Advertisement

The CDK inhibitors in cancer research and therapy

  • Jonas Cicenas
  • Mindaugas Valius
Review

Abstract

Chemical compounds that interfere with an enzymatic function of kinases are useful for gaining insight into the complicated biochemical processes in mammalian cells. Cyclin-dependent kinases (CDK) play an essential role in the control of the cell cycle and/or proliferation. These kinases as well as their regulators are frequently deregulated in different human tumors. Aberrations in CDK activity have also been observed in viral infections, Alzheimer’s, Parkinson’s diseases, ischemia and some proliferative disorders. This led to an intensive search for small-molecule CDK inhibitors not only for research purposes, but also for therapeutic applications. Here, we discuss seventeen CDK inhibitors and their use in cancer research or therapy. This review should help researchers to decide which inhibitor is best suited for the specific purpose of their research. For this purpose, the targets, commercial availability and IC50 values are provided for each inhibitor. The review will also provide an overview of the clinical studies performed with some of these inhibitors.

Keywords

CDK Kinases Small-molecule inhibitors Cancer Cell cycle 

Notes

Conflict of interest

Authors state no conflict of interests.

References

  1. Aklilu M, Kindler HL, Donehower RC, Mani S, Vokes EE (2003) Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann Oncol 14(8):1270–1273. doi: 10.1093/annonc/mdg343 PubMedCrossRefGoogle Scholar
  2. Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT, Greene JF Jr, Koss W, Morgan CD, Stinson SF, Siford TJ, Alvord WG, Klabansky RL, Sausville EA (1998) Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts. Blood 91(7):2482–2490PubMedGoogle Scholar
  3. Arris CE, Boyle FT, Calvert AH, Curtin NJ, Endicott JA, Garman EF, Gibson AE, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Lawrie AM, Newell DR, Noble ME, Sausville EA, Schultz R, Yu W (2000) Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem 43(15):2797–2804. doi: 10.1021/jm990628o PubMedCrossRefGoogle Scholar
  4. Benson C, White J, De Bono J, O’Donnell A, Raynaud F, Cruickshank C, McGrath H, Walton M, Workman P, Kaye S, Cassidy J, Gianella-Borradori A, Judson I, Twelves C (2007) 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 96(1):29–37. doi: 10.1038/sj.bjc.6603509 PubMedCrossRefGoogle Scholar
  5. Bergqvist J, Elmberger G, Ohd J, Linderholm B, Bjohle J, Hellborg H, Nordgren H, Borg AL, Skoog L, Bergh J (2006) Activated ERK1/2 and phosphorylated oestrogen receptor alpha are associated with improved breast cancer survival in women treated with tamoxifen. Eur J Cancer 42(8):1104–1112. doi: 10.1016/j.ejca.2006.01.028 PubMedCrossRefGoogle Scholar
  6. Berkofsky-Fessler W, Nguyen TQ, Delmar P, Molnos J, Kanwal C, DePinto W, Rosinski J, McLoughlin P, Ritland S, DeMario M, Tobon K, Reidhaar-Olson JF, Rueger R, Hilton H (2009) Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients. Mol Cancer Ther 8(9):2517–2525. doi: 10.1158/1535-7163.MCT-09-0083 PubMedCrossRefGoogle Scholar
  7. Bible KC, Lensing JL, Nelson SA, Lee YK, Reid JM, Ames MM, Isham CR, Piens J, Rubin SL, Rubin J, Kaufmann SH, Atherton PJ, Sloan JA, Daiss MK, Adjei AA, Erlichman C (2005) Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points. Clin Cancer Res 11(16):5935–5941. doi: 10.1158/1078-0432.CCR-04-2566 PubMedCrossRefGoogle Scholar
