Therapeutic opportunities to control tumor cell cycles

Abstract

Tumor cell proliferation is frequently associated to genetic or epigenetic alterations in key cell cycle regulators. Most human tumors deregulate this pathway to sustain proliferation with independence of external mitogenic factors. In addition, the alteration of cell cycle proteins may confer genomic instability that results in additional mutations in these tumor cells. The frequent alteration of the cell cycle in tumor cells has launched the identification for critical cell cycle regulators as anticancer targets. The inhibition of some cell cycle kinases such as cyclin-dependent kinases (CDKs) or the Aurora and Polo mitotic kinases is currently under study in several preclinical and clinical trials. Similarly, the clinical success of microtubule poisons such as taxol has promoted new applied research in mitosis regulation. Recent investigations have suggested new targets of interest including additional kinases, phosphatases and other mitotic regulators such as microtubule motor proteins (kinesins). Current research in this area will undoubtedly result in new and improved targeted therapies for cancer treatment.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Malumbres M, Barbacid M. RAS oncogenes: the first 50 years. Nat Rev Cancer. 2003;3:459–65.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Nurse, P. A long twentieth century of the cell cycle and beyond. Cell. 2000;100:71–8.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Massague, J.. G1 cell-cycle control and cancer. Nature 2004;432:298–306.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Malumbres M, Barbacid M. To cycle or no to cycle: a critical decision in cancer. Nat Rev Cancer. 2001;1:222–31.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Malumbres M, Carnero A. Cell cycle deregulation: a common motif in cancer. Progress Cell Cycle Res. 2003;5:5–18.

    Google Scholar 

  6. 6.

    Ortega S, Malumbres M, Barbacid M. Cdk4 and their INK4 inhibitors in tumor biology. Biochem Biophys Acta. 2002;87513:1–15.

    Google Scholar 

  7. 7.

    Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30:630–41.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Ciemerych MA, Sicinski P. Cell cycle in mouse development. Oncogene. 2005;24: 2877–98.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Senderowicz AM. Targeting cell cycle and apoptosis for the treatment of human malignancies. Curr Opin Cell Biol. 2004;16: 670–8.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Hirai H, Kawanishi N, Iwasawa Y. Recent advances in the development of selective small molecule inhibitors for cyclin-dependent kinases. Curr Top Med Chem. 2005; 5:167–79.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24:1770–83.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Ventura JJ, Nebreda AR. Protein kinases and phosphatases as therapeutic targets in cancer. Clin Transl Oncol. 2006;8:153–60.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Blagosklonny MV. Flavopiridol, an inhibitor of transcription. Implications, problems and solutions. Cell Cycle. 2004;3: 1557–42.

    Google Scholar 

  14. 14.

    Malumbres M, Barbacid M. Is Cyclin D1/Cdk4 kinase a bona-fide cancer target? Cancer Cell. 2006;9:2–4.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Bartek J, Lukas C, Lukas J. Checking on DNA damage in S phase. Nat Rev Mol Cell Biol. 2004;5:792–804.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Gottifredi V, Prives C. The S phase checkpoint: when the crowd meets at the fork. Semin Cell Dev Biol. 2005;16:355–68.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Kawabe T. G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther. 2004; 3:513–9.

    PubMed  CAS  Google Scholar 

  18. 18.

    Wood KW, Cornwell WD, Jackson JR. Past and future of the mitotic spindle as an oncology target. Curr Opin Pharmacol. 2001;1:370–7.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Hadfield JA, Ducki S, Hirst N, McGown AT. Tubulin and microtubules as targets for anticancer drugs. Prog Cell Cycle Res. 2003;5:309–25.

    PubMed  Google Scholar 

  20. 20.

    Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4:255–65.

    Article  Google Scholar 

  21. 21.

    Kops GJ, Weaver BA, Cleveland DW. On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005; 5:773–85.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Tao W. The mitotic checkpoint in cancer therapy. Cell Cycle. 2005;4:e103-e7.

    Google Scholar 

  23. 23.

    Schmidt M, Medema RH. Exploiting the compromised spindle assembly checkpoint function of tumor cells: dawn on the horizon? Cell Cycle. 2006;5:159–163.

    PubMed  CAS  Google Scholar 

  24. 24.

    Doxsey S, McCollum D, Theurkauf W. Centrosomes in cellular regulation. Annu Rev Cell Dev Biol. 2005;21:411–34.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Tsou MF, Stearns T. Controlling centrosome number: licenses and blocks. Curr Opin Cell Biol. 2006;18:74–8.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001;2:21–32.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Petretti C, Savoian M, Montembault E, Glover DM, Prigent C, Giet R. The PIT-SLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep. 2006;7:418–24.

    PubMed  CAS  Google Scholar 

  28. 28.

    Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842–54.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer. 2004;4:927–36.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides the mitotic spindle asembly checkpoint, inducing resistance to taxol. Cancer Cell. 2003;3:51–62.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growthin vivo. Nat Med. 2004;10:262–267.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Barr FA, Sillje HH, Nigg EA. Polo-like kinases and the orchestration of cell division. Nat Rev Mol Cell Biol. 2004;5:429–40.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Strebhardt K, Ullrich A. Targeting polo-like kinase 1 for cancer therapy. Nat Rev Cancer. 2006;6:321–30.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Liu X, Lei M, Erikson RL. Normal cells, but not cancer cells, survive severe plk1 depletion. Mol Cell Biol. 2006;26:2093–108.

