002) Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 113(Suppl 9B):71S–88S. doi: 10.1016/S0002-9343(01)00995-0 CrossRefPubMedGoogle Scholar
  9. 9.
    Shukla Y, Kalra N (2007) Cancer chemoprevention with garlic and its constituents. Cancer Lett 247:167–181. doi: 10.1016/j.canlet.2006.05.009 CrossRefPubMedGoogle Scholar
  10. 10.
    Ariga T, Seki T (2006) Antithrombotic and anticancer effects of garlic-derived sulfur compounds: a review. Biofactors 26:93–103. doi: 10.1002/biof.5520260201 CrossRefPubMedGoogle Scholar
  11. 11.
    Munchberg U, Anwar A, Mecklenburg S, Jacob C (2007) Polysulfides as biologically active ingredients of garlic. Org Biomol Chem 5:1505–1518. doi: 10.1039/b703832a CrossRefPubMedGoogle Scholar
  12. 12.
    Jacob C, Anwar A (2008) The chemistry behind redox regulation with a focus on sulphur redox systems. Physiol Plant 133:469–480. doi: 10.1111/j.1399-3054.2008.01080.x CrossRefPubMedGoogle Scholar
  13. 13.
    Moriarty RM, Naithani R, Surve B (2007) Organosulfur compounds in cancer chemoprevention. Mini Rev Med Chem 7:827–838. doi: 10.2174/138955707781387939 CrossRefPubMedGoogle Scholar
  14. 14.
    Xiao D, Zeng Y, Hahm ER, Kim YA, Ramalingam S, Singh SV (2008) Diallyl trisulfide selectively causes Bax- and Bak-mediated apoptosis in human lung cancer cells. Environ Mol Mutagen. [Epub ahead of print]Google Scholar
  15. 15.
    Herman-Antosiewicz A, Singh SV (2004) Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review. Mutat Res 555:121–131. doi: 10.1016/j.mrfmmm.2004.04.016 CrossRefPubMedGoogle Scholar
  16. 16.
    Chung LY (2006) The antioxidant properties of garlic compounds: allyl cysteine, alliin, allicin, and allyl disulfide. J Med Food 9:205–213. doi: 10.1089/jmf.2006.9.205 CrossRefPubMedGoogle Scholar
  17. 17.
    Dirsch VM, Gerbes AL, Vollmar AM (1998) Ajoene, a compound of garlic, induces apoptosis in human promyeloleukemic cells, accompanied by generation of reactive oxygen species and activation of nuclear factor kappaB. Mol Pharmacol 53:402–407CrossRefPubMedGoogle Scholar
  18. 18.
    Herman-Antosiewicz A, Stan SD, Hahm ER, Xiao D, Singh SV (2007) Activation of a novel ataxia-telangiectasia mutated and Rad3 related/checkpoint kinase 1-dependent prometaphase checkpoint in cancer cells by diallyl trisulfide, a promising cancer chemopreventive constituent of processed garlic. Mol Cancer Ther 6:1249–1261. doi: 10.1158/1535-7163.MCT-06-0477 CrossRefPubMedGoogle Scholar
  19. 19.
    Karmakar S, Banik NL, Patel SJ, Ray SK (2007) Garlic compounds induced calpain and intrinsic caspase cascade for apoptosis in human malignant neuroblastoma SH-SY5Y cells. Apoptosis 12:671–684. doi: 10.1007/s10495-006-0024-x CrossRefPubMedGoogle Scholar
  20. 20.
    Wu X, Kassie F, Mersch-Sundermann V (2005) Induction of apoptosis in tumor cells by naturally occurring sulfur-containing compounds. Mutat Res 589:81–102. doi: 10.1016/j.mrrev.2004.11.001 CrossRefPubMedGoogle Scholar
  21. 21.
    Jacob C (2006) A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms. Nat Prod Rep 23:851–863. doi: 10.1039/b609523m CrossRefPubMedGoogle Scholar
  22. 22.
    Jacob C, Knight I, Winyard PG (2006) Aspects of the biological redox chemistry of cysteine: from simple redox responses to sophisticated signalling pathways. Biol Chem 387:1385–1397. doi: 10.1515/BC.2006.174 CrossRefPubMedGoogle Scholar
  23. 23.
    Xiao D, Choi S, Johnson DE, Vogel VG, Johnson CS, Trump DL et al (2004) Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2. Oncogene 23:5594–5606. doi: 10.1038/sj.onc.1207747 CrossRefPubMedGoogle Scholar
  24. 24.
    Block E (1992) The organosulfur chemistry of the genus Allium: implications for the organic chemistry of sulfur. Angew Chem Int Ed Engl 31:1135–1178CrossRefGoogle Scholar
  25. 25.