  8. Blum W, Phelps MA, Klisovic RB, Rozewski DM, Ni W, Albanese KA, Rovin B, Kefauver C, Devine SM, Lucas DM, Johnson A, Schaaf LJ, Byrd JC, Marcucci G, Grever MR (2010) Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias. Haematologica 95(7):1098–1105. doi: 10.3324/haematol.2009.017103 PubMedCrossRefGoogle Scholar
  9. Burdette-Radoux S, Tozer RG, Lohmann RC, Quirt I, Ernst DS, Walsh W, Wainman N, Colevas AD, Eisenhauer EA (2004) Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma. Invest New Drugs 22(3):315–322. doi: 10.1023/B:DRUG.0000026258.02846.1c PubMedCrossRefGoogle Scholar
  10. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ (1996) Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 56(13):2973–2978PubMedGoogle Scholar
  11. Carvajal RD, Tse A, Shah MA, Lefkowitz RA, Gonen M, Gilman-Rosen L, Kortmansky J, Kelsen DP, Schwartz GK, O’Reilly EM (2009) A phase II study of flavopiridol (Alvocidib) in combination with docetaxel in refractory, metastatic pancreatic cancer. Pancreatology 9(4):404–409. doi: 10.1159/000187135 PubMedCrossRefGoogle Scholar
  12. Choi HS, Lee Y, Park KH, Sung JS, Lee JE, Shin ES, Ryu JS, Kim YH (2009) Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet 54(5):298–303. doi: 10.1038/jhg.2009.29 PubMedCrossRefGoogle Scholar
  13. Cicenas J (2007) The potential role of EGFR/ErbB2 heterodimer in breast cancer. Expert opinion Ther Patents 17(6):607–616. doi: 10.1517/13543776.17.6.607 CrossRefGoogle Scholar
  14. Cicenas J (2008) The potential role of Akt phosphorylation in human cancers. Int J Bio Markers 23(1):1–9Google Scholar
  15. Cicenas J, Kueng W, Wight E, Eppenberger-Castori S, Eppenberger U (2004) Prognostic value of phosphorylated Akt in primary breast cancer. [abstract]. In: Proceedings of the 95th annual meeting of the American Association for Cancer Research; 2004 March 27–31; Orlando, FL: AACR; 2004. http://aacrmeetingabstracts.org/cgi/content/abstract/2004/1/813-c
  16. Cicenas J, Urban P, Vuaroqueaux V, Labuhn M, Küng W, Wight E, Mayhew M, Eppenberger U, Eppenberger-Castori S (2005) Increased level of phosphorylated akt measured by chemiluminescence-linked immunosorbent assay is a predictor of poor prognosis in primary breast cancer overexpressing ErbB-2. Breast Cancer Res 7(4):R394–R401. doi: 10.1186/bcr1015 PubMedCrossRefGoogle Scholar
  17. Cicenas J, Urban P, Küng W, Vuaroqueaux V, Labuhn M, Wight E, Eppenberger U, Eppenberger-Castori S (2006) Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients. Eur J Cancer 42(5):636–645. doi: 10.1016/j.ejca.2005.11.012 PubMedCrossRefGoogle Scholar
  18. Cicenas J, Küng W, Eppenberger U, Eppenberger-Castori S (2010) Increased level of phosphorylated ShcA measured by chemiluminescence-linked immunoassay is a predictor of good prognosis in primary breast cancer expressing low levels of estrogen receptor. Cancers 2(1):153–164. doi: 10.3390/cancers2010153 Google Scholar
  19. Clarke RB (2003) p27KIP1 phosphorylation by PKB/Akt leads to poor breast cancer prognosis. Breast Cancer Res 5(3):162–163. doi: 10.1186/bcr596 PubMedCrossRefGoogle Scholar
  20. Derenzini M, Montanaro L, Vici M, Barbieri S, Ceccarelli C, Santini D, Taffurelli M, Martinelli GN, Treré D (2007) Relationship between the RB1 mRNA level and the expression of phosphorylated RB protein in human breast cancers: their relevance in cell proliferation activity and patient clinical outcome. Histol Histopathol 22(5):505–513PubMedGoogle Scholar
  21. Dhariwala FA, Rajadhyaksha MS (2008) An unusual member of the Cdk family: Cdk5. Cell Mol Neurobiol 28(3):351–369. doi: 10.1007/s10571-007-9242-1 PubMedCrossRefGoogle Scholar
