The impact of CDK inhibition in human malignancies associated with pronounced defects in apoptosis: Advantages of multi-targeting small molecules

Future Medicinal Chemistry

Volumn 4, Issue 4, 2012, Pages 395-424

  Wesierska Gadek, Józefa ^a   Kramer, Matthias P ^b  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b UNIVERSITY OF VIENNA   (Austria)

Author keywords

[No Author keywords available]

Indexed keywords

AT 7519; AT 9311; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE INHIBITOR; DINACICLIB; FLAVOPIRIDOL; INDISULAM; MICRORNA; MILCICLIB; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; PROTEIN BCL 6; RGB 286638; ROSCOVITINE; TRANSCRIPTION FACTOR FOXO; UNCLASSIFIED DRUG; ZK 304709;

APOPTOSIS; B LYMPHOCYTE; BONE MARROW SUPPRESSION; CELL CYCLE PROGRESSION; CELL CYCLE REGULATION; CHRONIC LYMPHATIC LEUKEMIA; DIARRHEA; ENZYME INHIBITION; HUMAN; HYPOTENSION; LYMPHOID CELL; MICROENVIRONMENT; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; TRANSCRIPTION REGULATION;

EID: 84858660493     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.12.12     Document Type: Review

References (300)

1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100(1), 57-70 (2000). (Pubitemid 30046295)
2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144(5), 646-674 (2011).
3. O'Brien S, Del Giglio A, Keating M. Advances in the biology and treatment of B-cell chronic lymphocytic leukemia. Blood 85(2), 307-318 (1995).
4. Meinhardt G, Wendtner CM, Hallek M. Molecular pathogenesis of chronic lymphocytic leukemia. Factors and signaling pathways regulating cell growth and survival. J. Mol. Med. 77(2), 282-293 (1999). (Pubitemid 29146579)
5. Bellosillo B, Villamor N, Colomer D, Pons G, Montserrat E, Gil J. In vitro evaluation of fludarabine in combination with cyclophosphamide and/or mitoxantrone in B-cell chronic lymphocytic leukemia. Blood 94(8), 2836-2843 (1999). (Pubitemid 29477312)
6. Castejon R, Vargas JA, Briz M et al. Induction of apoptosis by 2-chlorodeoxyadenosine in B-cell chronic lymphocytic leukemia. Leukemia 11(8), 1253-1257 (1997). (Pubitemid 27387301)
7. Gale RP, Caligaris-Cappio F, Dighiero G, Keating M, Montserrat E, Rai K. Recent progress in chronic lymphocytic leukemia. International Workshop on chronic Lymphocytic Leukemia. Leukemia 8(9), 1610-1614 (1994).
8. Genini D, Adachi S, Chao Q et al. Deoxyadenosine analogs induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 96(10), 3537-3543 (2000).
9. Marzo I, Perez-Galan P, Giraldo P, Rubio-Felix D, Anel A, Naval J. Cladribine induces apoptosis in human leukaemia cells by caspase-dependent and -independent pathways acting on mitochondria. Biochem. J. 359(Pt 3), 537-546 (2001). (Pubitemid 33063377)
10. Reed JC. Molecular biology of chronic lymphocytic leukemia: implications for therapy. Semin. Hematol. 35(3 Suppl. 3), 3-13 (1998). (Pubitemid 28326232)
11. Reed JC. Bcl-2-family proteins and hematologic malignancies: history and future prospects. Blood 111(7), 3322-3330 (2008).
12. Reed JC, Pellecchia M. Apoptosis-based therapies for hematologic malignancies. Blood 106(2), 408-418 (2005). (Pubitemid 40981231)
13. Abbas AK, Lichtman AH. Cellular and Molecular Immunology (5th Edition). Elsevier, Philadelphia, PA, USA (2005).
14. Norbury C, Nurse P. Animal cell cycles and their control. Annu. Rev. Biochem. 61, 441-470 (1992).
15. Van Den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262(5142), 2050-2054 (1993). (Pubitemid 24041887)
16. Minshull J, Pines J, Golsteyn R et al. The role of cyclin synthesis, modification and destruction in the control of cell division. J. Cell. Sci. Suppl. 12, 77-97 (1989). (Pubitemid 20038238)
17. Pines J. Cyclins: wheels within wheels. Cell Growth Differ. 2(6), 305-310 (1991).
18. Tarn WY, Lai MC. Translational control of cyclins. Cell Div. 6(1), 5 (2011).
19. Jeffrey PD, Russo AA, Polyak K et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 376(6538), 313-320 (1995).
20. Fesquet D, Labbe JC, Derancourt J et al. The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues. EMBO J. 12(8), 3111-3121 (1993). (Pubitemid 23232742)
21. Fisher RP, Morgan DO. A novel cyclin associates with MO15/CDK7 to form the CDK-activating kinase. Cell 78(4), 713-724 (1994). (Pubitemid 24268593)
22. Makela TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA. A cyclin associated with the CDK-activating kinase MO15. Nature 371(6494), 254-257 (1994). (Pubitemid 24293025)
23. Russo AA, Jeffrey PD, Pavletich NP. Structural basis of cyclin-dependent kinase activation by phosphorylation. Nat. Struct. Biol. 3(8), 696-700 (1996). (Pubitemid 26260060)
24. Mittnacht S, Weinberg RA. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment. Cell 65(3), 381-393 (1991). (Pubitemid 121002048)
25. Hatakeyama M, Brill JA, Fink GR, Weinberg RA. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 8(15), 1759-1771 (1994).
26. Kato J, Matsushime H, Hiebert SW, Ewen ME, Sherr CJ. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7(3), 331-342 (1993). (Pubitemid 23139228)
27. Obeyesekere MN, Herbert JR, Zimmerman SO. A model of the G1 phase of the cell cycle incorporating cyclin E/cdk2 complex and retinoblastoma protein. Oncogene 11(6), 1199-1205 (1995).
28. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14(19), 2393-2409 (2000).
29. Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol. Cell. Biol. 18(2), 753-761 (1998). (Pubitemid 28063408)
30. Friend SH, Bernards R, Rogelj S et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323(6089), 643-646 (1986). (Pubitemid 16008560)
31. Cobrinik D. Pocket proteins and cell cycle control. Oncogene 24(17), 2796-2809 (2005). (Pubitemid 40638091)
32. Zhu L. Tumour suppressor retinoblastoma protein Rb: a transcriptional regulator. Eur J. Cancer 41(16), 2415-2427 (2005). (Pubitemid 41540619)
33. Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424(6945), 223-228 (2003). (Pubitemid 36858693)
34. Sherr CJ, Roberts JM. CDK inhibitors. positive and negative regulators of G1-phase progression. Genes Dev. 13(12), 1501-1512 (1999). (Pubitemid 29297917)
35. Besson A, Dowdy SF, Roberts JM. CDK inhibitors. cell cycle regulators and beyond. Dev. Cell 14(2), 159-169 (2008). (Pubitemid 351189186)
36. Nakayama KI, Nakayama K. Ubiquitin ligases. cell-cycle control and cancer. Nat. Rev. Cancer. 6(5), 369-381 (2006).
37. Richards S, Watanabe C, Santos L, Craxton A, Clark EA. Regulation of B-cell entry into the cell cycle. Immunol. Rev. 224, 183-200 (2008).
