CDK Inhibitors in Multiple Myeloma

  • Yun Dai
  • Steven Grant
Part of the Contemporary Hematology book series (CH)

Functions of Cyclin-Dependent Kinases

Regulation of the Cell Cycle

Cell cycle progression represents the mechanism by which normal and neoplastic cells proliferate and grow. Typically, the cell cycle is composed of four distinct but tightly-related phases, that is, the periods associated with DNA synthesis (S phase) and mitosis (M phase), which are separated by two gaps (G1 and G2 phases). Following mitogenic stimulation, cells traverse the cell cycle through G1→S→G2→M phases, and subsequently divide equally to produce two daughter cells. The daughter cells can then enter the G1 phase once again to begin the next cycle, or, alternatively, exit from the cell cycle into the G0 phase (a quiescent state). A transition point (known as the restriction point) exists in the G1 phase, determining whether cell cycle progression occurs in a manner independent of external stimuli. Cell cycle procession is tightly controlled by cyclin-dependent kinase (CDK) complex. CDK holoenzyme complexes consist...


Multiple Myeloma Myeloma Cell Mantle Cell Lymphoma Multiple Myeloma Cell Multiple Myeloma Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by Public Health Service grants CA-63753, CA-93738, CA-100866, and CA88906 from the National Cancer Institute, award 6045-03 from the Leukemia and Lymphoma Society of America, and a Translational Research award from the V-foundation.


  1. 1.
    Knockaert M, Greengard P, Meijer L. Pharmacological inhibitors of cyclindependent kinases. Trends Pharmacol Sci 2002;23:417–425.PubMedGoogle Scholar
  2. 2.
    Lents NH, Keenan SM, Bellone C, Baldassare JJ. Stimulation of the Raf/MEK/ERK cascade is necessary and sufficient for activation and Thr-160 phosphorylation of a nuclear-targeted CDK2. J Biol Chem 2002;277:47469–47475.PubMedGoogle Scholar
  3. 3.
    Morris MC, Gondeau C, Tainer JA, Divita G. Kinetic mechanism of activation of the Cdk2/cyclin A complex. Key role of the C-lobe of the Cdk. J Biol Chem 2002;277:23847–23853.Google Scholar
  4. 4.
    Sandal T. Molecular aspects of the mammalian cell cycle and cancer. Oncologist 2002;7:73–81.PubMedGoogle Scholar
  5. 5.
    Ezhevsky SA, Ho A, Becker-Hapak M, Davis PK, Dowdy SF. Differential regulation of retinoblastoma tumor suppressor protein by G(1) cyclin-dependent kinase complexes in vivo. Mol Cell Biol 2001;21:4773–4784.PubMedGoogle Scholar
  6. 6.
    Calbo J, Parreno M, Sotillo E, et al. G1 cyclin/cyclin-dependent kinase-coordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 2002;277:50263–50274.PubMedGoogle Scholar
  7. 7.
    D'Angiolella V, Costanzo V, Gottesman ME, Avvedimento EV, Gautier J, Grieco D. Role for cyclin-dependent kinase 2 in mitosis exit. Curr Biol 2001;11:1221–1226.PubMedGoogle Scholar
  8. 8.
    Frouin I, Montecucco A, Biamonti G, Hubscher U, Spadari S, Maga G. Cell cycle-dependent dynamic association of cyclin/Cdk complexes with human DNA replication proteins. EMBO J 2002;21:2485–2495.PubMedGoogle Scholar
  9. 9.
    Yamochi T, Semba K, Tsuji K et al. ik31/Cables is a substrate for cyclin-dependent kinase 3 (cdk 3). Eur J Biochem 2001;268:6076–6082.PubMedGoogle Scholar
  10. 10.
    Sharma P, Veeranna, Sharma M et al. Phosphorylation of MEK1 by cdk5/p35 down-regulates the mitogen-activated protein kinase pathway. J Biol Chem 2002;277:528–534.PubMedGoogle Scholar
  11. 11.
    Shim EY, Walker AK, Shi Y, Blackwell TK. CDK-9/cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev 2002;16:2135–2146.Google Scholar
  12. 12.
    Price DH. P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II. Mol Cell Biol 2000;20:2629–2634.PubMedGoogle Scholar
  13. 13.
    Fu TJ, Peng J, Lee G, Price DH, Flores O. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem 1999;274:34527–34530.PubMedGoogle Scholar
  14. 14.
    Kiernan RE, Emiliani S, Nakayama K et al. Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome. Mol Cell Biol 2001;21:7956–7970.PubMedGoogle Scholar
  15. 15.
    Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 2001;414:317–322.PubMedGoogle Scholar
  16. 16.
    Nguyen VT, Kiss T, Michels AA, Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 2001;414:322–325.PubMedGoogle Scholar
  17. 17.
    Simone C, Bagella L, Bellan C, Giordano A. Physical interaction between pRb and cdk9/cyclinT2 complex. Oncogene 2002;21:4158–4165.PubMedGoogle Scholar
  18. 18.
    Wallenfang MR, Seydoux G. cdk-7 Is required for mRNA transcription and cell cycle progression in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 2002;99:5527–5532.PubMedGoogle Scholar
  19. 19.