  22. Dickson MA, Rathkopf DE, Carvajal RD, Grant S, Roberts JD, Reid JM, Ames MM, McGovern RM, Lefkowitz RA, Gonen M, Cane LM, Dials HJ, Schwartz GK (2010) A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Invest New Drugs May 12. [Epub ahead of print]. doi: 10.1007/s10637-010-9447-x
  23. DiGiovanna MP, Stern DF, Edgerton SM, Whalen SG, Moore D 2nd, Thor AD (2005) Relationship of epidermal growth factor receptor expression to ErbB-2 signaling activity and prognosis in breast cancer patients. J Clin Oncol 23(6):1152–1160. doi: 10.1200/JCO.2005.09.055 PubMedCrossRefGoogle Scholar
  24. Drees M, Dengler WA, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville EA, Fiebig HH (1997) Flavopiridol (L86–8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin Cancer Res 3(2):273–279PubMedGoogle Scholar
  25. Duan Y, He X, Yang H, Ji Y, Tao T, Chen J, Hu L, Zhang F, Li X, Wang H, Shen A, Lu X (2010) Cyclin D3/CDK11(p58) complex involved in Schwann cells proliferation repression caused by lipopolysaccharide. Inflammation 33(3):189–199. doi: 10.1007/s10753-009-9173-8 PubMedCrossRefGoogle Scholar
  26. El-Rayes BF, Gadgeel S, Parchment R, Lorusso P, Philip PA (2006) A phase I study of flavopiridol and docetaxel. Invest New Drugs 24(4):305–310. doi: 10.1007/s10637-005-4343-5 PubMedCrossRefGoogle Scholar
  27. Fekrazad HM, Verschraegen CF, Royce M, Smith HO, Chyi Lee F, Rabinowitz I (2010) A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer. Am J Clin Oncol 33(4):393–397. doi: 10.1097/COC.0b013e3181b2043f PubMedCrossRefGoogle Scholar
  28. Fischer PM, Gianella-Borradori A (2005) Recent progress in the discovery and development of cyclin-dependent kinase inhibitors. Expert Opin Investig Drugs 14(4):457–477. doi: 10.1517/13543784.14.4.457 PubMedCrossRefGoogle Scholar
  29. Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118(Pt 22):5171–5180. doi: 10.1242/jcs.02718 PubMedCrossRefGoogle Scholar
  30. Fornier MN, Rathkopf D, Shah M, Patil S, O’Reilly E, Tse AN, Hudis C, Lefkowitz R, Kelsen DP, Schwartz GK (2007) Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors. Clin Cancer Res 13(19):5841–5846. doi: 10.1158/1078-0432.CCR-07-1218 PubMedCrossRefGoogle Scholar
  31. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL (2004) Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 3(11):1427–1438PubMedGoogle Scholar
  32. George S, Kasimis BS, Cogswell J, Schwarzenberger P, Shapiro GI, Fidias P, Bukowski RM (2008) Phase I study of flavopiridol in combination with Paclitaxel and Carboplatin in patients with non-small-cell lung cancer. Clin Lung Cancer 9(3):160–165. doi: 10.3816/CLC.2008.n.024 PubMedCrossRefGoogle Scholar
  33. Grendys EC Jr, Blessing JA, Burger R, Hoffman J (2005) A phase II evaluation of flavopiridol as second-line chemotherapy of endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 98(2):249–253. doi: 10.1016/j.ygyno.2005.05.017 PubMedCrossRefGoogle Scholar
  34. Hansel DE, Dhara S, Huang RC, Ashfaq R, Deasel M, Shimada Y, Bernstein HS, Harmon J, Brock M, Forastiere A, Washington MK, Maitra A, Montgomery E (2005) CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target. Am J Surg Pathol 29(3):390–399PubMedCrossRefGoogle Scholar
  35. Heath EI, Bible K, Martell RE, Adelman DC, Lorusso PM (2008) A phase 1 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. doi: 10.1007/s10637-007-9090-3 PubMedCrossRefGoogle Scholar
  36. Helal CJ, Sanner MA, Cooper CB, Gant T, Adam M, Lucas JC, Kang Z, Kupchinsky S, Ahlijanian MK, Tate B, Menniti FS, Kelly K, Peterson M (2004) Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer’s disease. Bioorg Med Chem Lett 14(22):5521–5525. doi: 10.1016/j.bmcl.2004.09.006 PubMedCrossRefGoogle Scholar
