Skip to main content

Advertisement

SpringerLink
Log in

AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy

  • Research Article
  • Published:
Tumor Biology

Abstract

Prostate cancer is the frequent non-cutaneous tumor with high mortality in men. Prostate tumors contain cells with different status of androgen receptor. Androgen receptor plays important roles in progression and treatment of prostate cancer. Aurora B kinase, with oncogenic potential, is involved in chromosome segregation and cytokinesis, and its inhibition is a promising anti-cancer therapy. In the present study, we aimed to investigate the effects of Aurora B inhibitor, AZD1152-HQPA, on survival and proliferation of androgen receptor (AR)-positive prostate cancer cells. LNCaP was used as androgen-dependent prostate cancer cell line. We explored the effects of AZD1152-HQPA on cell viability, DNA content, micronuclei formation, and expression of genes involved in apoptosis and cell cycle. Moreover, the expression of Aurora B and AR were investigated in 23 benign prostatic hyperplasia and 38 prostate cancer specimens. AZD1152-HQPA treatment induced defective cell survival, polyploidy, and cell death in LNCaP cell line. Centromeric labeling with fluorescence in situ hybridization (FISH) showed that the loss of whole chromosomes is the origin of micronuclei, indicating on aneugenic action of AZD1152-HQPA. Treatment of AZD1152-HQPA decreased expression of AR. Moreover, we found weak positive correlations between the expression of Aurora B and AR in both benign prostatic hyperplasia and prostate cancer specimens (r = 0.25, r = 0.41). This is the first time to show that AZD1152-HQPA can be a useful therapeutic strategy for the treatment of androgen-dependent prostate cancer cell line. AZD1152-HQPA induces aneugenic mechanism of micronuclei production. Taken together, this study provides new insight into the direction to overcome the therapeutic impediments against prostate cancer.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Cotton P. Case for prostate therapy wanes despite more treatment options. JAMA. 1991;266(4):459–60.

    Article  CAS  PubMed  Google Scholar 

  2. Greenlee RT et al. Cancer statistics, 2000. CA Cancer J Clin. 2000;50(1):7–33.

    Article  CAS  PubMed  Google Scholar 

  3. Jemal A et al. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.

    Article  PubMed  Google Scholar 

  4. Loblaw DA et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596–605.

    Article  CAS  PubMed  Google Scholar 

  5. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276–308.

    Article  CAS  PubMed  Google Scholar 

  6. Pagliarulo V et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol. 2012;61(1):11–25.

    Article  CAS  PubMed  Google Scholar 

  7. Henshall SM et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res. 2001;61(2):423–7.

    CAS  PubMed  Google Scholar 

  8. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1(1):34–45.

    Article  CAS  PubMed  Google Scholar 

  9. Hsu JY et al. Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell. 2000;102(3):279–91.

    Article  CAS  PubMed  Google Scholar 

  10. Bischoff JR et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. Embo J. 1998;17(11):3052–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lee EC et al. Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res. 2006;66(10):4996–5002.

    Article  CAS  PubMed  Google Scholar 

  12. Li D et al. Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res. 2003;9(3):991–7.

    CAS  PubMed  Google Scholar 

  13. Wilkinson RW et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007;13(12):3682–8.

    Article  CAS  PubMed  Google Scholar 

  14. Mortlock AA 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(9):2213–24.

    Article  CAS  PubMed  Google Scholar 

  15. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205–19.

    Article  CAS  PubMed  Google Scholar 

  16. Taylor WR et al. Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell. 1999;10(11):3607–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Boss DS et al. Clinical evaluation of AZD1152, an i.v. inhibitor of Aurora B kinase, in patients with solid malignant tumors. Ann Oncol. 2011;22(2):431–7.

    Article  CAS  PubMed  Google Scholar 

  18. Dennis M et al. Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol. 2012;70(3):461–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schwartz GK et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs. 2012;31(2):370–80. doi:10.1007/s10637-012-9825-7.

  20. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–8.