38. Yusuf I, Fruman DA. Regulation of quiescence in lymphocytes. Trends Immunol. 24(7), 380-386 (2003). (Pubitemid 36830965)
39. Fruman DA, Ferl GZ, An SS, Donahue AC, Satterthwaite AB, Witte ON. Phosphoinositide 3-kinase and Bruton's tyrosine kinase regulate overlapping sets of genes in B-lymphocytes. Proc. Natl Acad. Sci. USA 99(1), 359-364 (2002). (Pubitemid 34060367)
40. Glynne R, Ghandour G, Rayner J, Mack DH, Goodnow CC. B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays. Immunol. Rev. 176, 216-246 (2000).
41. Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. Kruppel-like transcription factors: a functional family. Int. J. Biochem. Cell Biol. 40(10), 1996-2001 (2008). (Pubitemid 352004270)
42. Kuo CT, Veselits ML, Leiden JM. LKLF. A transcriptional regulator of single-positive T cell quiescence and survival. Science 277(5334), 1986-1990 (1997). (Pubitemid 27449139)
43. Hoek KL, Gordy LE, Collins PL et al. Follicular B-cell trafficking within the spleen actively restricts humoral immune responses. Immunity 33(2), 254-265 (2010).
44. Chen X, Johns DC, Geiman DE et al. Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J. Biol. Chem. 276(32), 30423-30428 (2001).
45. Segre JA, Bauer C, Fuchs E. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat. Genet. 22(4), 356-360 (1999). (Pubitemid 29369526)
46. Rowland BD, Peeper DS. KLF4, p21 and context-dependent opposing forces in cancer. Nat. Rev. Cancer. 6(1), 11-23 (2006). (Pubitemid 43053649)
47. Mcconnell BB, Yang VW. Mammalian Kruppel-like factors in health and diseases. Physiol. Rev. 90(4), 1337-1381 (2010).
48. Toyoshima H, Hunter T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78(1), 67-74 (1994). (Pubitemid 24228301)
49. Polyak K, Lee MH, Erdjument-Bromage H et al. Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78(1), 59-66 (1994).
50. Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer. prognostic potential and relevance to anticancer therapy. Nat. Rev. Cancer. 8(4), 253-267 (2008). (Pubitemid 351430863)
51. Sicinski P, Zacharek S, Kim C. Duality of p27Kip1 function in tumorigenesis. Genes Dev. 21(14), 1703-1706 (2007).
52. Millard SS, Yan JS, Nguyen H, Pagano M, Kiyokawa H, Koff A. Enhanced ribosomal association of p27(Kip1) mRNA is a mechanism contributing to accumulation during growth arrest. J. Biol. Chem. 272(11), 7093-7098 (1997). (Pubitemid 27166413)
53. Hengst L, Reed SI. Translational control of p27Kip1 accumulation during the cell cycle. Science 271(5257), 1861-1864 (1996).
54. Tam SW, Theodoras AM, Pagano M. Kip1 degradation via the ubiquitin-proteasome pathway. Leukemia 11(Suppl. 3), 363-366 (1997).
55. Miskimins WK, Wang G, Hawkinson M, Miskimins R. Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation. Mol. Cell. Biol. 21(15), 4960-4967 (2001). (Pubitemid 32656394)
56. Cho S, Kim JH, Back SH, Jang SK. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase. Mol. Cell. Biol. 25(4), 1283-1297 (2005). (Pubitemid 40204907)
57. Pagano M, Tam SW, Theodoras AM et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269(5224), 682-685 (1995).
58. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. 11(11), 1464-1478 (1997).
59. Montagnoli A, Fiore F, Eytan E et al. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dev. 13(9), 1181-1189 (1999). (Pubitemid 29233148)
60. Russo AA, Jeffrey PD, Patten AK, Massague J, Pavletich NP. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382(6589), 325-331 (1996). (Pubitemid 26260452)
61. Tomoda K, Kubota Y, Kato J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398(6723), 160-165 (1999).
62. Malek NP, Sundberg H, Mcgrew S, Nakayama K, Kyriakides TR, Roberts JM. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413(6853), 323-327 (2001). (Pubitemid 32905854)
63. Tomoda K, Kubota Y, Arata Y. et al. The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/ CSN5 and the COP9 signalosome complex. J. Biol. Chem 277(3), 2302-2310 (2002). (Pubitemid 34968817)
64. Reynisdottir I, Massague J. The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev. 11(4), 492-503 (1997). (Pubitemid 27097647)
65. Rodier G, Montagnoli A, Di Marcotullio L et al. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J. 20(23), 6672-6682 (2001). (Pubitemid 33134197)
66. Boehm M, Yoshimoto T, Crook MF et al. A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J. 21(13), 3390-3401 (2002). (Pubitemid 34760571)
67. Burgering BM, Kops GJ. Cell cycle and death control. long live Forkheads. Trends Biochem. Sci. 27(7), 352-360 (2002). (Pubitemid 34756518)
68. Tran H, Brunet A, Griffith EC, Greenberg ME. The many forks in FOXO's road. Sci. STKE 2003(172), RE5 (2003).
69. Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117(4), 421-426 (2004). (Pubitemid 38610228)
70. Stahl M, Dijkers PF, Kops GJ et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J. Immunol. 168(10), 5024-5031 (2002). (Pubitemid 34495965)
71. Yusuf I, Zhu X, Kharas MG, Chen J, Fruman DA. Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors. Blood 104(3), 784-787 (2004). (Pubitemid 38970574)
72. Yusuf I, Kharas MG, Chen J et al. KLF4 is a FOXO target gene that suppresses B-cell proliferation. Int. Immunol. 20(5), 671-681 (2008). (Pubitemid 351619235)
73. Okkenhaug K, Fruman DA. PI3Ks in lymphocyte signaling and development. Curr. Top. Microbiol. Immunol. 346, 57-85 (2010).
74. Brunet A, Bonni A, Zigmond MJ et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6), 857-868 (1999). (Pubitemid 29165088)
75. Su YW, Hao Z, Hirao A et al. 14-13-3sigma regulates B-cell homeostasis through stabilization of FOXO1. Proc. Natl Acad. Sci. USA 108(4), 1555-1560 (2011).
76. Ho KK, Myatt SS, Lam EW. Many forks in the path. Cycling with FoxO. Oncogene 27(16), 2300-2311 (2008).
77. Chen J, Yusuf I, Andersen HM, Fruman DA. FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B-lymphocytes. J. Immunol. 176(5), 2711-2721 (2006).