  37. Hirte HW, Raghunadharao D, Baetz T, Hotte S, Rajappa S, Iacobucci A, Sharma S, Parikh H, Kulkarni S, Patil S, Gaston S (2007) A phase 1 study of the selective cyclin dependent kinase inhibitor P276-00 in patients with advanced refractory neoplasms. J Clinical Oncol, ASCO Annual meeting proceedings part I. 25(18S) (June 20 Supplement):14117. http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/14117
  38. Hunter T, Cooper JA (1985) Protein-tyrosine kinases. Annu Rev Biochem 54:897–930. doi: 10.1146/annurev.bi.54.070185.004341 PubMedCrossRefGoogle Scholar
  39. Jeon S, Choi JY, Lee KM, Park SK, Yoo KY, Noh DY, Ahn SH, Kang D (2010) Combined genetic effect of CDK7 and ESR1 polymorphisms on breast cancer. Breast Cancer Res Treat 121(3):737–742. doi: 10.1007/s10549-009-0640-6 PubMedCrossRefGoogle Scholar
  40. Joshi KS, Rathos MJ, Joshi RD, Sivakumar M, Mascarenhas M, Kamble S, Lal B, Sharma S (2007) In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276–00. Mol Cancer Ther 6(3):918–925. doi: 10.1158/1535-7163.MCT-06-0613 PubMedCrossRefGoogle Scholar
  41. Kanematsu T, Yano S, Uehara H, Bando Y, Sone S (2003) Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients. Oncol Res 13(5):289–298PubMedGoogle Scholar
  42. Karp JE, Passaniti A, Gojo I, Kaufmann S, Bible K, Garimella TS, Greer J, Briel J, Smith BD, Gore SD, Tidwell ML, Ross DD, Wright JJ, Colevas AD, Bauer KS (2005) 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 11(23):8403–8412. doi: 10.1158/1078-0432.CCR-05-1201 PubMedCrossRefGoogle Scholar
  43. Karp JE, Smith BD, Resar LS, Greer JM, Blackford A, Zhao M, Moton-Nelson D, Alino K, Levis MJ, Gore SD, Joseph B, Carraway H, McDevitt MA, Bagain L, Mackey K, Briel J, Doyle LA, Wright JJ, Rudek MA (2011) Phase I and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. Blood 117(12):3302–3310. doi: 10.1182/blood-2010-09-310862 PubMedCrossRefGoogle Scholar
  44. Kasten M, Giordano A (2001) Cdk10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity. Oncogene 20(15):1832–1838PubMedCrossRefGoogle Scholar
  45. Kaur G, Stetler-Stevenson M, Sebers S, Worland P, Sedlacek H, Myers C, Czech J, Naik R, Sausville E (1992) Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86–8275. J Natl Cancer Inst 84(22):1736–1740. doi: 10.1093/jnci/84.22.1736 PubMedCrossRefGoogle Scholar
  46. Kim SJ, Nakayama S, Miyoshi Y, Taguchi T, Tamaki Y, Matsushima T, Torikoshi Y, Tanaka S, Yoshida T, Ishihara H, Noguchi S (2008) Determination of the specific activity of CDK1 and CDK2 as a novel prognostic indicator for early breast cancer. Ann Oncol 19(1):68–72. doi: 10.1093/annonc/mdm358 PubMedCrossRefGoogle Scholar
  47. Kouroukis CT, Belch A, Crump M, Eisenhauer E, Gascoyne RD, Meyer R, Lohmann R, Lopez P, Powers J, Turner R, Connors JM, National Cancer Institute of Canada Clinical Trials Group (2003) 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 21(9):1740–1745Google Scholar
  48. Kusume T, Tsuda H, Kawabata M, Inoue T, Umesaki N, Suzuki T, Yamamoto K (1999) The p16-cyclin D1/CDK4-pRb pathway and clinical outcome in epithelial ovarian cancer. Clin Cancer Res 5(12):4152–4157PubMedGoogle Scholar
  49. Lane ME, Yu B, Rice A, Lipson KE, Liang C, Sun L, Tang C, McMahon G, Pestell RG, Wadler S (2001) A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells. Cancer Res 61(16):6170–6177PubMedGoogle Scholar