    Agarwal KC (1996) Therapeutic actions of garlic constituents. Med Res Rev 16:111–124CrossRefPubMedGoogle Scholar
  26. 26.
    Ghibelli L, Fanelli C, Rotilio G, Lafavia E, Coppola S, Colussi C et al (1998) Rescue of cells from apoptosis by inhibition of active GSH extrusion. FASEB J 12:479–486CrossRefPubMedGoogle Scholar
  27. 27.
    Waterhouse NJ, Trapani JA (2003) A new quantitative assay for cytochrome c release in apoptotic cells. Cell Death Differ 10:853–855. doi: 10.1038/sj.cdd.4401263 CrossRefPubMedGoogle Scholar
  28. 28.
    Gray JW, Coffino P (1979) Cell cycle analysis by flow cytometry. Methods Enzymol 58:233–248. doi: 10.1016/S0076-6879(79)58140-3 CrossRefPubMedGoogle Scholar
  29. 29.
    Dini L, Coppola S, Ruzittu MT, Ghibelli L (1996) Multiple pathways for apoptotic nuclear fragmentation. Exp Cell Res 223:340–347. doi: 10.1006/excr.1996.0089 CrossRefPubMedGoogle Scholar
  30. 30.
    Doonan F, Cotter TG (2008) Morphological assessment of apoptosis. Methods 44:200–204. doi: 10.1016/j.ymeth.2007.11.006 CrossRefPubMedGoogle Scholar
  31. 31.
    Cameron AJ, McDonald KJ, Harnett MM, Allen JM (2002) Differentiation of the human monocyte cell line, U937, with dibutyryl cyclicAMP induces the expression of the inhibitory Fc receptor, FcgammaRIIb. Immunol Lett 83:171–179. doi: 10.1016/S0165-2478(02)00118-9 CrossRefPubMedGoogle Scholar
  32. 32.
    Cristofanon S, Nuccitelli S, D’Alessio M, Dicato M, Diederich M, Ghibelli L (2008) Oxidation-dependent maturation and survival of explanted blood monocytes via Bcl-2 up-regulation. Biochem Pharmacol 76:1533–1543. doi: 10.1016/j.bcp.2008.07.042 CrossRefPubMedGoogle Scholar
  33. 33.
    Ribas J, Gomez-Arbones X, Boix J (2005) Caspase 8/10 are not mediating apoptosis in neuroblastoma cells treated with CDK inhibitory drugs. Eur J Pharmacol 524:49–52. doi: 10.1016/j.ejphar.2005.09.021 CrossRefPubMedGoogle Scholar
  34. 34.
    Vermeulen K, Van Bockstaele DR, Berneman ZN (2005) Apoptosis: mechanisms and relevance in cancer. Ann Hematol 84:627–639. doi: 10.1007/s00277-005-1065-x CrossRefPubMedGoogle Scholar
  35. 35.
    Liu X, Zou H, Slaughter C, Wang X (1997) DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell 89:175–184. doi: 10.1016/S0092-8674(00)80197-X CrossRefGoogle Scholar
  36. 36.
    Gunawardana CG, Martinez RE, Xiao W, Templeton DM (2006) Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells. Am J Physiol Renal Physiol 290:F1074–F1082. doi: 10.1152/ajprenal.00067.2005 CrossRefPubMedGoogle Scholar
  37. 37.
    Zamzami N, Marchetti P, Castedo M, Zanin C, Vayssiere JL, Petit PX et al (1995) Reduction in mitochondrial potential constitutes an early irreversible step of programmed lymphocyte death in vivo. J Exp Med 181:1661–1672. doi: 10.1084/jem.181.5.1661 CrossRefPubMedGoogle Scholar
  38. 38.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES et al (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489. doi: 10.1016/S0092-8674(00)80434-1 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Bouillet P, Strasser A (2002) BH3-only proteins—evolutionarily conserved proapoptotic Bcl-2 family members essential for initiating programmed cell death. J Cell Sci 115:1567–1574PubMedPubMedCentralGoogle Scholar
  40. 40.
    Billen LP, Kokoski CL, Lovell JF, Leber B, Andrews DW (2008) Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol 6:e147. doi: 10.1371/journal.pbio.0060147 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Antignani A, Youle RJ (2006) How do Bax and Bak lead to permeabilization of the outer mitochondrial membrane? Curr Opin Cell Biol 18:685–689. doi: 10.1016/j.ceb.2006.10.004 CrossRefPubMedGoogle Scholar
  42. 42.