    Schneider E, Kartarius S, Schuster N, Montenarh M. The cyclin H/cdk7/Mat1 kinase activity is regulated by CK2 phosphorylation of cyclin H. Oncogene 2002;21:5031–5037.PubMedGoogle Scholar
  20. 20.
    Akoulitchev S, Chuikov S, Reinberg D. TFIIH is negatively regulated by cdk8 containing mediator complexes. Nature 2000;407:102–106.PubMedGoogle Scholar
  21. 21.
    Barette C, Jariel-Encontre I, Piechaczyk M, Piette J. Human cyclin C protein is stabilized by its associated kinase cdk8, independently of its catalytic activity. Oncogene 2001;20:551–562.PubMedGoogle Scholar
  22. 22.
    Hu D, Mayeda A, Trembley JH, Lahti JM, et al. Kidd VJ. CDK11 complexes promote pre-mRNA splicing. J Biol Chem 2003;278:8623–8629.Google Scholar
  23. 23.
    Kasten M, Giordano A. Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 2001;20:1832–1838.PubMedGoogle Scholar
  24. 24.
    Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment J Clin Oncol 2006;24:1770–1783.PubMedGoogle Scholar
  25. 25.
    Kohno T, Yokota J. Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer;Deduction from structural analysis of breakpoints for deletions. DNA Repair (Amst) 2006;5:1273–1281.Google Scholar
  26. 26.
    Chakravarti A, DeSilvio M, Zhang M. Prognostic value of p16 in locally advanced prostate cancer;A study based on Radiation Therapy Oncology Group Protocol 9202. J Clin Oncol 2007;25:3082–3089.PubMedGoogle Scholar
  27. 27.
    Auerkari EI. Methylation of tumor suppressor genes p16(INK4a), p27(Kip1) and E-cadherin in carcinogenesis. Oral Oncol 2006;42:5–13.PubMedGoogle Scholar
  28. 28.
    Lu F, Gladden AB, Diehl JA. An alternatively spliced cyclin D1 isoform, cyclin D1b, is a nuclear oncogene. Cancer Res 2003;63:7056–7061.PubMedGoogle Scholar
  29. 29.
    Carrere N, Belaud-Rotureau MA, Dubus P, Parrens M, de MA, Merlio JP. The relative levels of cyclin D1a and D1b alternative transcripts in mantle cell lymphoma may depend more on sample origin than on CCND1 polymorphism. Haematologica 2005;90:854–856.PubMedGoogle Scholar
  30. 30.
    Burd CJ, Petre CE, Morey LM. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci U S A 2006;103:2190–2195.PubMedGoogle Scholar
  31. 31.
    Krieger S, Gauduchon J, Roussel M, Troussard X, Sola B. Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma. BMC Cancer 2006;6:238.PubMedGoogle Scholar
  32. 32.
    Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1;Polymorphism, aberrant splicing and cancer risk. Oncogene 2006;25:1620–1628.PubMedGoogle Scholar
  33. 33.
    Delmer A, jchenbaum-Cymbalista F, et al. Tang R. Overexpression of cyclin D2 in chronic B-cell malignancies. Blood 1995;85:2870–2876.PubMedGoogle Scholar
  34. 34.
    Sonoki T, Harder L, Horsman DE et al. Cyclin D3 is a target gene of t(6;14)(p21.1;q32.3) of mature B-cell malignancies. Blood 2001;98:2837–2844.PubMedGoogle Scholar
  35. 35.
    Tashiro E, Tsuchiya A, Imoto M. Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci 2007;98:629–635.PubMedGoogle Scholar
  36. 36.
    Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview;Cyclin D1;Normal and abnormal functions. Endocrinology 2004;145:5439–5447.PubMedGoogle Scholar
  37. 37.
    Wolfel T, Hauer M, Schneider J et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995;269:1281–1284.PubMedGoogle Scholar
  38. 38.
    van Deursen JM. Rb loss causes cancer by driving mitosis mad. Cancer Cell 2007;11:1–3.PubMedGoogle Scholar
  39. 39.
    Lazarov M, Kubo Y, et al. Cai T. CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat Med 2002;8:1105–1114.PubMedGoogle Scholar
  40. 40.
    Landis MW, Pawlyk BS, Li T, Sicinski P, Hinds PW. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006;9:13–22.PubMedGoogle Scholar
  41. 41.
    Yu Q, Sicinska E, Geng Y. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9:23–32.PubMedGoogle Scholar
  42. 42.
    Lee YM, Sicinski P. Targeting cyclins and cyclin-dependent kinases in cancer;Lessons from mice, hopes for therapeutic applications in human. Cell Cycle 2006;5:2110–2114.PubMedGoogle Scholar
  43. 43.
    Deshpande A, Sicinski P, Hinds PW. Cyclins and cdks in development and cancer;A perspective. Oncogene 2005;24:2909–2915.PubMedGoogle Scholar
  44. 44.
    Malumbres M, Sotillo R, Santamaria D. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 2004;118:493–504.PubMedGoogle Scholar
  45. 45.
    Ortega S, Prieto I, Odajima J et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 2003;35:25–31.PubMedGoogle Scholar
  46. 46.