    Article  CAS  PubMed  Google Scholar 

  21. Niermann KJ et al. Enhanced radiosensitivity of androgen-resistant prostate cancer: AZD1152-mediated Aurora kinase B inhibition. Radiat Res. 2011;175(4):444–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang J et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007;110(6):2034–40.

    Article  CAS  PubMed  Google Scholar 

  23. Gully CP et al. Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer. 2010;9:42.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Stokes MP et al. Profiling of UV-induced ATM/ATR signaling pathways. Proc Natl Acad Sci U S A. 2007;104(50):19855–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Melino G, De Laurenzi V, Vousden KH. p73: friend or foe in tumorigenesis. Nat Rev Cancer. 2002;2(8):605–15.

    Article  CAS  PubMed  Google Scholar 

  26. Stros M et al. HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J Biol Chem. 2002;277(9):7157–64.

    Article  CAS  PubMed  Google Scholar 

  27. Macleod KF et al. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995;9(8):935–44.

    Article  CAS  PubMed  Google Scholar 

  28. Mirzayans R et al. New insights into p53 signaling and cancer cell response to DNA damage: implications for cancer therapy. J BioMed Biotechnol. 2012;2012:170325.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Godfrey B et al. Proteasomal degradation unleashes the pro-death activity of androgen receptor. Cell Res. 2010;20(10):1138–47.

    Article  CAS  PubMed  Google Scholar 

  30. Frezza M, Yang H, Dou QP. Modulation of the tumor cell death pathway by androgen receptor in response to cytotoxic stimuli. J Cell Physiol. 2011;226(11):2731–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu S et al. Androgen regulation of the cyclin-dependent kinase inhibitor p21 gene through an androgen response element in the proximal promoter. Mol Endocrinol. 1999;13(3):376–84.

    Article  CAS  PubMed  Google Scholar 

  32. Lu S, Tsai SY, Tsai MJ. Regulation of androgen-dependent prostatic cancer cell growth: androgen regulation of CDK2, CDK4, and CKI p16 genes. Cancer Res. 1997;57(20):4511–6.

    CAS  PubMed  Google Scholar 

  33. Lilly MA, Duronio RJ. New insights into cell cycle control from the Drosophila endocycle. Oncogene. 2005;24(17):2765–75.

    Article  CAS  PubMed  Google Scholar 

  34. Zhong W et al. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA-replication licensing. Nature. 2003;423(6942):885–9.

    Article  CAS  PubMed  Google Scholar 

  35. Nagata Y, Muro Y, Todokoro K. Thrombopoietin-induced polyploidization of bone marrow megakaryocytes is due to a unique regulatory mechanism in late mitosis. J Cell Biol. 1997;139(2):449–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vlaming ML, Lagas JS, Schinkel AH. Physiological and pharmacological roles of ABCG2 (BCRP): recent findings in Abcg2 knockout mice. Adv Drug Deliv Rev. 2009;61(1):14–25.

    Article  CAS  PubMed  Google Scholar 

  37. Marchetti S et al. Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA. Investig New Drugs. 2013;31(5):1125–35.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We sincerely thank AstraZeneca pharmaceutical company for providing AZD1152-HQPA. This study was supported by Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran

    Ali Zekri, Arash Salmaninejad & Mohammad H. Modarressi

  2. Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Seyed H. Ghaffari, Samad Ghanizadeh-Vesali, Marjan Yaghmaie, Kamran Alimoghaddam & Ardeshir Ghavamzadeh

Authors
  1. Ali Zekri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seyed H. Ghaffari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samad Ghanizadeh-Vesali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marjan Yaghmaie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arash Salmaninejad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kamran Alimoghaddam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mohammad H. Modarressi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ardeshir Ghavamzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Seyed H. Ghaffari or Mohammad H. Modarressi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zekri, A., Ghaffari, S.H., Ghanizadeh-Vesali, S. et al. AZD1152-HQPA induces growth arrest and apoptosis in androgen-dependent prostate cancer cell line (LNCaP) via producing aneugenic micronuclei and polyploidy. Tumor Biol. 36, 623–632 (2015). https://doi.org/10.1007/s13277-014-2664-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2664-8

Keywords

Search

Navigation