    Kim YA, Xiao D, Xiao H, Powolny AA, Lew KL, Reilly ML et al (2007) Mitochondria-mediated apoptosis by diallyl trisulfide in human prostate cancer cells is associated with generation of reactive oxygen species and regulated by Bax/Bak. Mol Cancer Ther 6:1599–1609. doi: 10.1158/1535-7163.MCT-06-0754 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi: 10.1126/science.1059108 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Hinds MG, Smits C, Fredericks-Short R, Risk JM, Bailey M, Huang DC et al (2007) Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 14:128–136. doi: 10.1038/sj.cdd.4401934 CrossRefPubMedGoogle Scholar
  45. 45.
    Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3-3 not BCL-X(L). Cell 87:619–628. doi: 10.1016/S0092-8674(00)81382-3 CrossRefPubMedGoogle Scholar
  46. 46.
    Halicka HD, Smolewski P, Darzynkiewicz Z, Dai W, Traganos F (2002) Arsenic trioxide arrests cells early in mitosis leading to apoptosis. Cell Cycle 1:201–209CrossRefPubMedGoogle Scholar
  47. 47.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. doi: 10.1038/47412 CrossRefPubMedGoogle Scholar
  48. 48.
    Allan LA, Clarke PR (2007) Phosphorylation of caspase-9 by CDK1/cyclin B1 protects mitotic cells against apoptosis. Mol Cell 26:301–310. doi: 10.1016/j.molcel.2007.03.019 CrossRefPubMedGoogle Scholar
  49. 49.
    Parry DH, O’Farrell PH (2001) The schedule of destruction of three mitotic cyclins can dictate the timing of events during exit from mitosis. Curr Biol 11:671–683. doi: 10.1016/S0960-9822(01)00204-4 CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Takahashi S, Hakoi K, Yada H, Hirose M, Ito N, Fukushima S (1992) Enhancing effects of diallyl sulfide on hepatocarcinogenesis and inhibitory actions of the related diallyl disulfide on colon and renal carcinogenesis in rats. Carcinogenesis 13:1513–1518. doi: 10.1093/carcin/13.9.1513 CrossRefPubMedGoogle Scholar
  51. 51.
    Wargovich MJ, Imada O, Stephens LC (1992) Initiation and post-initiation chemopreventive effects of diallyl sulfide in esophageal carcinogenesis. Cancer Lett 64:39–42. doi: 10.1016/0304-3835(92)90019-R CrossRefPubMedGoogle Scholar
  52. 52.
    Sparnins VL, Barany G, Wattenberg LW (1988) Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis 9:131–134. doi: 10.1093/carcin/9.1.131 CrossRefPubMedGoogle Scholar
  53. 53.
    Hayes MA, Rushmore TH, Goldberg MT (1987) Inhibition of hepatocarcinogenic responses to 1, 2-dimethylhydrazine by diallyl sulfide, a component of garlic oil. Carcinogenesis 8:1155–1157. doi: 10.1093/carcin/8.8.1155 CrossRefPubMedGoogle Scholar
  54. 54.
    Li M, Min JM, Cui JR, Zhang LH, Wang K, Valette A et al (2002) Z-ajoene induces apoptosis of HL-60 cells: involvement of Bcl-2 cleavage. Nutr Cancer 42:241–247. doi: 10.1207/S15327914NC422_14 CrossRefPubMedGoogle Scholar
  55. 55.
    Lea MA, Randolph VM, Patel M (1999) Increased acetylation of histones induced by diallyl disulfide and structurally related molecules. Int J Oncol 15:347–352PubMedGoogle Scholar
  56. 56.
    Lea MA, Rasheed M, Randolph VM, Khan F, Shareef A, desBordes C (2002) Induction of histone acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine. Nutr Cancer 43:90–102. doi: 10.1207/S15327914NC431_11 CrossRefPubMedGoogle Scholar
  57. 57.
    Kwon KB, Yoo SJ, Ryu DG, Yang JY, Rho HW, Kim JS et al (2002) Induction of apoptosis by diallyl disulfide through activation of caspase-3 in human leukemia HL-60 cells. Biochem Pharmacol 63:41–47. doi: 10.1016/S0006-2952(01)00860-7 CrossRefPubMedGoogle Scholar
  58. 58.
    Sundstrom C, Nilsson K (1976) Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer 17:565–577. doi: 10.1002/ijc.2910170504 CrossRefPubMedGoogle Scholar
  59. 59.
    Sriram N, Kalayarasan S, Ashokkumar P, Sureshkumar A, Sudhandiran G (2008) Diallyl sulfide induces apoptosis in Colo 320 DM human colon cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2. Mol Cell Biochem 311:157–165. doi: 10.1007/s11010-008-9706-8 CrossRefPubMedGoogle Scholar
  60. 60.
    Sandor V, Robbins AR, Robey R, Myers T, Sausville E, Bates SE et al (2000) FR901228 causes mitotic arrest but does not alter microtubule polymerization. Anticancer Drugs 11:445–454. doi: 10.1097/00001813-200007000-00005 CrossRefPubMedGoogle Scholar
  61. 61.