78. Chandramohan V, Jeay S, Pianetti S, Sonenshein GE. Reciprocal control of Forkhead box O 3a and c-Myc via the phosphatidylinositol 3-kinase pathway coordinately regulates p27Kip1 levels. J. Immunol. 172(9), 5522-5527 (2004). (Pubitemid 38542053)
79. Schmidt M, Fernandez De Mattos S, Van Der Horst A et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol. Cell. Biol. 22(22), 7842-7852 (2002). (Pubitemid 35217295)
80. Cambier JC, Gauld SB, Merrell KT, Vilen BJ. B-cell anergy. from transgenic models to naturally occurring anergic B-cells? Nat. Rev. Immunol. 7(8), 633-643 (2007). (Pubitemid 47123549)
81. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat. Rev. Immunol. 2(12), 945-956 (2002). (Pubitemid 37323215)
82. Dal Porto JM, Gauld SB, Merrell KT, Mills D, Pugh-Bernard AE, Cambier J. B-cell antigen receptor signaling 101. Mol. Immunol. 41(6-7), 599-613 (2004). (Pubitemid 38824617)
83. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol. Cell Biol. 85(6), 471-475 (2007). (Pubitemid 47367507)
84. Monroe JG. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat. Rev. Immunol. 6(4), 283-294 (2006).
85. Niiro H, Clark EA. Branches of the B-cell antigen receptor pathway are directed by protein conduits Bam32 and Carma1. Immunity 19(5), 637-640 (2003). (Pubitemid 37490788)
86. Dowler S, Currie RA, Downes CP, Alessi DR. DAPP1: a dual adaptor for phosphotyrosine and 3-phosphoinositides. Biochem. J. 342 (Part 1), 7-12 (1999). (Pubitemid 29410842)
87. Grumont RJ, Strasser A, Gerondakis S. B-cell growth is controlled by phosphatidylinosotol 3-kinase-dependent induction of Rel/ NF-kappaB regulated c-myc transcription. Mol. Cell 10(6), 1283-1294 (2002). (Pubitemid 36050871)
88. Piatelli MJ, Wardle C, Blois J et al. Phosphatidylinositol 3-kinase-dependent mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 and NF-kappa B signaling pathways are required for B-cell antigen receptor-mediated cyclin D2 induction in mature B-cells. J. Immunol. 172(5), 2753-2762 (2004). (Pubitemid 38263658)
89. Mohamedali A, Soeiro I, Lea NC et al. Cyclin D2 controls B-cell progenitor numbers. J. Leukoc. Biol. 74(6), 1139-1143 (2003). (Pubitemid 38040336)
90. Solvason N, Wu WW, Parry D et al. Cyclin D2 is essential for BCR-mediated proliferation and CD5 B-cell development. Int. Immunol. 12(5), 631-638 (2000). (Pubitemid 30248896)
91. Chiles TC. Regulation and function of cyclin D2 in B lymphocyte subsets. J. Immunol. 173(5), 2901-2907 (2004). (Pubitemid 39141991)
92. Cato MH, Chintalapati SK, Yau IW, Omori SA, Rickert RC. Cyclin D3 is selectively required for proliferative expansion of germinal center B-cells. Mol. Cell. Biol. 31(1), 127-137 (2011).
93. Craxton A, Draves KE, Clark EA. Bim regulates BCR-induced entry of B-cells into the cell cycle. Eur. J. Immunol. 37(10), 2715-2722 (2007). (Pubitemid 47591331)
94. Olson NE, Graves JD, Shu GL, Ryan EJ, Clark EA. Caspase activity is required for stimulated B-lymphocytes to enter the cell cycle. J. Immunol. 170(12), 6065-6072 (2003). (Pubitemid 36682588)
95. Graves JD, Craxton A, Clark EA. Modulation and function of caspase pathways in B-lymphocytes. Immunol. Rev. 197, 129-146 (2004). (Pubitemid 38142173)
96. Tumilasci VF, Oliere S, Nguyen TL, Shamy A, Bell J, Hiscott J. Targeting the apoptotic pathway with BCL-2 inhibitors sensitizes primary chronic lymphocytic leukemia cells to vesicular stomatitis virus-induced oncolysis. J. Virol. 82(17), 8487-8499 (2008).
97. 2+-driven apoptosis in chronic lymphocytic leukemia cells by peptide-mediated disruption of Bcl-2-IP3 receptor interaction. Blood 117(10), 2924-2934 (2011).
98. Baron BW, Nucifora G, Mccabe N, Espinosa R, 3rd, Le Beau MM, Mckeithan TW. Identification of the gene associated with therecurring chromosomal translocations t(3;14) (q27;q32) and t(3;22)(q27;q11) in B-cell lymphomas. Proc. Natl Acad. Sci. USA 90(11), 5262-5266 (1993). (Pubitemid 23183018)
99. Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C. LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nat. Genet. 5(1), 66-70 (1993). (Pubitemid 23261521)
100. Ye BH, Rao PH, Chaganti RS, Dalla-Favera R. Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res. 53(12), 2732-2735 (1993). (Pubitemid 23180506)
101. Seyfert VL, Allman D, He Y, Staudt LM. Transcriptional repression by the proto-oncogene BCL-6. Oncogene 12(11), 2331-2342 (1996). (Pubitemid 26192713)
102. Chang CC, Ye BH, Chaganti RS, Dalla-Favera R. BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. Proc. Natl Acad. Sci. USA 93(14), 6947-6952 (1996). (Pubitemid 26243480)
103. Jardin F, Ruminy P, Bastard C, Tilly H. The BCL6 proto-oncogene. a leading role during germinal center development and lymphomagenesis. Pathol. Biol. 55(1), 73-83 (2007). (Pubitemid 46216617)
104. Baron BW, Anastasi J, Thirman MJ et al. The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression. implications for a role of BCL6 in the down-regulation of apoptosis. Proc. Natl Acad. Sci. USA 99(5), 2860-2865 (2002). (Pubitemid 34240551)
105. Phan RT, Saito M, Basso K, Niu H, Dalla-Favera R. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B-cells. Nat. Immunol. 6(10), 1054-1060 (2005). (Pubitemid 41486191)
106. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-center B-cells. Nature 432(7017), 635-639 (2004). (Pubitemid 39626271)
107. Sahota SS, Davis Z, Hamblin TJ, Stevenson FK. Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia. Blood 95(11), 3534-3540 (2000). (Pubitemid 30428488)
108. Parekh S, Polo JM, Shaknovich R et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 110(6), 2067-2074 (2007). (Pubitemid 47443924)
109. Cotter TG. Apoptosis and cancer. the genesis of a research field. Nat. Rev. Cancer 9(7), 501-507 (2009).
110. Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol. Rev. 193, 10-21 (2003). (Pubitemid 36688035)
111. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87(1), 99-163 (2007). (Pubitemid 46209992)
112. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348(6299), 334-336 (1990). (Pubitemid 120029101)
113. Yang J, Liu X, Bhalla K et al. Prevention of apoptosis by Bcl-2. release of cytochrome c from mitochondria blocked. Science 275(5303), 1129-1132 (1997). (Pubitemid 27097312)
114. Del Gaizo Moore V, Brown JR, Certo M, Love TM, Novina CD, Letai A. Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J. Clin. Invest. 117(1), 112-121 (2007). (Pubitemid 46048458)
115. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B-cells. Blood 111(2), 846-855 (2008).
116. Pickering BM, De Mel S, Lee M et al. Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells. Oncogene 26(8), 1166-1177 (2007).