    Kohzato N, Dong Y, Sui L. Overexpression of cyclin E and cyclin-dependent kinase 2 is correlated with development of hepatocellular carcinomas. Hepatol Res 2001;21:27–39.PubMedGoogle Scholar
  47. 47.
    Li KK, Ng IO, Fan ST, Albrecht JH, Yamashita K, Poon RY. Activation of cyclin-dependent kinases CDC2 and CDK2 in hepatocellular carcinoma. Liver 2002;22:259–268.PubMedGoogle Scholar
  48. 48.
    Dong Y, Sui L, Tai Y, Sugimoto K, Tokuda M. The overexpression of cyclin-dependent kinase (CDK) 2 in laryngeal squamous cell carcinomas. Anticancer Res 2001;21:103–108.PubMedGoogle Scholar
  49. 49.
    Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000;92:376–387.PubMedGoogle Scholar
  50. 50.
    Dai Y, Grant S. Small molecule inhibitors targeting cyclin-dependent kinases as anticancer agents. Curr Oncol Rep 2004;6:123–130.PubMedGoogle Scholar
  51. 51.
    Schwartz GK, Shah MA. Targeting the cell cycle;A new approach to cancer therapy. J Clin Oncol 2005;23:9408–9421.PubMedGoogle Scholar
  52. 52.
    Benson C, Kaye S, Workman P, Garrett M, Walton M, de BJ. Clinical anticancer drug development;Targeting the cyclin-dependent kinases. Br J Cancer 2005;92:7–12.PubMedGoogle Scholar
  53. 53.
    Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 2003;3:233–245.PubMedGoogle Scholar
  54. 54.
    Cai D, Latham VM, Jr., Zhang X, Shapiro GI. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 2006;66:9270–9280.PubMedGoogle Scholar
  55. 55.
    Sausville EA. Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends Mol Med 2002;8:S32–S37.PubMedGoogle Scholar
  56. 56.
    Senderowicz AM. The cell cycle as a target for cancer therapy;Basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. Oncologist 2002;7, Suppl 3:12–19.Google Scholar
  57. 57.
    Colevas D, Blaylock B, Gravell A. Clinical trials referral resource. Flavopiridol Oncology (Williston Park) 2002;16:1204–1202, 1214.Google Scholar
  58. 58.
    Zhai S, Senderowicz AM, Sausville EA, Figg WD. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development. Ann Pharmacother 2002;36:905–911.PubMedGoogle Scholar
  59. 59.
    Shapiro GI, Supko JG, Patterson A et al. A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res 2001;7:1590–1599.PubMedGoogle Scholar
  60. 60.
    Schwartz GK, Ilson D, Saltz L. et al. Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 2001;19:1985–1992.PubMedGoogle Scholar
  61. 61.
    Lin TS, Howard OM, Neuberg DS, Kim HH, Shipp MA. Seventy-two hour continuous infusion flavopiridol in relapsed and refractory mantle cell lymphoma. Leuk Lymphoma 2002;43:793–797.PubMedGoogle Scholar
  62. 62.
    Tan AR, Headlee D, Messmann R et al. Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 2002;20:4074–4082.PubMedGoogle Scholar
  63. 63.
    Karp JE, Passaniti A, Gojo I et al. Phase I and pharmacokinetic study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine and mitoxantrone in relapsed and refractory adult acute leukemias. Clin Cancer Res 2005;11:8403–8412.PubMedGoogle Scholar
  64. 64.
    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 2007;109:399–404.PubMedGoogle Scholar
  65. 65.
    Sedlacek HH. Mechanisms of action of flavopiridol. Crit Rev Oncol Hematol 2001;38:139–170.PubMedGoogle Scholar
  66. 66.
    Hardcastle IR, Golding BT, Griffin RJ. Designing inhibitors of cyclin-dependent kinases. Annu Rev Pharmacol Toxicol 2002;42:325–348.PubMedGoogle Scholar
  67. 67.
    Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res 2004;10:4270s–4275s.PubMedGoogle Scholar
  68. 68.
    Fry DW, Bedford DC, Harvey PH et al. Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. J Biol Chem 2001;276:16617–16623.Google Scholar
  69. 69.
    Dai Y, Grant S. Cyclin-dependent kinase inhibitors. Curr Opin Pharmacol 2003;3:362–370.PubMedGoogle Scholar
  70. 70.
    Davies TG, Bentley J, Arris CE et al. Structure-based design of a potent purine based cyclin-dependent kinase inhibitor. Nat Struct Biol 2002;9:745–749.PubMedGoogle Scholar
  71. 71.
    Ikuta M, Kamata K, Fukasawa K et al. Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein. J Biol Chem 2001;276:27548–27554.PubMedGoogle Scholar
  72. 72.
    Honma T, Hayashi K, Aoyama T et al. Structure-based generation of a new class of potent Cdk4 inhibitors;New de novo design strategy and library design. J Med Chem 2001;44:4615–4627.PubMedGoogle Scholar
  73. 73.
    Chao SH, Fujinaga K, Marion JE et al. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem 2000;275:28345–28348.PubMedGoogle Scholar
  74. 74.
    Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001;276:31793–31799.PubMedGoogle Scholar
  75. 75.
    De AW, Jr., Canduri F, da Silveira NJ. Structural basis for inhibition of cyclin-dependent kinase 9 by flavopiridol. Biochem Biophys Res Commun 2002;293:566–571.Google Scholar
  76. 76.
