Skip to main content

Advertisement

SpringerLink
Log in

Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo

  • Original Article
  • Published:
Tumor Biology

Abstract

As the first member of glycylcycline bacteriostatic agents, tigecycline is approved as a novel expanded-spectrum antibiotic, which is clinically available. However, accumulating evidence indicated that tigecycline was provided with the potential application in cancer therapy. In this paper, tigecycline was shown to exert an anti-proliferative effect on neuroblastoma cell lines. Furthermore, it was found that tigecycline induced G1-phase cell cycle arrest instead of apoptosis by means of Akt pathway inhibition. In neuroblastoma cell lines, the Akt activator insulin-like growth factor-1 (hereafter referred to as IGF-1) reversed tigecycline-induced cell cycle arrest. Besides, tigecycline inhibited colony formation and suppressed neuroblastoma cells xenograft formation and growth. After tigecycline treatment in vivo, the Akt pathway inhibition was confirmed as well. Collectively, our data provided strong evidences that tigecycline inhibited neuroblastoma cells growth and proliferation through the Akt pathway inhibition in vitro and in vivo. In addition, these results were supported by previous studies concerning the application of tigecycline in human tumors treatment, suggesting that tigecycline might act as a potential candidate agent for neuroblastoma treatment.

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

Similar content being viewed by others

References

  1. Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003;8:278–92.

    Article  PubMed  Google Scholar 

  2. Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3:203–16.

    Article  CAS  PubMed  Google Scholar 

  3. Schleiermacher G, Janoueix-Lerosey I, Delattre O. Recent insights into the biology of neuroblastoma. Int J Cancer. 2014;135:2249–61.

    Article  CAS  PubMed  Google Scholar 

  4. Maris JM. Medical progress: recent advances in neuroblastoma. N Engl J Med. 2010;362:2202–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Castel V, Grau E, Noguera R, Martinez F. Molecular biology of neuroblastoma. Clin Transl Oncol. 2007;9:478–83.

    Article  CAS  PubMed  Google Scholar 

  6. Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob Chemother. 2005;56:611–4.

    Article  CAS  PubMed  Google Scholar 

  7. Nakazato A, Ohta K, Sekiguchi Y, Okuyama S, Chaki S, Kawashima Y, et al. Design, synthesis, structure-activity relationships, and biological characterization of novel arylalkoxyphenylalkylamine σ ligands as potential antipsychotic drugs. J Med Chem. 1999;42:1076–87.

    Article  CAS  PubMed  Google Scholar 

  8. Petersen PJ, Jacobus N, Weiss W, Sum P, Testa R. In vitro and in vivo antibacterial activities of a novel glycylcycline, the 9-t-butylglycylamido derivative of minocycline (gar-936). Antimicrob Agents Chemother. 1999;43:738–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bergeron J, Ammirati M, Danley D, James L, Norcia M, Retsema J, et al. Glycylcyclines bind to the high-affinity tetracycline ribosomal binding site and evade tet(m)- and tet(o)-mediated ribosomal protection. Antimicrob Agents Chemother. 1996;40:2226–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lamb R, Ozsvari B, Lisanti CL, Tanowitz HB, Howell A, Martinez-Outschoorn UE, et al. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease. Oncotarget. 2015;6:4569–84.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chen Z, Wang Y, Liu W, Zhao G, Lee S, Balogh A, et al. Doxycycline inducible Kruppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells. PLoS One. 2014;9:e105331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu W-T, Lin C-H, Hsiao M, Gean P-W. Minocycline inhibits the growth of glioma by inducing autophagy. Autophagy. 2011;7:166–75.

    Article  CAS  PubMed  Google Scholar 

  13. Tang C, Yang L, Jiang X, Xu C, Wang M, Wang Q, et al. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells. Biochem Biophys Res Commun. 2014;446:105–12.

    Article  CAS  PubMed  Google Scholar 

  14. Li H, Jiao S, Li X, Banu H, Hamal S, Wang X. Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting wnt/beta-catenin signaling. Biochem Biophys Res Commun. 2015;467:14–20.

    Article  CAS  PubMed  Google Scholar 

  15. Bucaneve G, Micozzi A, Picardi M, Ballanti S, Cascavilla N, Salutari P, et al. Results of a multicenter, controlled, randomized clinical trial evaluating the combination of piperacillin/tazobactam and tigecycline in high-risk hematologic patients with cancer with febrile neutropenia. J Clin Oncol : Off J Am Soc Clin Oncol. 2014;32:1463–71.

    Article  CAS  Google Scholar 

  16. Opel D, Poremba C, Simon T, Debatin K-M, Fulda S. Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res. 2007;67:735–45.

    Article  CAS  PubMed  Google Scholar 

  17. West KA, Sianna Castillo S, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002;5:234–48.

    Article  CAS  PubMed  Google Scholar 

  18. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell. 1999;96:857–68.