117. Crook NE, Clem RJ, Miller LK. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J. Virol. 67(4), 2168-2174 (1993). (Pubitemid 23088392)
118. Birnbaum MJ, Clem RJ, Miller LK. An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His-sequence motifs. J. Virol. 68(4), 2521-2528 (1994). (Pubitemid 24091932)
119. Salvesen GS, Duckett CS. IAP proteins. Blocking the road to death's door. Nat. Rev. Mol. Cell. Biol. 3(6), 401-410 (2002). (Pubitemid 34685698)
120. Gyrd-Hansen M, Meier P. IAPs. From caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat. Rev. Cancer 10(8), 561-574 (2010).
121. Schliep S, Decker T, Schneller F, Wagner H, Hacker G. Functional evaluation of the role of inhibitor of apoptosis proteins in chronic lymphocytic leukemia. Exp. Hematol. 32(6), 556-562 (2004). (Pubitemid 38739467)
122. Nakagawa Y, Yamaguchi S, Hasegawa M et al. Differential expression of survivin in bone marrow cells from patients with acute lymphocytic leukemia and chronic lymphocytic leukemia. Leuk. Res. 28(5), 487-494 (2004). (Pubitemid 38453061)
123. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat. Med. 3(8), 917-921 (1997). (Pubitemid 27353455)
124. Altieri DC, Marchisio PC. Survivin apoptosis. An interloper between cell death and cell proliferation in cancer. Lab. Invest. 79(11), 1327-1333 (1999).
125. Badran A, Yoshida A, Ishikawa K et al. Identification of a novel splice variant of the human anti-apoptopsis gene survivin. Biochem. Biophys. Res. Commun. 314(3), 902-907 (2004). (Pubitemid 38112885)
126. Caldas H, Honsey LE, Altura RA. Survivin 2alpha. A novel Survivin splice variant expressed in human malignancies. Mol. Cancer 4(1), 11 (2005).
127. Conway EM, Pollefeyt S, Cornelissen J et al. Three differentially expressed survivin cDNA variants encode proteins with distinct antiapoptotic functions. Blood 95(4), 1435-1442 (2000). (Pubitemid 30099858)
128. Mahotka C, Wenzel M, Springer E, Gabbert HE, Gerharz CD. Survivin-deltaEx3 and survivin-2B. Two novel splice variants of the apoptosis inhibitor survivin with different antiapoptotic properties. Cancer Res. 59(24), 6097-6102 (1999). (Pubitemid 30035627)
129. Horn HF, Vousden KH. Coping with stress. multiple ways to activate p53. Oncogene 26(9), 1306-1316 (2007). (Pubitemid 46328472)
130. Toledo F, Wahl GM. Regulating the p53 pathway. In vitro hypotheses, in vivo veritas. Nat. Rev. Cancer 6(12), 909-923 (2006). (Pubitemid 44862676)
131. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 54(12), 3131-3135 (1994). (Pubitemid 24208916)
132. Mirza A, Mcguirk M, Hockenberry TN et al. Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21(17), 2613-2622 (2002). (Pubitemid 34478319)
133. Hoffman WH, Biade S, Zilfou JT, Chen J, Murphy M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277(5), 3247-3257 (2002). (Pubitemid 34953189)
134. Delmer A, Ajchenbaum-Cymbalista F, Tang R et al. Over-expression of cyclin D1 in chronic B-cell malignancies with abnormality of chromosome 11q13. Br. J. Haematol. 89(4), 798-804 (1995).
135. Delmer A, Ajchenbaum-Cymbalista F, Tang R et al. Overexpression of cyclin D2 in chronic B-cell malignancies. Blood 85(10), 2870-2876 (1995).
136. Fluckiger AC, Rossi JF, Bussel A, Bryon P, Banchereau J, Defrance T. Responsiveness of chronic lymphocytic leukemia B-cellsactivated via surface Igs or CD40 to B-cell tropic factors. Blood 80(12), 3173-3181 (1992). (Pubitemid 23004522)
137. Decker T, Schneller F, Hipp S et al. Cell cycle progression of chronic lymphocytic leukemia cells is controlled by cyclin D2, cyclin D3, cyclin-dependent kinase (cdk) 4 and the cdk inhibitor p27. Leukemia 16(3), 327-334 (2002). (Pubitemid 34228819)
138. Wolowiec D, Benchaib M, Pernas P et al. Expression of cell cycle regulatory proteins in chronic lymphocytic leukemias. Comparison with non-Hodgkin's lymphomas and non-neoplastic lymphoid tissue. Leukemia 9(8), 1382-1388 (1995).
139. Decker T, Hipp S, Hahntow I, Schneller F, Peschel C. Expression of cyclin E in resting and activated B-chronic lymphocytic leukaemia cells. Cyclin E/cdk2 as a potential therapeutic target. Br. J. Haematol. 125(2), 141-148 (2004). (Pubitemid 38534964)
140. Porter DC, Zhang N, Danes C et al. Tumor-specific proteolytic processing of cyclin E generates hyperactive lower-molecular-weight forms. Mol. Cell. Biol. 21(18), 6254-6269 (2001). (Pubitemid 34263525)
141. Harwell RM, Porter DC, Danes C, Keyomarsi K. Processing of cyclin E differs between normal and tumor breast cells. Cancer Res. 60(2), 481-489 (2000). (Pubitemid 30070779)
142. Wingate H, Bedrosian I, Akli S, Keyomarsi K. The low molecular weight (LMW) isoforms of cyclin E deregulate the cell cycle of mammary epithelial cells. Cell Cycle 2(5), 461-466 (2003).
143. Bagheri-Yarmand R, Nanos-Webb A, Biernacka A, Bui T, Keyomarsi K. Cyclin E deregulation impairs mitotic progression through premature activation of Cdc25C. Cancer Res. 70(12), 5085-5095 (2010).
144. Vrhovac R, Delmer A, Tang R, Marie JP, Zittoun R, Ajchenbaum-Cymbalista F. Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia. Blood 91(12), 4694-4700 (1998). (Pubitemid 28270319)
145. Newcomb EW, Rao LS, Giknavorian SS, Lee SY. Alterations of multiple tumor suppressor genes (p53 (17p13), p16INK4 (9p21), and DBM (13q14)) in B-cell chronic lymphocytic leukemia. Mol. Carcinog. 14(3), 141-146 (1995).
146. El Rouby S, Thomas A, Costin D et al. p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 82(11), 3452-3459 (1993). (Pubitemid 23356719)
147. Wattel E, Preudhomme C, Hecquet B et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84(9), 3148-3157 (1994).
148. Dohner H, Fischer K, Bentz M et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 85(6), 1580-1589 (1995).
149. Lens D, Dyer MJ, Garcia-Marco JM et al. p53 abnormalities in CLL are associated with excess of prolymphocytes and poor prognosis. Br. J. Haematol. 99(4), 848-857 (1997). (Pubitemid 28047150)
150. Antosz H, Paterski A, Marzec-Kotarska B, Sajewicz J, Dmoszynska A. Alterations in TP53, cyclin D2, c-Myc, p21WAF1/CIP1 and p27KIP1 expression associated with progression in B-CLL. Folia Histochem. Cytobiol. 48(4), 534-541 (2010).