  50. Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, Chiao J, Armour S, Frame S, Green SR, Gianella-Borradori A, Diéras V, Raymond E (2010) Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer 46(18):3243–3250. doi: 10.1016/j.ejca.2010.08.001 PubMedCrossRefGoogle Scholar
  51. Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, Blum KA, Flynn JM, Jones JA, Hu W, Moran ME, Mitchell SM, Smith LL, Wagner AJ, Raymond CA, Schaaf LJ, Phelps MA, Villalona-Calero MA, Grever MR, Byrd JC (2009) Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 27(35):6012–6018. doi: 10.1200/JCO.2009.22.694470 PubMedCrossRefGoogle Scholar
  52. Liu G, Gandara DR, Lara PN Jr, Raghavan D, Doroshow JH, Twardowski P, Kantoff P, Oh W, Kim K, Wilding G (2004) A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res 10(3):924–928. doi: 10.1158/1078-0432.CCR-03-0050 PubMedCrossRefGoogle Scholar
  53. Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G (2010) Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. Mar 31. [Epub ahead of print]. doi: 10.1007/s12032-010-9510-7
  54. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ (1994) Potent inhibition of CDC2 kinase activity by the flavonoid L86–8275. Biochem Biophys Res Commun 201(2):589–595. doi: 10.1006/bbrc.1994.1742 PubMedCrossRefGoogle Scholar
  55. Loyer P, Trembley JH, Grenet JA, Busson A, Corlu A, Zhao W, Kocak M, Kidd VJ, Lahti JM (2008) Characterization of cyclin L1 and L2 interactions with CDK11 and splicing factors: influence of cyclin L isoforms on splice site selection. J Biol Chem 283(12):7721–7732. doi: 10.1074/jbc.M708188200 PubMedCrossRefGoogle Scholar
  56. Mahadevan D, Plummer R, Squires MS, Rensvold D, Kurtin S, Pretzinger C, Dragovich T, Adams J, Lock V, Smith DM, Von Hoff D, Calvert H (2011) A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Ann Oncol. Feb 16 [Epub ahead of print]. doi: 10.1093/annonc/mdq734
  57. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30(11):630–641. doi: 10.1016/j.tibs.2005.09.005 PubMedCrossRefGoogle Scholar
  58. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, Morgan DO, Tsai LH, Wolgemuth DJ (2009) Cyclin-dependent kinases: a family portrait. Nat Cell Biol 11(11):1275–1276. doi: 10.1038/ncb1109-1275 Google Scholar
  59. Marone M, Scambia G, Giannitelli C, Ferrandina G, Masciullo V, Bellacosa A, Benedetti-Panici P, Mancuso S (1998) Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression. Int J Cancer 75(1):34–39. doi: 10.1002/(SICI)1097-0215(19980105)75:1<34::AID-IJC6>3.0.CO;2-2
  60. Mihara M, Shintani S, Nakahara Y, Kiyota A, Ueyama Y, Matsumura T, Wong DT (2001) Overexpression of CDK2 is a prognostic indicator of oral cancer progression. Jpn J Cancer Res 92(3):352–360PubMedGoogle Scholar
  61. Milde-Langosch K, Bamberger AM, Rieck G, Grund D, Hemminger G, Müller V, Löning T (2005) Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer 92(12):2206–2215. doi: 10.1038/sj.bjc.6602655 PubMedCrossRefGoogle Scholar
  62. Morris DG, Bramwell VH, Turcotte R, Figueredo AT, Blackstein ME, Verma S, Matthews S, Eisenhauer EA (2006) A phase II study of flavopiridol in patients with previously untreated advanced soft tissue sarcoma. Sarcoma 2006:64374. doi: 10.1155/SRCM/2006/64374 PubMedCrossRefGoogle Scholar
  63. Nakayama S, Torikoshi Y, Takahashi T, Yoshida T, Sudo T, Matsushima T, Kawasaki Y, Katayama A, Gohda K, Hortobagyi GN, Noguchi S, Sakai T, Ishihara H, Ueno NT (2009) Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells. Breast Cancer Res 11(1):R12. doi: 10.1186/bcr2231 Google Scholar