    Lu X, Burgan WE, Cerra MA et al. Transcriptional signature of flavopiridol induced tumor cell death. Mol Cancer Ther 2004;3:861–872.PubMedGoogle Scholar
  77. 77.
    Coqueret O. Linking cyclins to transcriptional control. Gene 2002;299:35–55.PubMedGoogle Scholar
  78. 78.
    Fu M, Rao M, Bouras T et al. Cyclin D1 inhibits peroxisome proliferator-activated receptor gamma-mediated adipogenesis through histone deacetylase recruitment. J Biol Chem 2005;280:16934–16941.PubMedGoogle Scholar
  79. 79.
    Rodriguez-Bravo V, Guaita-Esteruelas S, Florensa R, Bachs O, Agell N. Chk1 and Claspin-Dependent but ATR/ATM- and Rad17-Independent DNA Replication Checkpoint Response in HeLa Cells. Cancer Res 2006;66:8672–8679.PubMedGoogle Scholar
  80. 80.
    Hosokawa Y, Arnold A. Mechanism of cyclin D1 (CCND1, PRAD1) overexpression in human cancer cells;Analysis of allele-specific expression. Genes Chromosomes Cancer 1998;22:66–71.PubMedGoogle Scholar
  81. 81.
    Jirmanova L, Afanassieff M, Gobert-Gosse S, Markossian S Savatier P. Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 2002;21:5515–5528.PubMedGoogle Scholar
  82. 82.
    Lavoie JN, Rivard N, L'Allemain G, Pouyssegur J. A temporal and biochemical link between growth factor-activated MAP kinases, cyclin D1 induction and cell cycle entry. Prog Cell Cycle Res 1996;2:49–58.PubMedGoogle Scholar
  83. 83.
    Hulit J, Bash T, Fu M et al. The cyclin D1 gene is transcriptionally repressed by caveolin-1. J Biol Chem 2000;275:21203–21209.PubMedGoogle Scholar
  84. 84.
    Shi Y, Sharma A, Wu H, Lichtenstein A, Gera J. Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38. J Biol Chem 2005;280:10964–10973.PubMedGoogle Scholar
  85. 85.
    Diehl JA, Zindy F, Sherr CJ. Inhibition of cyclin D1 phosphorylation on threonine 286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997;11:957–972.PubMedGoogle Scholar
  86. 86.
    Shao J, Sheng H, DuBois RN, Beauchamp RD. Oncogenic Ras-mediated cell growth arrest and apoptosis are associated with increased ubiquitin-dependent cyclin D1 degradation. J Biol Chem 2000;275:22916–22924.PubMedGoogle Scholar
  87. 87.
    Takahashi-Yanaga F, Mori J, Matsuzaki E. Involvement of GSK-3beta and DYRK1B in differentiation-inducing factor-3-induced phosphorylation of cyclin D1 in HeLa cells. J Biol Chem 2006;281:38489–38497.PubMedGoogle Scholar
  88. 88.
    Radu A, Neubauer V, Akagi T, Hanafusa H, Georgescu MM. PTEN induces cell cycle arrest by decreasing the level and nuclear localization of cyclin D1. Mol Cell Biol 2003;23:6139–6149.PubMedGoogle Scholar
  89. 89.
    Carlson B, Lahusen T, Singh S et al. Down-regulation of cyclin D1 by transcriptional repression in MCF-7 human breast carcinoma cells induced by flavopiridol. Cancer Res 1999;59:4634–4641.PubMedGoogle Scholar
  90. 90.
    Patel V, Senderowicz AM, Pinto D, Jr. 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 1998;102:1674–1681.PubMedGoogle Scholar
  91. 91.
    Bible KC, Bible RH, Jr., Kottke TJ et al. Flavopiridol binds to duplex DNA. Cancer Res 2000;60:2419–2428.PubMedGoogle Scholar
  92. 92.
    Kouroukis CT, Belch A, Crump M et al. Flavopiridol in untreated or relapsed mantle-cell lymphoma;Results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21:1740–1745.PubMedGoogle Scholar
  93. 93.
    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 2001;114:70–77.PubMedGoogle Scholar
  94. 94.
    Semenov I, Akyuz C, Roginskaya V, Chauhan D, Corey SJ. Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol. Leuk Res 2002;26:271–280.PubMedGoogle Scholar
  95. 95.
    Ma Y, Cress WD, Haura EB. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003;2:73–81.PubMedGoogle Scholar
  96. 96.
    Blagosklonny MV. Flavopiridol, an inhibitor of transcription;Implications, problems and solutions. Cell Cycle 2004;3:1537–1542.PubMedGoogle Scholar
  97. 97.
    Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF. The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 1999;19:6195–6206.PubMedGoogle Scholar
  98. 98.
    Croxton R, Ma Y, Song L, Haura EB, Cress WD. Direct repression of the Mcl-1 promoter by E2F1. Oncogene 2002;21:1359–1369.PubMedGoogle Scholar
  99. 99.
    Lee YK, Isham CR, Kaufman SH, Bible KC. Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy. Mol Cancer Ther 2006;5:138–148.PubMedGoogle Scholar
  100. 100.