151. Pettitt AR, Sherrington PD, Stewart G, Cawley JC, Taylor AM, Stankovic T. p53 dysfunction in B-cell chronic lymphocytic leukemia. Inactivation of ATM as an alternative to TP53 mutation. Blood 98(3), 814-822 (2001).
152. Martel V, Guerci A, Humbert JC et al. De novo methylation of tumour suppressor genes CDKN2A and CDKN2B is a rare finding in B-cell chronic lymphocytic leukaemia. Br. J. Haematol. 99(2), 320-324 (1997). (Pubitemid 27497561)
153. Pinyol M, Cobo F, Bea S et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas. Blood 91(8), 2977-2984 (1998). (Pubitemid 28227549)
154. Frank DA, Mahajan S, Ritz J. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. J. Clin. Invest. 100(12), 3140-3148 (1997). (Pubitemid 28022852)
155. Ringshausen I, Schneller F, Bogner C et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL. association with protein kinase Cdelta. Blood 100(10), 3741-3748 (2002). (Pubitemid 35303946)
156. Michie AM, Nakagawa R. Elucidating the role of protein kinase C in chronic lymphocytic leukaemia. Hematol. Oncol. 24(3), 134-138 (2006). (Pubitemid 44483906)
157. Wiestner A, Rosenwald A, Barry TS et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 101(12), 4944-4951 (2003). (Pubitemid 36857758)
158. Rossi D, Bruscaggin A, Spina V et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia. association with progression and fludarabine-refractoriness. Blood 118(26), 6904-6908 (2011).
159. Rosati E, Sabatini R, Rampino G et al. Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood 113(4), 856-865 (2009).
160. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 294(5543), 853-858 (2001). (Pubitemid 33032103)
161. Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294(5543), 858-862 (2001). (Pubitemid 33032104)
162. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science 294(5543), 862-864 (2001). (Pubitemid 33032105)
163. Nicoloso MS, Kipps TJ, Croce CM, Calin GA. MicroRNAs in the pathogeny of chronic lymphocytic leukaemia. Br. J. Haematol. 139(5), 709-716 (2007). (Pubitemid 350115732)
164. Calin GA, Dumitru CD, Shimizu M et al. Frequent deletions and downregulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 99(24), 15524-15529 (2002). (Pubitemid 35403967)
165. Calin GA, Cimmino A, Fabbri M et al. MiR-15a and miR-16-11 cluster functions in human leukemia. Proc. Natl Acad. Sci. USA 105(13), 5166-5171 (2008). (Pubitemid 351738528)
166. Cimmino A, Calin GA, Fabbri M et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc. Natl Acad. Sci. USA 102(39), 13944-13949 (2005). (Pubitemid 41377683)
167. Salerno E, Scaglione BJ, Coffman FD et al. Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity. Mol. Cancer Ther. 8(9), 2684-2692 (2009).
168. Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K, Malek SN. Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14. Cancer Res. 68(4), 1012-1021 (2008). (Pubitemid 351272218)
169. Palamarchuk A, Efanov A, Nazaryan N et al. 13q14 deletions in CLL involve cooperating tumor suppressors. Blood 115(19), 3916-3922 (2010).
170. Frenquelli M, Muzio M, Scielzo C et al. MicroRNA and proliferation control in chronic lymphocytic leukemia. functional relationship between miR-221/222 cluster and p27. Blood 115(19), 3949-3959 (2010).
171. He L, He X, Lowe SW, Hannon GJ. microRNAs join the p53 network-another piece in the tumour-suppression puzzle. Nat. Rev. Cancer 7(11), 819-822 (2007). (Pubitemid 350006254)
172. Pekarsky Y, Santanam U, Cimmino A et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res. 66(24), 11590-11593 (2006). (Pubitemid 46094168)
173. Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer. rationale, strategies and challenges. Nat. Rev. Drug Discov. 9(10), 775-789 (2010).
174. Bissell MJ, Hines WC. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17(3), 320-329 (2011).
175. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B-cells but not normal B-cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 91(7), 2387-2396 (1998).
176. Ghia P, Caligaris-Cappio F. The indispensable role of microenvironment in the natural history of low-grade B-cell neoplasms. Adv. Cancer Res. 79, 157-173 (2000). (Pubitemid 30228123)
177. Ponzoni M, Doglioni C, Caligaris-Cappio F. Chronic lymphocytic leukemia. the pathologist's view of lymph node microenvironment. Semin. Diagn. Pathol. 28(2), 161-166 (2011).
178. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin. Cancer Res. 14(9), 2519-2526 (2008).
179. Kurtova AV, Balakrishnan K, Chen R et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis. development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood 114(20), 4441-4450 (2009).
180. Malumbres M, Pevarello P, Barbacid M, Bischoff JR. CDK inhibitors in cancer therapy. What is next? Trends Pharmacol. Sci. 29(1), 16-21 (2008).
181. Wȩsierska-Ga̧dek J, Maurer M. Promotion of apoptosis in cancer cells by selective purine-derived pharmacological CDK inhibitors. one outcome, many mechanisms. Curr. Pharm. Des. 17(3), 256-271 (2011).
182. Wȩsierska-Ga̧dek J, Chamrad I, Krystof V. Novel potent pharmacological cyclin-dependent kinase inhibitors. Future Med. Chem. 1(9), 1561-1581 (2009).
183. Galons H, Oumata N, Meijer L. Cyclin-dependent kinase inhibitors. a survey of recent patent literature. Expert Opin. Ther. Pat. 20(3), 377-404 (2010).
184. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 8(7), 547-566 (2009).
185. Rizzolio F, Tuccinardi T, Caligiuri I, Lucchetti C, Giordano A. CDK inhibitors. from the bench to clinical trials. Curr. Drug Targets 11(3), 279-290 (2010).
186. Wȩsierska-Ga̧dek J, Schmid G. Dual action of the inhibitors of cyclin-dependent kinases. targeting of the cell-cycle progression and activation of wild-type p53 protein. Expert Opin. Investig. Drugs. 15(1), 23-38 (2006). (Pubitemid 43034149)
187. Wȩsierska-Ga̧dek J, Kramer MP. The impact of multi-targeted cyclin-dependent kinase inhibition in breast cancer cells. clinical implications. Expert Opin. Invest. Drugs 20(12), 1611-28 (2011).
188. Berman HM, Westbrook J, Feng Z et al. The Protein Data Bank. Nucleic Acids Res. 28(1), 235-242 (2000). (Pubitemid 30047768)
189. Fischmann TO, Hruza A, Duca JS et al. Structure-guided discovery of cyclin-dependent kinase inhibitors. Biopolymers 89(5), 372-379 (2008).
190. De Vivo M, Bottegoni G, Berteotti A, Recanatini M, Gervasio FL, Cavalli A. Cyclin-dependent kinases: bridging their structure and function through computations. Future Med. Chem. 3(12), 1551-1559 (2011).
