Skip to main content

Advertisement

SpringerLink
Log in

Induction of G1 Cell Cycle Arrest in Human Glioma Cells by Salinomycin Through Triggering ROS-Mediated DNA Damage In Vitro and In Vivo

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Chemotherapy has always been one of the most effective ways in combating human glioma. However, the high metastatic potential and resistance toward standard chemotherapy severely hindered the chemotherapy outcomes. Hence, searching effective chemotherapy drugs and clarifying its mechanism are of great significance. Salinomycin an antibiotic shows novel anticancer potential against several human tumors, including human glioma, but its mechanism against human glioma cells has not been fully elucidated. In the present study, we demonstrated that salinomycin treatment time- and dose-dependently inhibited U251 and U87 cells growth. Mechanically, salinomycin-induced cell growth inhibition against human glioma was mainly achieved by induction of G1-phase arrest via triggering reactive oxide species (ROS)-mediated DNA damage, as convinced by the activation of histone, p53, p21 and p27. Furthermore, inhibition of ROS accumulation effectively attenuated salinomycin-induced DNA damage and G1 cell cycle arrest, and eventually reversed salinomycin-induced cytotoxicity. Importantly, salinomycin treatment also significantly inhibited the U251 tumor xenograft growth in vivo through triggering DNA damage-mediated cell cycle arrest with involvement of inhibiting cell proliferation and angiogenesis. The results above validated the potential of salinomycin-based chemotherapy against human glioma.

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. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  2. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  3. Niu CS, Li DX, Liu YH, Fu XM, Tang SF, Li J (2011) Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells. Oncol Rer 26(3):593–601

    CAS  Google Scholar 

  4. Aghi MK, Nahed BV, Sloan AE, Ryken TC, Kalkanis SN, Olson JJ (2015) The role of surgery in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 125:503–530

    Article  PubMed  Google Scholar 

  5. Ryken TC, Parney I, Buatti J, Kalkanis SN, Olson JJ (2015) The role of radiotherapy in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol 125:551–583

    Article  CAS  PubMed  Google Scholar 

  6. Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L (2005) The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 63:47–55

    Article  PubMed  Google Scholar 

  7. Bourkoula E, Mangoni D, Ius T, Pucer A, Isola M, Musiello D, Marzinotto S, Toffoletto B, Sorrentino M, Palma A (2014) Glioma-associated stem cells: a novel class of tumor-supporting cells able to predict prognosis of human low-grade gliomas. Stem Cells 32:1239–1253

    Article  CAS  PubMed  Google Scholar 

  8. Mitani M, Yamanishi T, Miyazaki Y (1975) Salinomycin: a new monovalent cation ionophore. Biochem Biophys Res Commun 66:1231–1236

    Article  CAS  PubMed  Google Scholar 

  9. Butaye P, Devriese LA, Haesebrouck F (2003) Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin Microbiol Rev 16:175–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miyazaki Y, Shibuya M, Sugawara H, Kawaguchi O, Hirsoe C (1974) Salinomycin, a new polyether antibiotic. J Antibiot (Tokyo) 27:814–821

    Article  CAS  Google Scholar 

  11. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138:645–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schenk M, Aykut B, Teske C, Giese NA, Weitz J, Welsch T (2015) Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity. Cancer Lett 358:161–169

    Article  CAS  PubMed  Google Scholar 

  13. Zhang B, Wang X, Cai F, Chen W, Loesch U, Bitzer J, Zhong XY (2012) Effects of salinomycin on human ovarian cancer cell line OV2008 are associated with modulating p38 MAPK. Tumour Biol 33:1855–1862

    Article  CAS  PubMed  Google Scholar 

  14. Zhi QM, Chen XH, Ji J, Zhang JN, Li JF, Cai Q, Liu BY, Gu QL, Zhu ZG, Yu YY (2011) Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer. Biomed Pharmacother 65:509–515

    Article  CAS  PubMed  Google Scholar 

  15. Al DY, Attoub S, Arafat K, Abuqamar S, Eid A, Al FN, Iratni R (2013) Salinomycin induces apoptosis and senescence in breast cancer: upregulation of p21, downregulation of survivin and histone H3 and H4 hyperacetylation. Biochim Biophys Acta 1830:3121–3135

    Article  Google Scholar 

  16. Yu SM, Kim SJ (2016) Salinomycin causes migration and invasion of human fibrosarcoma cells by inducing MMP-2 expression via PI3-kinase, ERK-1/2 and p38 kinase pathways. Int J Oncol 48:2686–2692

    CAS  PubMed  Google Scholar 

  17. Xipell E, Gonzalez-Huarriz M, de Irujo JJ, Garcia-Garzon A, Lang FF, Jiang H, Fueyo J, Gomez-Manzano C, Alonso MM (2016) Salinomycin induced ROS results in abortive autophagy and leads to regulated necrosis in glioblastoma. Oncotarget 7:30626–30641

    PubMed  PubMed Central  Google Scholar 

  18. Chen T, Yi L, Li F, Hu R, Hu SL, Yin Y, Lan C, Li Z, Fu CH, Cao L, Chen Z, Xian JH, Feng H (2015) Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells. Mol Med Rep 11:2407–2412

    CAS  PubMed  Google Scholar 

  19. Qin LS, Jia PF, Zhang ZQ, Zhang SM (2015) ROS-p53-cyclophilin-D signaling mediates salinomycin-induced glioma cell necrosis. J Exp Clin Cancer Res 34:57

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lu D, Carson DA (2011) Inhibition of Wnt signaling and cancer stem cells. Oncotarget 2:587

    PubMed  PubMed Central  Google Scholar 

  21. Li T, Liu X, Shen Q, Yang W, Huo Z, Liu Q, Jiao H, Chen J (2016) Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis. Oncotarget 7:26580–26592