    Aggarwal BB, Sethi G, Ahn KS et al. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer;Modern target but ancient solution. Ann N Y Acad Sci 2006;1091:151–169.PubMedGoogle Scholar
  101. 101.
    Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. Annu Rev Biochem 2000;69:217–245.PubMedGoogle Scholar
  102. 102.
    Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 2006;25:4798–4811.PubMedGoogle Scholar
  103. 103.
    Scaffidi C, Fulda S, Srinivasan A et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998;17:1675–1687.PubMedGoogle Scholar
  104. 104.
    Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 2002;297:1352–1354.PubMedGoogle Scholar
  105. 105.
    Zou H, Li Y, Liu X, Wang X. An APAF-1. cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J Biol Chem 1999;274:11549–11556.PubMedGoogle Scholar
  106. 106.
    Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004;305:626–629.PubMedGoogle Scholar
  107. 107.
    Micheau O. Cellular FLICE-inhibitory protein;An attractive therapeutic target? Expert Opin Ther Targets 2003;7:559–573.PubMedGoogle Scholar
  108. 108.
    Zamzami N, Kroemer G. The mitochondrion in apoptosis;How Pandora's box opens. Nat Rev Mol Cell Biol 2001;2:67–71.PubMedGoogle Scholar
  109. 109.
    Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 2005;6:287–297.PubMedGoogle Scholar
  110. 110.
    Verhagen AM, Vaux DL. Cell death regulation by the mammalian IAP antagonist Diablo/Smac. Apoptosis 2002;7:163–166.PubMedGoogle Scholar
  111. 111.
    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 2000;96:393–397.PubMedGoogle Scholar
  112. 112.
    Achenbach TV, Muller R, Slater EP. Bcl-2 independence of flavopiridol-induced apoptosis. Mitochondrial depolarization in the absence of cytochrome c release. J Biol Chem 2000;275:32089–32097.Google Scholar
  113. 113.
    Decker RH, Dai Y, Grant S. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in human leukemia cells (U937) through the mitochondrial rather than the receptor-mediated pathway. Cell Death Differ 2001;8:715–724.PubMedGoogle Scholar
  114. 114.
    Yu C, Rahmani M, Dai Y et al. The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphati-dylinositol 3-kinase/Akt-dependent process. Cancer Res 2003;63:1822–1833.PubMedGoogle Scholar
  115. 115.
    Dai Y, Hamm TE, Dent P, Grant S. Cyclin D1 overexpression increases the susceptibility of human U266 myeloma cells to CDK inhibitors through a process involving p130-, p107- and E2F-dependent S phase entry. Cell Cycle 2006;5:437–446.PubMedGoogle Scholar
  116. 116.
    Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003;3:17–22.PubMedGoogle Scholar
  117. 117.
    Decker RH, Wang S, Dai Y, Dent P, Grant S. Loss of the Bcl-2 phosphorylation loop domain is required to protect human myeloid leukemia cells from flavopiridol-mediated mitochondrial damage and apoptosis. Cancer Biol Ther 2002;1:136–144.PubMedGoogle Scholar
  118. 118.
    Rosato RR, Almenara JA, Kolla SS et al. Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions. Mol Cancer Ther 2007;6:692–702.PubMedGoogle Scholar
  119. 119.
    Gao N, Dai Y, Rahmani M, Dent P, Grant S. Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol. Mol Pharmacol 2004;66:956–963.PubMedGoogle Scholar
  120. 120.
    Newcomb EW. Flavopiridol;Pleiotropic biological effects enhance its anti-cancer activity. Anticancer Drugs 2004;15:411–419.PubMedGoogle Scholar
  121. 121.
    Brusselbach S, Nettelbeck DM, Sedlacek HH, Muller R. Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. Int J Cancer 1998;77:146–152.PubMedGoogle Scholar
  122. 122.
    Newcomb EW, Ali MA, Schnee T et al. Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway;Implications for in vivo therapy. Neuro Oncol 2005;7:225–235.PubMedGoogle Scholar
  123. 123.
    Oikonomakos NG, Schnier JB, Zographos SE, Skamnaki VT, Tsitsanou KE, Johnson LN. Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J Biol Chem 2000;275:34566–34573.PubMedGoogle Scholar
  124. 124.
    Kaiser A, Nishi K, Gorin FA, Walsh DA, Bradbury EM, Schnier JB. The cyclin-dependent kinase (CDK) inhibitor flavopiridol inhibits glycogen phosphorylase. Arch Biochem Biophys 2001;386:179–187.PubMedGoogle Scholar
  125. 125.
    Fuse E, Kuwabara T, Sparreboom A, Sausville EA, Figg WD. Review of UCN-01 development;A lesson in the importance of clinical pharmacology. J Clin Pharmacol 2005;45:394–403.PubMedGoogle Scholar
  126. 126.
    Dees EC, Baker SD, O'Reilly S et al. A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res 2005;11:664–671.PubMedGoogle Scholar
  127. 127.
    Edelman MJ, Bauer KS, Jr., Wu S, Smith R, Bisacia S, Dancey J. Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors. Clin Cancer Res 2007;13:2667–2674.PubMedGoogle Scholar
  128. 128.