191. Sedlacek H, Czech J, Naik R et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. 9(6), 1143-1168 (1996). (Pubitemid 26393307)
192. Senderowicz AM, Headlee D, Stinson SF et al. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J. Clin. Oncol. 16(9), 2986-2999 (1998). (Pubitemid 28417418)
193. Vesely J, Havlicek L, Strnad M et al. Inhibition of cyclin-dependent kinases by purine analogues. Eur. J. Biochem. 224(2), 771-786 (1994). (Pubitemid 24282865)
194. De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, Kim SH. Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur. J. Biochem. 243(1-2), 518-526 (1997). (Pubitemid 27060442)
195. Havlicek L, Hanus J, Vesely J et al. Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J. Med. Chem. 40(4), 408-412 (1997). (Pubitemid 27080019)
196. Meijer L, Borgne A, Mulner O et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243(1-2), 527-536 (1997). (Pubitemid 27060443)
197. Chao SH, Fujinaga K, Marion JE et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J. Biol. Chem. 275(37), 28345-28348 (2000).
198. Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J. Biol. Chem. 276(34), 31793-31799 (2001).
199. Shima D, Yugami M, Tatsuno M, Wada T, Yamaguchi Y, Handa H. Mechanism of H-8 inhibition of cyclin-dependent kinase 9: study using inhibitor-immobilized matrices. Genes Cells 8(3), 215-223 (2003). (Pubitemid 36511703)
200. Blagosklonny MV. Analysis of FDA approved anticancer drugs reveals the future of cancer therapy. Cell Cycle 3(8), 1035-1042 (2004). (Pubitemid 40268661)
201. Baumli S, Lolli G, Lowe ED et al. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation. EMBO J. 27(13), 1907-1918 (2008).
202. Patel V, Senderowicz AM, Pinto Jr D et al. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J. Clin. Invest. 102(9), 1674-1681 (1998). (Pubitemid 28516252)
203. Blagosklonny MV. Flavopiridol, an inhibitor of transcription: implications, problems and solutions. Cell Cycle 3(12), 1537-1542 (2004). (Pubitemid 40521407)
204. Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin. Cancer Res. 10(12 Pt 2), 4270s-4275s (2004). (Pubitemid 38812461)
205. Byrd JC, Shinn C, Waselenko JK et al. Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 92(10), 3804-3816 (1998). (Pubitemid 28525207)
206. Kitada S, Zapata JM, Andreeff M, Reed JC. Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 96(2), 393-397 (2000). (Pubitemid 30463354)
207. Pepper C, Thomas A, Hoy T, Fegan C, Bentley P. Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia. Br. J. Haematol. 114(1), 70-77 (2001). (Pubitemid 32702635)
208. Sedlacek HH. Mechanisms of action of flavopiridol. Crit. Rev. Oncol. Hematol. 38(2), 139-170 (2001). (Pubitemid 32328317)
209. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL. The novel cyclin-dependent kinase inhibitor flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cellleukemia lines. Blood 90(11), 4307-4312 (1997). (Pubitemid 27508436)
210. Billard C, Kern C, Tang R, Ajchenbaum-Cymbalista F, Kolb JP. Flavopiridol downregulates the expression of both the inducible NO synthase and p27(kip1) in malignant cells from B-cell chronic lymphocytic leukemia. Leukemia 17(12), 2435-2443 (2003). (Pubitemid 38072582)
211. Thomas JP, Cleary JF, Tutsch KD et al. Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother. Pharmacol. 50(6), 465-472 (2002). (Pubitemid 35435525)
212. Flinn IW, Byrd JC, Bartlett N et al. Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leuk. Res. 29(11), 1253-1257 (2005). (Pubitemid 41297636)
213. Christian BA, Grever MR, Byrd JC, Lin TS. Flavopiridol in chronic lymphocytic leukemia: a concise review. Clin. Lymphoma Myeloma 9(Suppl. 3), S179-S185 (2009).
214. Byrd JC, Peterson BL, Gabrilove J et al. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from Cancer and Leukemia Group B study 19805. Clin. Cancer Res. 11(11), 4176-4181 (2005). (Pubitemid 40791583)
215. Byrd JC, Lin TS, Dalton JT et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109(2), 399-404 (2007). (Pubitemid 46105932)
216. Misra RN, Xiao HY, Kim KS et al. N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2- oxazolyl] methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J. Med. Chem. 47(7), 1719-1728 (2004). (Pubitemid 38380915)
217. Conroy A, Stockett DE, Walker D et al. SNS-032 is a potent and selective CDK 2, 7 and 9 inhibitor that drives target modulation in patient samples. Cancer Chemother. Pharmacol. 64(4), 723-732 (2009).
218. Chen R, Wierda WG, Chubb S et al. Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia. Blood 113(19), 4637-4645 (2009).
219. Kruse U, Pallasch CP, Bantscheff M et al. Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells. Leukemia 25(1), 89-100 (2011).
220. Reddy M, Arbitrario J, Jones J, Silverman J, Howlett A, Taverna P. SNS-032 has potent antitumor activity in vivo against human leukemia and multiple myeloma xenografts. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics: Discovery, Biology, and Clinical Applications. San Francisco, CA, USA, 23 October 2007 (Poster A258).
221. Ali MA, Choy H, Habib AA, Saha D. SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor. Neoplasia 9(5), 370-381 (2007). (Pubitemid 46799980)
222. Heath EI, Bible K, Martell RE, Adelman DC, Lorusso PM. A Phase I study of SNS-032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors. Invest. New Drugs 26(1), 59-65 (2008).
223. Kamath AV, Chong S, Chang M, Marathe PH. P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats. Cancer Chemother. Pharmacol. 55(2), 110-116 (2005). (Pubitemid 40110053)
224. Tong WG, Chen R, Plunkett W et al. Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2, 7, and 9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma. J. Clin. Oncol. 28(18), 3015-3022 (2010).
225. Mcclue SJ, Blake D, Clarke R et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer 102(5), 463-468 (2002). (Pubitemid 35315999)
226. Kotala V, Uldrijan S, Horky M, Trbusek M, Strnad M, Vojtesek B. Potent induction of wild-type p53-dependent transcription in tumour cells by a synthetic inhibitor of cyclin-dependent kinases. Cell. Mol. Life Sci. 58(9), 1333-1339 (2001). (Pubitemid 32844102)
227. Wojciechowski J, Horky M, Gueorguieva M, Wȩsierska-Ga̧dek J. Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells. Int. J. Cancer 106(4), 486-495 (2003). (Pubitemid 36969788)
228. Lu W, Chen L, Peng Y, Chen J. Activation of p53 by roscovitine-mediated suppression of MDM2 expression. Oncogene 20(25), 3206-3216 (2001). (Pubitemid 32553673)
229. Whittaker SR, Walton MI, Garrett MD, Workman P. The Cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res. 64(1), 262-272 (2004). (Pubitemid 38114107)
230. Wȩsierska-Ga̧dek J, Gueorguieva M, Horky M. Roscovitine-induced up-regulation of p53AIP1 protein precedes the onset of apoptosis in human MCF-7 breast cancer cells. Mol. Cancer Ther. 4(1), 113-124 (2005). (Pubitemid 40276781)
231. Whittaker SR, Te Poele RH, Chan F et al. The cyclin-dependent kinase inhibitor seliciclib (R-roscovitine; CYC202) decreases the expression of mitotic control genes and prevents entry into mitosis. Cell Cycle 6(24), 3114-3131 (2007).