    Blagosklonny MV, Fojo T (1999) Molecular effects of paclitaxel: myths and reality (a critical review). Int J Cancer 83:151–156. doi: 10.1002/(SICI)1097-0215(19991008)83:2<151::AID-IJC1>3.0.CO;2-5 CrossRefPubMedGoogle Scholar
  62. 62.
    Nian H, Delage B, Pinto JT, Dashwood RH (2008) Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis 29:1816–1824. doi: 10.1093/carcin/bgn165 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kepp O, Rajalingam K, Kimmig S, Rudel T (2007) Bak and Bax are non-redundant during infection- and DNA damage-induced apoptosis. EMBO J 26:825–834. doi: 10.1038/sj.emboj.7601533 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Neise D, Graupner V, Gillissen BF, Daniel PT, Schulze-Osthoff K, Janicke RU et al (2008) Activation of the mitochondrial death pathway is commonly mediated by a preferential engagement of Bak. Oncogene 27:1387–1396. doi: 10.1038/sj.onc.1210773 CrossRefPubMedGoogle Scholar
  65. 65.
    Upreti M, Chu R, Galitovskaya E, Smart SK, Chambers TC (2008) Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine. Mol Cancer Ther 7:2224–2232. doi: 10.1158/1535-7163.MCT-07-2299 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337. doi: 10.1038/sj.onc.1210220 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Zhou L, Chang DC (2008) Dynamics and structure of the Bax-Bak complex responsible for releasing mitochondrial proteins during apoptosis. J Cell Sci 121:2186–2196. doi: 10.1242/jcs.024703 CrossRefPubMedGoogle Scholar
  68. 68.
    Chen C, Pung D, Leong V, Hebbar V, Shen G, Nair S et al (2004) Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radic Biol Med 37:1578–1590. doi: 10.1016/j.freeradbiomed.2004.07.021 CrossRefPubMedGoogle Scholar
  69. 69.
    Liang Y, Nylander KD, Yan C, Schor NF (2002) Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2. Mol Pharmacol 61:142–149. doi: 10.1124/mol.61.1.142 CrossRefPubMedGoogle Scholar
  70. 70.
    Lin H, Zhang XM, Chen C, Chen BD (2000) Apoptosis of Mo7e leukemia cells is associated with the cleavage of Bcl-2 into a shortened fragment that is not functional for heterodimerization with Bcl-2 and Bax. Exp Cell Res 261:180–186. doi: 10.1006/excr.2000.5036 CrossRefPubMedGoogle Scholar
  71. 71.
    Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A et al (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278:1966–1968. doi: 10.1126/science.278.5345.1966 CrossRefPubMedGoogle Scholar
  72. 72.
    Ling YH, Liebes L, Ng B, Buckley M, Elliott PJ, Adams J et al (2002) PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis. Mol Cancer Ther 1:841–849PubMedGoogle Scholar
  73. 73.
    Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80:285–291. doi: 10.1016/0092-8674(95)90411-5 CrossRefPubMedGoogle Scholar
  74. 74.
    Miyawaki T, Mashiko T, Ofengeim D, Flannery RJ, Noh KM, Fujisawa S et al (2008) Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons. Proc Natl Acad Sci USA 105:4892–4897. doi: 10.1073/pnas.0800628105 CrossRefPubMedGoogle Scholar
  75. 75.
    Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5:647–654. doi: 10.1038/ncb1005 CrossRefPubMedGoogle Scholar
  76. 76.
    Holzman D (1996) Apoptosis provides new targets for chemotherapy. J Natl Cancer Inst 88:1098–1100. doi: 10.1093/jnci/88.16.1098 CrossRefPubMedGoogle Scholar
  77. 77.
    McDonald ERIII, El-Deiry WS (2000) Cell cycle control as a basis for cancer drug development. Int J Oncol 16:871–886 (Review)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Claudia Cerella
    • 1
  • Christiane Scherer
    • 1
    • 2
  • Silvia Cristofanon
    • 1
  • Estelle Henry
    • 1
  • Awais Anwar
    • 2
  • Corinna Busch
    • 3
  • Mathias Montenarh
    • 3
  • Mario Dicato
    • 1
  • Claus Jacob
    • 2
  • Marc Diederich
    • 1
  1. 1.Laboratoire de Biologie Moléculaire et Cellulaire de CancerHôpital KirchbergLuxembourgLuxembourg
  2. 2.Division of Bioorganic Chemistry, School of PharmacySaarland UniversitySaarbruckenGermany
  3. 3.Division of Medicinal Biochemistry and Molecular BiologySaarland UniversityHomburgGermany

Personalised recommendations