    Sampath D, Cortes J, Estrov Z et al. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood 2006;107:2517–2524.PubMedGoogle Scholar
  129. 129.
    Hofmann J. Protein kinase C isozymes as potential targets for anticancer therapy. Curr Cancer Drug Targets 2004;4:125–146.PubMedGoogle Scholar
  130. 130.
    Johnson LN, De ME, Brown NR et al. Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2. Pharmacol Ther 2002;93:113–124.PubMedGoogle Scholar
  131. 131.
    Akiyama T, Yoshida T, Tsujita T et al. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip1/WAF1/Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 1997;57:1495–1501.PubMedGoogle Scholar
  132. 132.
    Patel V, Lahusen T, Leethanakul C et al. Antitumor activity of UCN-01 in carcinomas of the head and neck is associated with altered expression of cyclin D3 and p27(KIP1). Clin Cancer Res 2002;8:3549–3560.PubMedGoogle Scholar
  133. 133.
    Zhou BB, Bartek J. Targeting the checkpoint kinases;Chemosensitization versus chemoprotection. Nat Rev Cancer 2004;4:216–225.PubMedGoogle Scholar
  134. 134.
    Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003;3:421–429.PubMedGoogle Scholar
  135. 135.
    Tse AN, Carvajal R, Schwartz GK. Targeting checkpoint kinase 1 in cancer therapeutics. Clin Cancer Res 2007;13:1955–1960.PubMedGoogle Scholar
  136. 136.
    Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. p53-deficient cells rely on ATM and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 2007;11:175–189.PubMedGoogle Scholar
  137. 137.
    Vogel C, Hager C, Bastians H. Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. Cancer Res 2007;67:339–345.PubMedGoogle Scholar
  138. 138.
    Zhao B, Bower MJ, McDevitt PJ et al. Structural basis for Chk1 inhibition by UCN-01. J Biol Chem 2002;277:46609–46615.PubMedGoogle Scholar
  139. 139.
    Yu Q, La RJ, Zhang H, Takemura H, Kohn KW, Pommier Y. UCN-01 inhibits p53 up-regulation and abrogates gamma-radiation-induced G(2)-M checkpoint independently of p53 by targeting both of the checkpoint kinases, Chk2 and Chk1. Cancer Res 2002;62:5743–5748.PubMedGoogle Scholar
  140. 140.
    Karlsson-Rosenthal C, Millar JB. Cdc25;Mechanisms of checkpoint inhibition and recovery. Trends Cell Biol 2006;16:285–292.PubMedGoogle Scholar
  141. 141.
    Kohn EA, Ruth ND, Brown MK, Livingstone M, Eastman A. Abrogation of the S phase DNA damage checkpoint results in S phase progression or premature mitosis depending on the concentration of 7-hydroxystaurosporine and the kinetics of Cdc25C activation. J Biol Chem 2002;277:26553–26564.PubMedGoogle Scholar
  142. 142.
    Callegari AJ, Kelly TJ. Shedding light on the DNA damage checkpoint. Cell Cycle 2007;6:660–666.PubMedGoogle Scholar
  143. 143.
    Harrison JC, Haber JE. Surviving the breakup;The DNA damage checkpoint. Annu Rev Genet 2006;40:209–235.PubMedGoogle Scholar
  144. 144.
    Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 2004;3:513–519.PubMedGoogle Scholar
  145. 145.
    Gottifredi V, Prives C. The S phase checkpoint;When the crowd meets at the fork. Semin Cell Dev Biol 2005;16:355–368.PubMedGoogle Scholar
  146. 146.
    Heffernan TP, Simpson DA, Frank AR et al. An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Mol Cell Biol 2002;22:8552–8561.PubMedGoogle Scholar
  147. 147.
    Sato S, Fujita N, Tsuruo T. Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene 2002;21:1727–1738.PubMedGoogle Scholar
  148. 148.
    Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM. Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoi-nositide-dependent protein kinase-1) inhibition. Biochem J 2003;375:255–262.PubMedGoogle Scholar
  149. 149.
    Castedo M, Perfettini JL, Roumier T, Kroemer G. Cyclin-dependent kinase-1;Linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 2002;9:1287–1293.PubMedGoogle Scholar
  150. 150.
    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 2002;102:463–468.PubMedGoogle Scholar
  151. 151.
    Tang L, Li MH, Cao P et al. Crystal structure of pyridoxal kinase in complex with roscovitine and derivatives. J Biol Chem 2005;280:31220–31229.PubMedGoogle Scholar
  152. 152.
    Bach S, Knockaert M, Reinhardt J et al. Roscovitine targets, protein kinases and pyridoxal kinase. J Biol Chem 2005;280:31208–31219.PubMedGoogle Scholar
  153. 153.
    Raynaud FI, Whittaker SR, Fischer PM et al. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 2005;11:4875–4887.PubMedGoogle Scholar
  154. 154.
    Benson C, White J, de BJ et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202;R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer 2007;96:29–37.PubMedGoogle Scholar
  155. 155.
    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 2004;64:262–272.PubMedGoogle Scholar
  156. 156.
    Lacrima K, Valentini A, Lambertini C et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (Seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol 2005;16:1169–1176.PubMedGoogle Scholar
  157. 157.