232. Wȩsierska-Ga̧dek J, Schmitz ML, Ranftler C. Roscovitine-activated HIP2 kinase induces phosphorylation of wild-type p53 at Ser-46 in human MCF-7 breast cancer cells. J. Cell. Biochem. 100(4), 865-874 (2007).
233. Wȩsierska-Ga̧dek J, Borza A, Walzi E et al. Outcome of treatment of human HeLa cervical cancer cells with roscovitine strongly depends on the dosage and cell cycle status prior to the treatment. J. Cell. Biochem. 106(5), 937-955 (2009).
234. Rogalinska M, Blonski JZ, Komina O et al. R-roscovitine (Seliciclib) affects CLL cells more strongly than combinations of fludarabine or cladribine with cyclophosphamide: inhibition of CDK7 sensitizes leukemic cells to caspase-dependent apoptosis. J. Cell. Biochem. 109(1), 217-235 (2010).
235. Maccallum DE, Melville J, Frame S et al. Seliciclib (CYC202, R-roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 65(12), 5399-5407 (2005). (Pubitemid 40827353)
236. Lacrima K, Valentini A, Lambertini C et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas. Annu. Oncol. 16(7), 1169-1176 (2005). (Pubitemid 41418321)
237. Kim EH, Kim SU, Shin DY, Choi KS. Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Oncogene 23(2), 446-456 (2004). (Pubitemid 38174999)
238. Raje N, Kumar S, Hideshima T et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood 106(3), 1042-1047 (2005). (Pubitemid 41076452)
239. Wȩsierska-Ga̧dek J, Gritsch D, Zulehner N, Komina O, Maurer M. Roscovitine, a selective CDK inhibitor, reduces the basal andestrogen-induced phosphorylation of ER-alpha in human ER-positive breast cancer cells. J. Cell. Biochem. 112(3), 761-772 (2011).
240. Wȩsierska-Ga̧dek J, Gritsch D, Zulehner N, Komina O, Maurer M. Interference with ER-alpha enhances the therapeutic efficacy of the selective CDK inhibitor roscovitine towards ER-positive breast cancer cells. J. Cell. Biochem. 112(4), 1103-1117 (2011).
241. Alvi AJ, Austen B, Weston VJ et al. A novel CDK inhibitor, CYC202 (R-roscovitine), overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival. Blood 105(11), 4484-4491 (2005). (Pubitemid 40720798)
242. Hahntow IN, Schneller F, Oelsner M et al. Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 18(4), 747-755 (2004). (Pubitemid 38500193)
243. Paprskarova M, Krystof V, Jorda R et al. Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine. J. Cell. Biochem. 107(3), 428-437 (2009).
244. Garrofe-Ochoa X, Cosialls AM, Ribas J, Gil J, Boix J. Transcriptional modulation of apoptosis regulators by roscovitine and related compounds. Apoptosis 16(7), 660-670 (2011).
245. Pleyer L, Egle A, Hartmann TN, Greil R. Molecular and cellular mechanisms of CLL: novel therapeutic approaches. Nat. Rev. Clin. Oncol. 6(7), 405-418 (2009).
246. Hallek M. Therapy of chronic lymphocytic leukaemia. Best Pract. Res. Clin. Haematol. 23(1), 85-96 (2010).
247. Maddocks KJ, Lin TS. Update in the management of chronic lymphocytic leukemia. J. Hematol. Oncol. 2, 29 (2009).
248. Robak T, Jamroziak K, Robak P. Current and emerging treatments for chronic lymphocytic leukaemia. Drugs 69(17), 2415-2449 (2009).
249. Vousden KH, Lu X. Live or let die: the cell's response to p53. Nat. Rev. Cancer 2(8), 594-604 (2002). (Pubitemid 37328926)
250. Jantus Lewintre E, Reinoso Martin C, Garcia Ballesteros C et al. BCL6: somatic mutations and expression in early-stage chronic lymphocytic leukemia. Leuk. Lymphoma 50(5), 773-780 (2009).
251. Dent AL, Vasanwala FH, Toney LM. Regulation of gene expression by the proto-oncogene BCL-6. Crit. Rev. Oncol. Hematol. 41(1), 1-9 (2002). (Pubitemid 34051578)
252. Wagner SD, Ahearne M, Ferrigno PK. The role of BCL6 in lymphomas and routes to therapy. Br. J. Haematol. 152(1), 3-12 (2011).
253. Pepper C, Thomas A, Hidalgo De Quintana J, Davies S, Hoy T, Bentley P. Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia - the role of Bcl-2 family dysregulation. Leuk. Res. 23(11), 1007-1014 (1999). (Pubitemid 29488647)
254. Menzel T, Rahman Z, Calleja E et al. Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 87(3), 1056-1063 (1996). (Pubitemid 26043533)
255. Zenz T, Mohr J, Eldering E et al. miR-34a as part of the resistance network in chronic lymphocytic leukemia. Blood 113(16), 3801-3808 (2009).
256. Calin GA. MiR-sensing chemotherapy resistance in CLL. Blood 113(16), 3652-3653 (2009).
257. Fabbri M, Bottoni A, Shimizu M et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. JAMA 305(1), 59-67 (2011).
258. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood 98(6), 1979-1981 (2001).
259. Morton LM, Curtis RE, Linet MS et al. Second malignancy risks after non-Hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J. Clin. Oncol. 28(33), 4935-4944 (2010).
260. Royle JA, Baade PD, Joske D, Girschik J, Fritschi L. Second cancer incidence and cancer mortality among chronic lymphocytic leukaemia patients: a population-based study. Br. J. Cancer 105(7), 1076-1081 (2011).
261. Raynaud FI, Whittaker SR et al. In vitro and in vivo pharmacokinetic- pharmacodynamic relationship for the trisubstitute aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin. Cancer Res. 11(13), 4875-4888 (2005). (Pubitemid 41557208)
262. Tirado OM, Mateo-Lozano S, Notario V. Roscovitine is an effective induces of apoptosis of Ewing's sarcoma family tumor cells in vitro and in vivo. Cancer Res. 65(29), 9320-9327 (2005). (Pubitemid 41507999)
263. Hsieh WS, Soo R, Peh BK et al. Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin. Cancer Res. 15(4), 1435-1442 (2009).
264. Siegel-Lakhai WS, Rodenstein DO, Beijnen JH, Gianella-Borradori A, Schellens JH, Talbot DC. Phase I study of seliciclib (CYC202 or R-roscovitine) in combination with gemcitabine (gem)/cisplatin (cis) in patients with advanced non-small cell lung cancer (NSCLC). Presented at: ASCO Annual Meeting Proceedings. Orlando, FL, USA, 13-17 May 2005.
265. Paruch K, Dwyer MP, Alvarez C et al. Discovery of dinaciclib (sch 727965): a potent and selective inhibitor of cyclin-dependent kinases. ACS Med. Chem. Lett. 1(5), 204-208 (2010).