  64. Niesvizky R, Lentzsch S, Badros AZ, Chanan-Khan AA, Singhal SB, Zonder JA, Vij R, Huang X, DiLiberto M, Courtney R, Shaik MN, Kim ST, Randolph S, Ely SA, Chen-Kiang S (2010) A phase I study of PD 0332991: complete CDK4/6 inhibition and tumor response in sequential combination with bortezomib and dexamethasone for relapsed and refractory multiple myeloma. Oral session: myeloma—therapy, excluding transplantation: myeloma phase I/II trials and correlative studies. http://ash.confex.com/ash/2010/webprogram/Paper26540.html
  65. Patel V, Senderowicz AM, Pinto D Jr, Igishi T, Raffeld M, Quintanilla-Martinez L, Ensley JF, Sausville EA, Gutkind JS (1998) 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. doi: 10.1172/JCI3661 PubMedCrossRefGoogle Scholar
  66. Phelps MA, Lin TS, Johnson AJ, Hurh E, Rozewski DM, Farley KL, Wu D, Blum KA, Fischer B, Mitchell SM, Moran ME, Brooker-McEldowney M, Heerema NA, Jarjoura D, Schaaf LJ, Byrd JC, Grever MR, Dalton JT (2009) Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 113(12):2637–2645. doi: 10.1182/blood-2008-07-168583 PubMedCrossRefGoogle Scholar
  67. Poomsawat S, Buajeeb W, Khovidhunkit SO, Punyasingh J (2010) Alteration in the expression of cdk4 and cdk6 proteins in oral cancer and premalignant lesions. J Oral Pathol Med 39(10):793–799. doi: 10.1111/j.1600-0714.2010.00909.x PubMedCrossRefGoogle Scholar
  68. Rathkopf D, Dickson MA, Feldman DR, Carvajal RD, Shah MA, Wu N, Lefkowitz R, Gonen M, Cane LM, Dials HJ, Winkelmann JL, Bosl GJ, Schwartz GK (2009) Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors. Clin Cancer Res 15(23):7405–7411. doi: 10.1158/1078-0432.CCR-09-1502 PubMedCrossRefGoogle Scholar
  69. Roll DM, Ireland CM, Lu HSM, Clardy J (1988) Fascaplysin, an unusual antimicrobial pigment from the marine sponge Fascaplysinopsis sp. J Org Chem 53(14):3276–3278. doi: 10.1021/jo00249a025 CrossRefGoogle Scholar
  70. Ryu CK, Kang HY, Lee SK, Nam KA, Hong CY, Ko WG, Lee BH (2000) 5-Arylamino-2-methyl-4, 7-dioxobenzothiazoles as inhibitors of cyclin-dependent kinase 4 and cytotoxic agents. Bioorg Med Chem Lett 10(5):461–464. doi: 10.1016/S0960-894X(00)00014-7 PubMedCrossRefGoogle Scholar
  71. Schwartz GK, Ilson D, Saltz L, O’Reilly E, Tong W, Maslak P, Werner J, Perkins P, Stoltz M, Kelsen D (2001) Phase II study of the cyclin-dependent kinase inhibitor flavopiridol administered to patients with advanced gastric carcinoma. J Clin Oncol 19(7):1985–1992PubMedGoogle Scholar
  72. Schwartz GK, O’Reilly E, Ilson D, Saltz L, Sharma S, Tong W, Maslak P, Stoltz M, Eden L, Perkins P, Endres S, Barazzoul J, Spriggs D, Kelsen D (2002) Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20(8):2157–2170. doi: 10.1200/JCO.2004.01.0660 PubMedCrossRefGoogle Scholar
  73. Semczuk A, Miturski R, Skomra D, Jakowicki JA (2004) Expression of the cell-cycle regulatory proteins (pRb, cyclin D1, p16INK4A and cdk4) in human endometrial cancer: correlation with clinicopathological features. Arch Gynecol Obstet 269(2):104–110. doi: 10.1007/s00404-002-0449-6 PubMedCrossRefGoogle Scholar
  74. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA (1998) Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 16(9):2986–2999PubMedGoogle Scholar
  75. Shah MA, Kortmansky J, Motwani M, Drobnjak M, Gonen M, Yi S, Weyerbacher A, Cordon-Cardo C, Lefkowitz R, Brenner B, O’Reilly E, Saltz L, Tong W, Kelsen DP, Schwartz GK (2005) A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol. Clin Cancer Res 11(10):3836–3845. doi: 10.1158/1078-0432.CCR-04-2651 PubMedCrossRefGoogle Scholar
  76. Shapiro GI, Supko JG, Patterson A, Lynch C, Lucca J, Zacarola PF, Muzikansky A, Wright JJ, Lynch TJ Jr, Rollins BJ (2001) 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 7(6):1590–1599PubMedGoogle Scholar