    Lacrima K, Rinaldi A, Vignati S et al. Cyclin-dependent kinase inhibitor seliciclib shows in vitro activity in diffuse large B-cell lymphomas. Leuk Lymphoma 2007;48:158–167.PubMedGoogle Scholar
  158. 158.
    Hahntow IN, Schneller F, Oelsner M et al. Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia 2004;18:747–755.PubMedGoogle Scholar
  159. 159.
    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 2005 ;105 ;4484–4491.PubMedGoogle Scholar
  160. 160.
    Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 2002;99:1885–1893.PubMedGoogle Scholar
  161. 161.
    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 2005;106:1042–1047.PubMedGoogle Scholar
  162. 162.
    Rossi AG, Sawatzky DA, Walker A et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 2006;12:1056–1064.PubMedGoogle Scholar
  163. 163.
    Coley HM, Shotton CF, Thomas H. Seliciclib (CYC202;r-roscovitine) in combination with cytotoxic agents in human uterine sarcoma cell lines. Anticancer Res 2007;27:273–278.PubMedGoogle Scholar
  164. 164.
    Coley HM, Shotton CF, Kokkinos MI, Thomas H. The effects of the CDK inhibitor seliciclib alone or in combination with cisplatin in human uterine sarcoma cell lines. Gynecol Oncol 2007;105:462–469.PubMedGoogle Scholar
  165. 165.
    Ribas J, Boix J, Meijer L. (R)-roscovitine (CYC202, Seliciclib) sensitizes SH-SY5Y neuroblastoma cells to nutlin-3-induced apoptosis. Exp Cell Res 2006;312:2394–2400.PubMedGoogle Scholar
  166. 166.
    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 2004;47:1719–1728.PubMedGoogle Scholar
  167. 167.
    Senderowicz AM. Small-molecule cyclin-dependent kinase modulators. Oncogene 2003;22:6609–6620.PubMedGoogle Scholar
  168. 168.
    Ma Y, Freeman SN, Cress WD. E2F4 deficiency promotes drug-induced apoptosis. Cancer Biol Ther 2004;3:1262–1269.PubMedGoogle Scholar
  169. 169.
    Ma Y, Cress WD. Transcriptional upregulation of p57 (Kip2) by the cyclin-dependent kinase inhibitor BMS-387032 is E2F dependent and serves as a negative feedback loop limiting cytotoxicity. Oncogene 2007;26:3532–3540.PubMedGoogle Scholar
  170. 170.
    Mukhopadhyay P, Ali MA, Nandi A, Carreon P, Choy H, Saha D. The cyclin-dependent kinase 2 inhibitor down-regulates interleukin-1beta-mediated induction of cyclooxygenase-2 expression in human lung carcinoma cells. Cancer Res 2006;66:1758–1766.PubMedGoogle Scholar
  171. 171.
    Kramer A, Schultheis B, Bergmann J et al. Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma. Leukemia 2002;16:1844–1851.PubMedGoogle Scholar
  172. 172.
    Lesage D, Troussard X, Sola B. The enigmatic role of cyclin D1 in multiple myeloma. Int J Cancer 2005;115:171–176.PubMedGoogle Scholar
  173. 173.
    Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J, Jr. Cyclin D dysregulation;An early and unifying pathogenic event in multiple myeloma. Blood 2005;106:296–303.PubMedGoogle Scholar
  174. 174.
    Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J Clin Oncol 2005;23:6333–6338.PubMedGoogle Scholar
  175. 175.
    Agnelli L, Bicciato S, Mattioli M. Molecular classification of multiple myeloma;A distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations. J Clin Oncol 2005;23:7296–7306.PubMedGoogle Scholar
  176. 176.
    Perez-Simon JA, Garcia-Sanz R, Tabernero MD et al. Prognostic value of numerical chromosome aberrations in multiple myeloma;A FISH analysis of 15 different chromosomes. Blood 1998;91:3366–3371.PubMedGoogle Scholar
  177. 177.
    Ely S, Di LM, Niesvizky R. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res 2005;65:11345–11353.PubMedGoogle Scholar
  178. 178.
    Urashima M, Ogata A, Chauhan D. Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood 1996;88:2219–2227.PubMedGoogle Scholar
  179. 179.
    Tricot G, Barlogie B, Jagannath S et al. Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities. Blood 1995;86:4250–4256.PubMedGoogle Scholar
  180. 180.
    Drexler HG. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia 1998;12:845–859.PubMedGoogle Scholar
  181. 181.
    Tasaka T, Berenson J, Vescio R et al. Analysis of the p16INK4A, p15INK4B and p18INK4C genes in multiple myeloma. Br J Haematol 1997;96:98–102.PubMedGoogle Scholar
  182. 182.
    Chen-Kiang S. Cell-cycle control of plasma cell differentiation and tumorigenesis. Immunol Rev 2003;194:39–47.PubMedGoogle Scholar
  183. 183.
    Ng MH, Chung YF, Lo KW, Wickham NW, Lee JC, Huang DP. Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 1997;89:2500–2506.PubMedGoogle Scholar
  184. 184.
    Galm O, Wilop S, Reichelt J et al. DNA methylation changes in multiple myeloma. Leukemia 2004;18:1687–1692.PubMedGoogle Scholar
  185. 185.