266. Parry D, Guzi T, Shanahan F et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 9(8), 2344-2353 (2010).
267. Feldmann G, Mishra A, Bisht S et al. Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol. Ther. 12(7), 598-609 (2011).
268. Fu W, Ma L, Chu B et al. The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Mol. Cancer Ther. 10(6), 1018-1027 (2011).
269. Rogoff HA, Pickering MT, Frame FM et al. Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/ Nbs1/Chk2. Mol. Cell. Biol. 24(7), 2968-2977 (2004). (Pubitemid 38381285)
270. Johnson AJ, Smith LL, Raymond CA et al. The cyclin dependent kinase inhibitor SCH 727965 demonstrates dramatic pre-clinical activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia. AACR 100th Annual Meeting. Abstract 4777 (2009).
271. Flynn JM, Johnson AJ, Andritsos L et al. The cyclin dependent kinase inhibitor sch 727965 demonstrates promising pre-clinical and early clinical activity in chronic lymphocytic leukemia. 51st ASH Annual Meeting and Exposition, Abstract 886 (2009).
272. Johnson AJ, Smith LL, Wagner AJ et al. Dinaciclib (SCH727965) Is a novel cyclin dependent kinase inhibitor that promotes selective apoptosis in CLL cells and abrogates the protective effects of microenvironment cytokines. 52nd ASH Annual Meeting and Exposition, Abstract 971 (2010).
273. Siemeister G, Luecking U, Wagner C, Detjen K, Mc Coy C, Bosslet K. Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed. Pharmacother. 60(6), 269-272 (2006). (Pubitemid 44223936)
274. Ahmed S, Molife R, Shaw H et al. Phase I dose-escalation study of ZK 304709, an oral multi-target tumor growth inhibitor (MTGI), administered for 14 days of a 28-day cycle. Presented at: ASCO Annual Meeting Proceedings. Orlando, FL, USA. 20 June 2006.
275. Scholz A, Wagner K, Welzel M et al. The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model. Gut 58(2), 261-270 (2009).
276. Graham JS, Plummer R, Mccoy C et al. Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery). Eur. J. Cancer 44(15), 2162-2168 (2008).
277. Scott EN, Thomas AL, Molife LR et al. A Phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 64(2), 425-429 (2009).
278. Wyatt PG, Woodhead AJ, Berdini V et al. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based x-ray crystallography and structure based drug design. J. Med. Chem. 51(16), 4986-4999 (2008).
279. Squires MS, Feltell RE, Wallis NG et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther. 8(2), 324-332 (2009).
280. Squires MS, Cooke L, Lock V et al. AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. Mol. Cancer Ther. 9(4), 920-928 (2010).
281. MahadeVan D, Plummer R, Squires MS et al. A Phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Annu. Oncol. 22(9), 2137-2143 (2011).
282. Alessandri AL, Duffin R, Leitch AE et al. Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation. PLoS One 6(9), e25683 (2011).
283. Brasca MG, Amboldi N, Ballinari D et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydr o-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J. Med. Chem. 52(16), 5152-5163 (2009).
284. Albanese C, Alzani R, Amboldi N et al. Dual targeting of CDK and tropomyosin receptor kinase families by the oral inhibitor PHA-848125, an agent with broad-spectrum antitumor efficacy. Mol. Cancer Ther. 9(8), 2243-2254 (2010).
285. Degrassi A, Russo M, Nanni C et al. Efficacy of PHA-848125, a cyclin-dependent kinase inhibitor, on the K-Ras(G12D)LA2 lung adenocarcinoma transgenic mouse model: evaluation by multimodality imaging. Mol. Cancer Ther. 9(3), 673-681 (2010).
286. Caporali S, Alvino E, Starace G et al. The cyclin-dependent kinase inhibitor PHA-848125 suppresses the in vitro growth of human melanomas sensitive or resistant to temozolomide, and shows synergistic effects in combination with this triazene compound. Pharmacol. Res. 61(5), 437-448 (2010).
287. Caligiuri M, Bockovich N, Oalmann C et al. Induction of tumor regression by the broad-spectrum cyclin dependent kinase inhibitor, RGB-286638. AACR 97th Annual Meeting 2006 (2006).
288. Caligiuri M, Gabriele Zybarth G, Ivanov I, Amon P, Loferer H, Kley N. RGB-286638, a multi-targeted protein kinase inhibitor, induces apoptosis involving the inhibition of RNA polymerase II carboxyl-terminal domain phosphorylation and the loss of the anti-apoptotic BCL2 family member Mcl-1. AACR 100th Annual Meeting 2009, Abstract 3265 (2009).
289. Cirstea D, Hideshima T, Pozzi S et al. RGB 286638, a novel multi-targeted small molecule inhibitor, induces multiple myeloma (MM) cell death through abrogation of CDK-dependent and independent survival mechanisms. 50th ASH Annual Meeting and Exposition, Abstact 2759 (2008).
290. Cirstea D, Hideshima T, Santo L et al. A novel multi-targeted small molecule inhibitor RGB 286638 triggers apoptosis and necrosis in multiple myeloma via dual cell death pathways. AACR 100th Annual Meeting 2009, Abstract 1994 (2009).
291. Cirstea D, Hideshima T, Pozzi S et al. Pleiotropic activity of the novel cyclin-dependent kinase inhibitor RGB 286638 predicts therapeutic potential in multiple myeloma. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings, Abstract 14602 (2008).
292. De Jonge M, Mathijssen R, Loos W et al. Phase I study on RGB-286638, a novel, multi-targeted protein kinase inhibitor, administered as a 1-hour infusion on five consecutive days every 4 weeks in patients with recurrent or refractory solid tumors. Presented at: 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Brussels, Belgium, 15-19 November 2010.
293. Williamson DS, Parratt MJ, Bower JF et al. Structure-guided design of pyrazolo[1,5-a] pyrimidines as inhibitors of human cyclin-dependent kinase 2. Bioorg. Med. Chem. Lett. 15(4), 863-867 (2005) (Pubitemid 40467433)
294. Heathcote DA, Patel H, Kroll SH et al. A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration. J. Med. Chem. 53(24), 8508-8522 (2010).
295. Ali S, Heathcote DA, Kroll SH et al. The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity. Cancer Res. 69(15), 6208-6215 (2009).
296. Mcmillin DW, Delmore J, Negri J et al. Molecular and cellular effects of multi-targeted cyclin-dependent kinase inhibition in myeloma: biological and clinical implications. Br. J. Haematol. 152(4), 420-432 (2011).
297. Kitano H. Systems biology: a brief overview. Science 295(5560), 1662-1664 (2002). (Pubitemid 34202893)
298. Van Riel NA. Dynamic modelling and analysis of biochemical networks: mechanism-based models and model-based experiments. Brief Bioinform. 7(4), 364-374 (2006).
299. De Jong H, Ropers D. Strategies for dealing with incomplete information in the modeling of molecular interaction networks. Brief Bioinform. 7(4), 354-363 (2006). (Pubitemid 44896738)
300. Molina F, Dehmer M, Perco P et al. Systems biology: opening new avenues in clinical research. Nephrol. Dial. Transplant. 25(4), 1015-1018 (2010).