LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: Elsevier
Languages: English
Types: Article
Subjects: RC, R, RC0254
OBJECTIVE\ud \ud Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536.\ud \ud MATERIALS AND METHODS\ud \ud We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents.\ud \ud RESULTS\ud \ud We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G(2)/M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells.\ud \ud CONCLUSIONS\ud \ud Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Takaki T, Trenz K, Costanzo V, Petronczki M. Polo-like kinase 1 reaches beyond mitosisdcytokinesis, DNA damage response, and development. Curr Opin Cell Biol. 2008;20:650-660.
    • 2. Ikezoe T, Yang J, Nishioka C, et al. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies. Leukemia. 2009;23:1564-1576.
    • 3. Renner A, Dos Santos C, Recher C, et al. Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells. Blood. 2009;114:659-662.
    • 4. Steegmaier M, Hoffmann M, Baum A, et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 2007;17:316-322.
    • 5. Ramasamy K, Khatun H, Macpherson L, Mufti GJ, Schey S, Calle Y. Direct effect on the stroma by the conventional anti-multiple myeloma drug dexamethasone results in resistance of multiple myeloma plasma cells against therapy. Sensitisation to dexamethasone by the kinase inhibitor dasatinib. American Society of Haematology Annual Scientific Meeting, Abstract 193, December 2010.
    • 6. Stewart HJ, Guildford AL, Lawrence-Watt DJ, Santin M. Substrateinduced phenotypical change of monocytes/macrophages into myofibroblast-like cells: a new insight into the mechanism of instent restenosis. J Biomed Mater Res A. 2009;90:465-471.
    • 7. Tategu M, Nakagawa H, Sasaki K, et al. Transcriptional regulation of human polo-like kinases and early mitotic inhibitor. J Genet Genom. 2008;35:215-224.
    • 8. Dezorella N, Pevsner-Fischer M, Deutsch V, et al. Mesenchymal stromal cells revert multiple myeloma cells to less differentiated phenotype by the combined activities of adhesive interactions and interleukin-6. Exp Cell Res. 2009;315:1904-1913.
    • 9. Poder K, Chauhan D, Anderson KC. Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia. 2009;23:10-24.
    • 10. Strebhardt K. Multifaceted polo-like kinases drug targets and antitargets for cancer therapy. Nat Rev Drug Discov. 2010;9:643-660.
    • 11. Scho€ffski P. Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology. Oncologist. 2009;14:559-570.
    • 12. Winkless J, Alberts G. Differential regulation of polo-like kinases 1,2,3 and 4 gene expression in mammalian cells and tissues. Oncogene. 2005;24:260-266.
    • 13. Zimmerman W, Erikson R. Polo-like kinase 3 is required for entry into S phase. Proc Natl Acad Sci U S A. 2007;104:1847-1852.
    • 14. Dai W, Liu T, Wang Q, Rao CV, Reddy BS. Down-regulation of PLK3 gene expression by types and amount of dietary fat in rat colon tumors. Int J Oncol. 2002;20:121-126.
    • 15. Habedanck R, Stierhof YD, Wilkinson CJ, Nigg EA. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol. 2005;7: 1140-1146.
    • 16. Drewinko B, Alexanian R, Boyer H, Barlogie B, Rubinow SI. The growth fraction of human myeloma cells. Blood. 1981;57: 333-338.
    • 17. Sebastian M, Reck M, Waller CF, et al. The efficacy and safety of BI 2536, a novel Plk-1 inhibitor, in patients with stage IIIB/IV non-small cell lung cancer who had relapsed after, or failed, chemotherapy: results from an open-label, randomized phase II clinical trial. J Thorac Oncol. 2010;5:1060-1067.
    • 18. Lens SMA, Voest EE, Medema RH. Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer. 2010; 10:825-841.
    • 19. Fulda S. Caspase-8 in cancer biology and therapy. Cancer Lett. 2009; 281:128-133.
    • 20. Basak GW, Srivastava AS, Malhotra R, Carrier E. Multiple myeloma bone marrow niche. Curr Pharm Biotechnol. 2009;10:345-346.
    • 21. Meads MB, Hazlehurst LA, Dalton WS. The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res. 2008;14:2519-2526.
    • 22. Zhang XG, Klein B, Bataille R. Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma. Blood. 1989;74:11-13.
    • 23. Negri JM, McMillin DW, Delomore J, et al. In vitro anti-myeloma activity of the aurora kinase inhibitor VE-465. Br J Haematol. 2009; 147:672-676.
    • 24. Macurek L, Lindqvist A, Lim D, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 2008;455: 119-123.
    • 25. Shi Y, Reiman T, Li W, et al. Targeting aurora kinases as therapy in multiple myeloma. Blood. 2007;109:3915-3921.
    • 26. Chng WJ, Braggio E, Mulligan G, et al. The centrosome index is a powerful prognostic marker in myeloma and identifies a cohort of patients that might benefit from aurora kinase inhibition. Blood. 2008;111:1603-1609.
    • 27. Evans RP, Naber C, Steffler T, et al. The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma. Br J Haematol. 2008;140:295-302.
    • 28. Hose D, Reme T, Meissner T, et al. Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma. Blood. 2009; 113:4331-4340.
    • 29. Evans R, Naber C, Steffler T, et al. Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells. Leuk Lymphoma. 2008;49:559-569.
    • 30. Wang X, Sinn AL, Pollok K, et al. Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. Br J Haematol. 2010;150:313-325.
    • 31. Go€rgu€n G, Calabrese E, Hideshima T, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010;115:5202-5213.
    • 32. Chopra P, Sethi G, Dastidar SG, Ray A. Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics. Exp Opin Invest Drugs. 2010;19:27-43.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article