    Article  CAS  PubMed  Google Scholar 

  19. Greer EL, Brunet A. Foxo transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.

    Article  CAS  PubMed  Google Scholar 

  20. Guo L, Xie B, Mao Z. Autophagy in premature senescent cells is activated via AMPK pathway. Int J Mol Sci. 2012;13:3563–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. de Mattos SF, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS, et al. Foxo3a and bcr-abl regulate cyclin d2 transcription through a stat5/bcl6-dependent mechanism. Mol Cell Biol. 2004;24:10058–71.

    Article  CAS  Google Scholar 

  22. Essafi A, Fernandez de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene. 2005;24:2317–29.

    Article  CAS  PubMed  Google Scholar 

  23. Besson A, Dowdy SF, Roberts JM. Cdk inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–69.

    Article  CAS  PubMed  Google Scholar 

  24. Kurihara S, Hakuno F. Takahashi S-i: insulin-like growth factor-i-dependent signal transduction pathways leading to the induction of cell growth and differentiation of human neuroblastoma cell line sh-sy5y: the roles of map kinase pathway and pi 3-kinase pathway. Endocr J. 2000;47:739–51.

    Article  CAS  PubMed  Google Scholar 

  25. Yan X, Ke XX, Zhao H, Huang M, Hu R, Cui H. Triptolide inhibits cell proliferation and tumorigenicity of human neuroblastoma cells. Mol Med Rep. 2015;11:791–6.

    CAS  PubMed  Google Scholar 

  26. Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis. 2005;41:S303–14.

    Article  CAS  PubMed  Google Scholar 

  27. Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol. 2011;7:1459–70.

    Article  CAS  PubMed  Google Scholar 

  28. Jitkova Y, Gronda M, Hurren R, Wang X, Goard CA, Jhas B, et al. A novel formulation of tigecycline has enhanced stability and sustained antibacterial and antileukemic activity. PLoS One. 2014;9:e95281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Garcia Z, Kumar A, Marques M, Cortes I, Carrera AC. Phosphoinositide 3-kinase controls early and late events in mammalian cell division. EMBO J. 2006;25:655–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.

    Article  CAS  PubMed  Google Scholar 

  31. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17:590–603.

    Article  CAS  PubMed  Google Scholar 

  32. Fekete M, Santiskulvong C, Eng C, Dorigo O. Effect of PI3K/Akt pathway inhibition-mediated g1 arrest on chemosensitization in ovarian cancer cells. Anticancer Res. 2012;32:445–52.

    CAS  PubMed  Google Scholar 

  33. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol : CB. 1997;7:261–9.

    Article  CAS  PubMed  Google Scholar 

  34. Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J. 2000;346:561–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.

    Article  CAS  PubMed  Google Scholar 

  36. Vincent EE, Elder DJ, Thomas EC, Phillips L, Morgan C, Pawade J, et al. Akt phosphorylation on Thr308 but not on Ser473 correlates with Akt protein kinase activity in human non-small cell lung cancer. Br J Cancer. 2011;104:1755–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng WH, Quirion R. Insulin-like growth factor-1 (igf-1) induces the activation/phosphorylation of Akt kinase and camp response element-binding protein (CREB) by activating different signaling pathways in pc12 cells. BMC Neurosci. 2006;7:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Basic Research Program of China (No. 2012cb114603), National Nature Science Foundation of China (81201551), and the Fundamental Research Funds for the central universities (swu111014).

Author information

Author notes

  1. Juan Tan

    Present address: Institute of Pathology and Southwest Cancer Centre, Southwest Hospital, Third Military Medical University, Chongqing, China

Authors and Affiliations

  1. State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China

    Xiaoxia Zhong, Erhu Zhao, Chunling Tang, Weibo Zhang, Juan Tan, Zhen Dong & Hongjuan Cui

  2. Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA, 30912, USA

    Han-Fei Ding

Authors
  1. Xiaoxia Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erhu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunling Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weibo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juan Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhen Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Han-Fei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongjuan Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongjuan Cui.

Ethics declarations

Conflicts of interest

None.

Additional information

Xiaoxia Zhong and Erhu Zhao contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplemental Fig. 1

IGF-1 rescued cell cycle arrest induced by tigecycline treatment. Cell cycle was analyzed by FACS assay. BE2C and SK-N-AS cells were pretreated with 10 μM tigecycline for 48 h. After this, the cells were treated with 10nM IGF-1 for the indicated time. BE2C and SK-N-AS cells were harvested, fixed with 75 % ethanol, stained with PI, and analyzed by FACS assay. DMSO was used as a control.

High resolution image.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhong, X., Zhao, E., Tang, C. et al. Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo. Tumor Biol. 37, 7615–7623 (2016). https://doi.org/10.1007/s13277-015-4613-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4613-6

Keywords

Search

Navigation