    Kulkarni MS, Daggett JL, Bender TP, Kuehl WM, Bergsagel PL, Williams ME. Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines;Ectopic p18 expression inhibits growth and induces apoptosis. Leukemia 2002;16:127–134.PubMedGoogle Scholar
  186. 186.
    Dib A, Peterson TR, Raducha-Grace L et al. Paradoxical expression of INK4c in proliferative multiple myeloma tumors;Bi-allelic deletion vs increased expression. Cell Div 2006;1:23.PubMedGoogle Scholar
  187. 187.
    Sarasquete ME, Garcia-Sanz R, Armellini A et al. The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma. Haematologica 2006;91:1551–1554.PubMedGoogle Scholar
  188. 188.
    Chim CS, Fung TK, Liang R. Disruption of INK4/CDK/Rb cell cycle pathway by gene hypermethylation in multiple myeloma and MGUS. Leukemia 2003;17:2533–2535.PubMedGoogle Scholar
  189. 189.
    Gojo I, Zhang B, Fenton RG. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res 2002;8:3527–3538.PubMedGoogle Scholar
  190. 190.
    Rosato RR, Dai Y, Almenara JA, Maggio SC, Grant S. Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation. Leukemia 2004;18:1780–1788.PubMedGoogle Scholar
  191. 191.
    Fandy TE, Ross DD, Gore SD, Srivastava RK. Flavopiridol synergizes TRAIL cytotoxicity by downregulation of FLIPL. Cancer Chemother Pharmacol 2007;60:313–319.PubMedGoogle Scholar
  192. 192.
    Pei XY, Dai Y, Grant S. The small-molecule Bcl-2 inhibitor HA14–1 interacts synergistically with flavopiridol to induce mitochondrial injury and apoptosis in human myeloma cells through a free radical-dependent and Jun NH2-terminal kinase-dependent mechanism. Mol Cancer Ther 2004;3:1513–1524.PubMedGoogle Scholar
  193. 193.
    Dai Y, Rahmani M, Grant S. Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-kappaB-dependent process. Oncogene 2003;22:7108–7122.PubMedGoogle Scholar
  194. 194.
    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 2005;65:5399–5407.PubMedGoogle Scholar
  195. 195.
    Dai Y, Yu C, Singh V et al. Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. Cancer Res 2001;61:5106–5115.PubMedGoogle Scholar
  196. 196.
    Dai Y, Landowski TH, Rosen ST, Dent P, Grant S. Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism. Blood 2002;100:3333–3343.PubMedGoogle Scholar
  197. 197.
    Dai Y, Dent P, Grant S. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) promotes mitochondrial dysfunction and apoptosis induced by 7-hydroxystaurosporine and mitogen-activated protein kinase kinase inhibitors in human leukemia cells that ectopically express Bcl-2 and Bcl-xL. Mol Pharmacol 2003;64:1402–1409.PubMedGoogle Scholar
  198. 198.
    Dai Y, Pei XY, Rahmani M, Conrad DH, Dent P, Grant S. Interruption of the NF-kappaB pathway by Bay 11–7082 promotes UCN-01-mediated mitochondrial dysfunction and apoptosis in human multiple myeloma cells. Blood 2004 ;103:2761–2770.PubMedGoogle Scholar
  199. 199.
    Pei XY, Dai Y, Rahmani M, Li W, Dent P, Grant S. The farnesyltransferase inhibitor L744832 potentiates UCN-01-induced apoptosis in human multiple myeloma cells. Clin Cancer Res 2005;11:4589–4600.PubMedGoogle Scholar
  200. 200.
    Dai Y, Khanna P, Chen S, Pei XY, Dent P, Grant S. Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood 2007;109:4415–4423.PubMedGoogle Scholar
  201. 201.
    Pei XY, Li W, Dai Y, Dent P, Grant S. Dissecting the roles of checkpoint kinase 1/CDC2 and mitogen-activated protein kinase kinase 1/2/extracellular signal-regulated kinase 1/2 in relation to 7-hydroxystaurosporine-induced apoptosis in human multiple myeloma cells. Mol Pharmacol 2006;70:1965–1973.PubMedGoogle Scholar
  202. 202.
    Pei X Y, Dai Y, Tenorio S et al. MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. Blood 2007Google Scholar
  203. 203.
    Baughn LB, Di Liberto M, Wu K et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res 2006;66;7661–7667.PubMedGoogle Scholar
  204. 204.
    Dispenzieri A, Gertz MA, Lacy MQ et al. Flavopiridol in patients with relapsed or refractory multiple myeloma;A phase 2 trial with clinical and pharmacodynamic end-points. Haematologica 2006;91:390–393.PubMedGoogle Scholar
  205. 205.
    Dai Y, Rahmani M, Pei XY, Dent P, Grant S. Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 2004;104:509–518.PubMedGoogle Scholar
  206. 206.
    S, Grant Sullivan D,. et al. Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms. Blood 2005;104.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Yun Dai
    • 1
  • Steven Grant
    • 2
  1. 1.Department of MedicineVirginia Commonwealth University and Massey Cancer CenterRichmondUSA
  2. 2.Department of Medicine, Biochemistry and PharmacologyVirginia Commonwealth University and Massey Cancer CenterRichmondUSA

Personalised recommendations