    PubMed  Article  Google Scholar 

  35. 35.

    Jallepalli PV, Lengauer C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer. 2001;1:109–17.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Baker D, Chen J, Deursen JMA. The mitotic checkpoint in cancer and aging: what have mice taught us? Curr Opin Cell Biol. 2005;17:583–9.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Quarmby LM, Mahjoub MR. Caught Neking: cilia and centrioles. J Cell Sci. 2005; 118:5161–9.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Hayward DG, Fry AM. Nek2 kinase in chromosome instability and cancer. Cancer Lett. 2005; [doi:10.1016/j.canlet. 2005. 06.017].

  39. 39.

    Fisk HA, Mattison CP, Winey M. A field guide to the Mps1 family of protein kinases. Cell Cycle 2004;3:439–42.

    PubMed  CAS  Google Scholar 

  40. 40.

    Dorer RK, Zhong S, Tallarico JA, Wong WH, Mitchison TJ, Murray AW. A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes. Curr Biol. 2005;15:1070–6.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Schmidt M, Budirahardja Y, Klompmaker R, Medema RH. Ablation of the spindle assembly checkpoint by a compound targeting Mps1. EMBO Rep. 2005;6:866–72.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Donzelli M, Draetta GF. Regulating mammalian checkpoints through Cdc25 inactivation. EMBO Rep. 2003;4:671–7.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Eckstein JW. Cdc25 as a potential target of anticancer agents. Invest New Drugs. 2000;18:149–56.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Kristjansdottir K, Rudolph J. Cdc25 phosphatases and cancer. Chem Biol. 2004;11: 1043–51.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Stegmeier F, Amon A. Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. Annu Rev Genet. 2004;38: 203–32.

    PubMed  Article  CAS  Google Scholar 

  46. 45.

    Mailand N, Lukas C, Kaiser BK, Jackson PK, Bartek J, Lukas J. Deregulated human Cdc14A phosphatase disrupts centrosome separation and chromosome segregation. Nat Cell Biol. 2002;4:317–322.

    PubMed  Article  CAS  Google Scholar 

  47. 46.

    Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science. 1999;286:971–4.

    PubMed  Article  CAS  Google Scholar 

  48. 47.

    Bergnes G, Brejc K, Belmont L. Mitotic kinesins: prospects for antimitotic drug discovery. Curr Top Med Chem. 2005;5:127–45.

    PubMed  Article  CAS  Google Scholar 

  49. 48.

    Duhl DM, Renhowe PA. Inhibitors of kinesin motor proteins-research and clinical progress. Curr Opin Drug Discov Devel. 2005;8:431–6.

    PubMed  CAS  Google Scholar 

  50. 49.

    Carleton M, Mao M, Biery M, et al. RNA interference-mediated silencing of mitotic kinesin KIF14 disrupts cell cycle progression and induced cytokinesis failure. Mol Cell Biol. 2006;26:3853–63.

    PubMed  Article  CAS  Google Scholar 

  51. 50.

    Malumbres M. Revisiting the “Cdk-centric” view of the mammalian cell cycle. Cell Cycle. 2005;4:206–10.

    PubMed  CAS  Google Scholar 

  52. 51.

    Sotillo R, Renner O, Dubus P, et al. Cooperation between Cdk4 and p27Kip1 in Tumor Development: a Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity. Cancer Res. 2005;65:3846–52.

    PubMed  Article  CAS  Google Scholar 

  53. 52.

    Weaver BA, Cleveland DW. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell. 2005;8:7–12.

    PubMed  Article  CAS  Google Scholar 

  54. 53.

    Eggert US, Kiger AA, Richter C, et al. Parallel chemical genetic and genomewide RNAi screens identify cytokinesis inhibitors and targets. PLoS Biol. 2004;2: 2135–43.

    Article  CAS  Google Scholar 

  55. 54.

    Toogood PL. Progress toward the development of agents to modulate the cell cycle. Curr Opin Chem Biol. 2002;6:472–8.

    PubMed  Article  CAS  Google Scholar 

  56. 55.

    Prevost GP, Brezak MC, Goubin F, et al. Inhibitors of the CDC25 phosphatases. Prog Cell Cycle Res. 2003;5:225–34.

    PubMed  Google Scholar 

  57. 56.

    Brezak MC, Quaranta M, Mondesert O, et al. A novel synthetic inhibitor of CDC25 phosphatases: BN82002. Cancer Res. 2004; 64:3320–5.

    PubMed  Article  CAS  Google Scholar 

  58. 57.

    Skoufias DA, Debonis S, Saoudi Y, et al. S-trityl-l-cysteine is a reversible, tight-binding inhibitor of the human kinesin eg5 that specifically blocks mitotic progression. J Biol Chem. 2006 [J. Biol. Chem, 10.1074/jbc.M511735200].

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Marcos Malumbres.

Additional information

Supported by an unrestricted educational grant from Pfizer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Malumbres, M. Therapeutic opportunities to control tumor cell cycles. Clin Transl Oncol 8, 399–408 (2006). https://doi.org/10.1007/s12094-006-0193-7

Download citation

Key words

  • cyclin-dependent kinases
  • Aurora
  • Polo
  • phosphatases
  • kinesins
  • cell cycle
  • genomic instability
  • cancer therapy