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Published in: Tumor Biology 6/2016

01-06-2016 | Original Article

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

Authors: Xiaoxia Zhong, Erhu Zhao, Chunling Tang, Weibo Zhang, Juan Tan, Zhen Dong, Han-Fei Ding, Hongjuan Cui

Published in: Tumor Biology | Issue 6/2016

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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.
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Literature
1.
go back to reference Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003;8:278–92.CrossRefPubMed Weinstein JL, Katzenstein HM, Cohn SL. Advances in the diagnosis and treatment of neuroblastoma. Oncologist. 2003;8:278–92.CrossRefPubMed
2.
go back to reference Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3:203–16.CrossRefPubMed Brodeur GM. Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer. 2003;3:203–16.CrossRefPubMed
3.
go back to reference Schleiermacher G, Janoueix-Lerosey I, Delattre O. Recent insights into the biology of neuroblastoma. Int J Cancer. 2014;135:2249–61.CrossRefPubMed Schleiermacher G, Janoueix-Lerosey I, Delattre O. Recent insights into the biology of neuroblastoma. Int J Cancer. 2014;135:2249–61.CrossRefPubMed
5.
go back to reference Castel V, Grau E, Noguera R, Martinez F. Molecular biology of neuroblastoma. Clin Transl Oncol. 2007;9:478–83.CrossRefPubMed Castel V, Grau E, Noguera R, Martinez F. Molecular biology of neuroblastoma. Clin Transl Oncol. 2007;9:478–83.CrossRefPubMed
6.
go back to reference Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob Chemother. 2005;56:611–4.CrossRefPubMed Livermore DM. Tigecycline: what is it, and where should it be used? J Antimicrob Chemother. 2005;56:611–4.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
9.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
10.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
11.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
12.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRef 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.CrossRef
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference West KA, Sianna Castillo S, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002;5:234–48.CrossRefPubMed West KA, Sianna Castillo S, Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 2002;5:234–48.CrossRefPubMed
18.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
19.
go back to reference Greer EL, Brunet A. Foxo transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.CrossRefPubMed Greer EL, Brunet A. Foxo transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.CrossRefPubMed
21.
go back to reference 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.CrossRef 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.CrossRef
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference Besson A, Dowdy SF, Roberts JM. Cdk inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–69.CrossRefPubMed Besson A, Dowdy SF, Roberts JM. Cdk inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14:159–69.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.PubMed 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.PubMed
26.
go back to reference Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis. 2005;41:S303–14.CrossRefPubMed Noskin GA. Tigecycline: a new glycylcycline for treatment of serious infections. Clin Infect Dis. 2005;41:S303–14.CrossRefPubMed
27.
go back to reference Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol. 2011;7:1459–70.CrossRefPubMed Giamarellou H, Poulakou G. Pharmacokinetic and pharmacodynamic evaluation of tigecycline. Expert Opin Drug Metab Toxicol. 2011;7:1459–70.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
29.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
30.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
31.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
32.
go back to reference 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.PubMed 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.PubMed
33.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
34.
35.
go back to reference Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.CrossRefPubMed Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
37.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
Metadata
Title
Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo
Authors
Xiaoxia Zhong
Erhu Zhao
Chunling Tang
Weibo Zhang
Juan Tan
Zhen Dong
Han-Fei Ding
Hongjuan Cui
Publication date
01-06-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 6/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-4613-6

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