Advertisement

Tumor Biology

, Volume 36, Issue 3, pp 1797–1802 | Cite as

Alisertib (MLN8237), a selective Aurora-A kinase inhibitor, induces apoptosis in human tongue squamous cell carcinoma cell both in vitro and in vivo

Research Article

Abstract

Aurora-A kinases are overexpressed in many cancer tissues and cells. Alisertib is an investigational, orally administered, selective, small-molecule Aurora-A kinase inhibitor with preclinical activity against a broad range of tumors. Our study was aimed to detect the effects of alisertib on human tongue squamous cell carcinoma (HTSCC). Treatment of a human tongue squamous cell carcinoma cell line, HSC-3, with alisertib to inhibition of Aurora-A kinases reduced proliferation and induced apoptosis, which was accompanied by activation of the ATM/Chk2/p53 pathway. In vivo, inhibition of Aurora-A kinases in established xenografted tumors decreased tumor size and weight. Kaplan-Meyer survival analysis demonstrated that the cumulative survival time of mice without Aurora-A kinases was significantly longer than those with Aurora-A kinases. Our data provide the basis for developing alisertib to treat human tongue squamous cell carcinoma.

Keywords

Alisertib Aurora-A Proliferation Apoptosis Survival rate 

Notes

Acknowledgments

We appreciate the thoughtful advice of Yan Bai (China Medical University).

Conflict of interest

The authors declare no conflicts of interest

References

  1. 1.
    Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol. 2001;2:21–32.CrossRefPubMedGoogle Scholar
  2. 2.
    Keen N, Taylor S. Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer. 2004;4:927–36.CrossRefPubMedGoogle Scholar
  3. 3.
    Marumoto T, Zhang D, Saya H. Aurora-A a guardian of poles. Nat Rev Cancer. 2005;5:42–5.CrossRefPubMedGoogle Scholar
  4. 4.
    Tavanti E, Sero V, Vella S, Fanelli M, Michelacci F, Landuzzi L, et al. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma. Br J Cancer. 2013;109:2607–18.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Goos JA, Coupe VM, Diosdado B, Delis-Van Diemen PM, Karga C, Beliën JA, et al. Aurora kinase A (AURKA) expression in colorectal cancer liver metastasis is associated with poor prognosis. Br J Cancer. 2013;109:2445–2.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wang W, Zhang N, Wang J, Bu XM, Zhao CH. Inhibition of proliferation, viability, migration and invasion of gastric cancer cells by Aurora-A deletion. Asian Pac J Cancer Prev. 2011;12:2717–20.PubMedGoogle Scholar
  7. 7.
    Liu LL, Long ZJ, Wang LX, Zheng FM, Fang ZG, Yan M, et al. Inhibition of mTOR pathway sensitizes acute myeloid leukemia cells to aurora inhibitors by suppression of glycolytic metabolism. Mol Cancer Res. 2013;11:1326–36.CrossRefPubMedGoogle Scholar
  8. 8.
    Zou Z, Yuan Z, Zhang Q, Long Z, Chen J, Tang Z, et al. Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy. 2012;8:1798–810.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Chakravarty A, Shinde V, Tabernero J, Cervantes A, Cohen RB, Dees EC, et al. Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase. Cancer Res. 2011;71:675–85.CrossRefPubMedGoogle Scholar
  10. 10.
    Gorgun G, Calabrese E, Hideshima T, Ecsedy J, Perrone G, Mani M, et al. A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma. Blood. 2010;115:5202–13.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17:7614–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Kelly KR, Shea TC, Goy A, Berdeja JG, Reeder CB, McDonagh KT, et al. Phase I study of MLN8237-investigational Aurora A kinase inhibitor-in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs. 2013; [Epub ahead of print].Google Scholar
  13. 13.
    Friedberg JW, Mahadevan D, Cebula E, Persky D, Lossos I, Agarwal AB, et al. Phase II study of alisertib, a selective Aurora A kinase inhibitor, in relapsed and refractory aggressive B- and T-cell non-Hodgkin lymphomas. J Clin Oncol. 2004;32:44–50.CrossRefGoogle Scholar
  14. 14.
    Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18:4775–84.CrossRefPubMedGoogle Scholar
  15. 15.
    Qi W, Spier C, Liu X, Agarwal A, Cooke LS, Persky DO, et al. Alisertib (MLN8237) an investigational agent suppresses Aurora A and B activity, inhibits proliferation, promotes endo-reduplication and induces apoptosis in T-NHL cell lines supporting its importance in PTCL treatment. Leuk Res. 2013;37:434–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol. 2003;4:842–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Mortlock AA, Foote KM, Heron NM, Jung FH, Pasquet G, Lohmann JJ, et al. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. J Med Chem. 2007;50:2213–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Sardon T, Peset I, Petrova B, Vernos I. Dissecting the role of Aurora A during spindle assembly. EMBO J. 2008;27:2567–79.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kelly KR, Nawrocki ST, Espitia CM, Zhang M, Yang JJ, Padmanabhan S, et al. Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer. 2012;131:2693–703.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Meraldi P, Honda R, Nigg EA. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J. 2002;21:483–92.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Stracker TH, Usui T, Petrini JH. Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair (Amst). 2009;8:1047–54.CrossRefGoogle Scholar
  22. 22.
    Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999;283:1321–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Sun X, Liu B, Wang J, Li J, Ji WY. Inhibition of p21-activated kinase 4 expression suppresses the proliferation of Hep-2 laryngeal carcinoma cells via activation of the ATM/Chk1/2/p53 pathway. Int J Oncol. 2013;42:683–9.PubMedGoogle Scholar
  24. 24.
    Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet. 2004;36:55–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Sun H, Wang Y, Wang Z, Meng J, Qi Z, Yang G. Aurora-A controls cancer cell radio- and chemoresistance via ATM/Chk2-mediated DNA repair networks. Biochim Biophys Acta. 1843;2014:934–44.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Orthodontics, School of StomatologyChina Medical University; Liaoning Institute of Dental ResearchShenyangPeople’s Republic of China

Personalised recommendations