  77. Simon R, Struckmann K, Schraml P, Wagner U, Forster T, Moch H, Fijan A, Bruderer J, Wilber K, Mihatsch MJ, Gasser T, Sauter G (2002) Amplification pattern of 12q13–q15 genes (MDM2, CDK4, GLI) in urinary bladder cancer. Oncogene 21(16):2476–2483. doi: 10.1038/sj/onc/1205304 PubMedCrossRefGoogle Scholar
  78. Slamon DJ, Hurvitz SA, Applebaum S, Glaspy JA, Allison MK, DiCarlo BA, Courtney RD, Kim ST, Randolph S, Finn S (2010) Phase I study of PD 0332991, cyclin-D kinase (CDK) 4/6 inhibitor in combination with letrozole for first-line treatment of patients with ER-positive, HER2-negative breast cancer. J Clinical Oncol, 2010 ASCO annual meeting proceedings (Post-meeting edition). 28(15) (May 20 Supplement):3060Google Scholar
  79. Svensson S, Jirström K, Rydén L, Roos G, Emdin S, Ostrowski MC, Landberg G (2005) ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumors with good prognosis. Oncogene 24(27):4370–4379. doi: 10.1038/sj.onc.1208626 PubMedCrossRefGoogle Scholar
  80. Tan AR, Headlee D, Messmann R, Sausville EA, Arbuck SG, Murgo AJ, Melillo G, Zhai S, Figg WD, Swain SM, Senderowicz AM (2002) Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms. J Clin Oncol 20(19):4074–4082. doi: 10.1200/JCO.2002.01.043 PubMedCrossRefGoogle Scholar
  81. Tan AR, Yang X, Berman A, Zhai S, Sparreboom A, Parr AL, Chow C, Brahim JS, Steinberg SM, Figg WD, Swain SM (2004) Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res 10(15):5038–5047. doi: 10.1158/1078-0432.CCR-04-0025 PubMedCrossRefGoogle Scholar
  82. Thomas JP, Tutsch KD, Cleary JF, Bailey HH, Arzoomanian R, Alberti D, Simon K, Feierabend C, Binger K, Marnocha R, Dresen A, Wilding G (2002) Phase I clinical and pharmacokinetic trial of the cyclin-dependent kinase inhibitor flavopiridol. Cancer Chemother Pharmacol 50(6):465–472. doi: 10.1007/s00280-002-0527-2 PubMedCrossRefGoogle Scholar
  83. Tong WG, Chen R, Plunkett W, Siegel D, Sinha R, Harvey RD, Badros AZ, Popplewell L, Coutre S, Fox JA, Mahadocon K, Chen T, Kegley P, Hoch U, Wierda WG (2010) 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. doi: 10.1200/JCO.2009.26.1347 PubMedCrossRefGoogle Scholar
  84. Van Veldhuizen PJ, Faulkner JR, Lara PN Jr, Gumerlock PH, Goodwin JW, Dakhil SR, Gross HM, Flanigan RC, Crawford ED, Southwest Oncology Group (2005) A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109. Cancer Chemother Pharmacol 56(1):39–45. doi: 10.1007/s00280-004-0969-9 PubMedCrossRefGoogle Scholar
  85. Villerbu N, Gaben AM, Redeuilh G, Mester J (2002) Cellular effects of purvalanol A: a specific inhibitor of cyclin-dependent kinase activities. Int J Cancer 97(6):761–769. doi: 10.1002/ijc.10125 PubMedCrossRefGoogle Scholar
  86. Whitlock JA, Krailo M, Reid JM, Ruben SL, Ames MM, Owen W, Reaman G (2005) Children’s oncology group study. Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children’s Oncology Group Study. J Clin Oncol 23(36):9179–9186. doi: 10.1200/JCO.2004.01.0660 PubMedCrossRefGoogle Scholar
  87. Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y, Zhou BP, Hung MC (2004) Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients. Clin Cancer Res 10(11):3815–3824. doi: 10.1158/1078-0432.CCR-03-0527 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Medicine, Institute of AnatomyUniversity of FribourgFribourgSwitzerland
  2. 2.MAP Kinase ResourceBernSwitzerland
  3. 3.Department of Developmental BiologyInstitute of BiochemistryVilniusLithuania

Personalised recommendations