    PubMed  PubMed Central  Google Scholar 

  22. Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C (2009) Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun 390:743–749

    Article  CAS  PubMed  Google Scholar 

  23. Jangamreddy JR, Ghavami S, Grabarek J, Kratz G, Wiechec E, Fredriksson BA, Rao PR, Cieslar-Pobuda A, Panigrahi S, Los MJ (2013) Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells. Biochim Biophys Acta 1833:2057–2069

    Article  CAS  PubMed  Google Scholar 

  24. Wang K, Fu XT, Li Y, Hou YJ, Yang MF, Sun JY, Yi SY, Fan CD, Fu XY, Zhai J, Sun BL (2016) Induction of S-phase arrest in human glioma cells by selenocystine, a natural selenium-containing agent via triggering reactive oxygen species-mediated DNA damage and modulating MAPKs and AKT pathways. Neurochem Res 41:1439–1447

    Article  CAS  PubMed  Google Scholar 

  25. Abudayyak M, Gurkaynak TA, Özhan G (2016) In vitro toxicological assessment of cobalt ferrite nanoparticles in several mammalian cell types. Biol Trace Elem Res. doi:10.1007/s12011-016-0803-3

    Google Scholar 

  26. Fu XY, Zhang S, Wang K, Yang MF, Fan CD, Sun BL (2015) Caudatin inhibits human glioma cells growth through triggering DNA damage-mediated cell cycle arrest. Cell Mol Neurobiol 35:953–959

    Article  CAS  PubMed  Google Scholar 

  27. Fan C, Zheng W, Fu X, Li X, Wong YS, Chen T (2014) Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. Cell Death Dis 5:e1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fan C, Zheng W, Fu X, Li X, Wong YS, Chen T (2014) Strategy to enhance the therapeutic effect of doxorubicin in human hepatocellular carcinoma by selenocystine, a synergistic agent that regulates the ROS-mediated signaling. Oncotarget 5:2853–2863

    Article  PubMed  PubMed Central  Google Scholar 

  29. Zhu LZ, Hou YJ, Zhao M, Yang MF, Fu XT, Sun JY, Fu XY, Shao LR, Zhang HF, Fan CD, Gao HL, Sun BL (2016) Caudatin induces caspase-dependent apoptosis in human glioma cells with involvement of mitochondrial dysfunction and reactive oxygen species generation. Cell Mol Toxicol 32:333–345

    Article  CAS  Google Scholar 

  30. Verdoodt B, Vogt M, Schmitz I, Liffers ST, Tannapfel A, Mirmohammadsadegh A (2012) Salinomycin induces autophagy in colon and breast cancer cells with concomitant generation of reactive oxygen species. PloS One 7:e44132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chinni SR, Li Y, Upadhyay S, Koppolu PK, Sarkar FH (2001) Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells. Oncogene 20:2927–2936

    Article  CAS  PubMed  Google Scholar 

  32. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, Thor AD (2009) Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle 8:909–915

    Article  CAS  PubMed  Google Scholar 

  33. Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 7:812–821

    Article  CAS  PubMed  Google Scholar 

  34. Tian HL, Yu T, Xu NN, Feng C, Zhou LY, Luo HW, Chang DC, Le XF, Luo KQ (2010) A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway. Cancer Lett 297:18–30

    Article  CAS  PubMed  Google Scholar 

  35. Kim BM, Choi YJ, Lee YH, Joe YA, Hong SH (2010) N,N-dimethyl phytosphingosine sensitizes HL-60/MX2, a multidrug-resistant variant of HL-60 cells, to doxorubicin-induced cytotoxicity through ROS-mediated release of cytochrome c and AIF. Apoptosis 15:982–993

    Article  CAS  PubMed  Google Scholar 

  36. Bennett MR (2001) Reactive oxygen species and death: oxidative DNA damage in atherosclerosis. Circ Res 88:648–650

    Article  CAS  PubMed  Google Scholar 

  37. Kim JH, Chae M, Kim WK, Kim YJ, Kang HS, Kim HS, Yoon S (2011) Salinomycin sensitizes cancer cells to the effects of doxorubicin and etoposide treatment by increasing DNA damage and reducing p21 protein. Br J Pharmacol 162:773–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Boehmerle W, Muenzfeld Hanna, Springer A, Huehnchen P, Endres M (2014) Specific targeting of neurotoxic side effects and pharmacological profile of the novel cancer stem cell drug salinomycin in mice. J Mol Med 92:889–900

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by Key Research and Development Program of Shandong No. 2016GSF202036 to C.-D. Fan and No. 2015GSF119023 to J. Zhai. Natural Science Foundation of Shandong No. ZR2015HL050 to D.-W. Li and ZR2011HL046 to J. Zhai.

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurology, Shandong University School of Medicine, Jinan, Shandong, 250012, China

      Shi-Jun Zhao

    2. Taishan Medical University, Taian, Shandong, 271000, China

      Shi-Jun Zhao, Qing-Jian Wu, Chao Liu, Da-Wei Li, Xiao-Ting Fu, Hui-Fang Zhang, Lu-Rong Shao, Jing-Yi Sun, Bao-Liang Sun, Jing Zhai & Cun-Dong Fan

    3. Department of Neurology, Baotou Central Hospital, Baotou, Inner Mongolia, 014040, China

      Shi-Jun Zhao

    4. Department of Neurology, Linyi People’s Hospital, Linyi, Shandong, 276000, China

      Xian-Jun Wang

    Authors
    1. Shi-Jun Zhao
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Xian-Jun Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Qing-Jian Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Chao Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Da-Wei Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Xiao-Ting Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hui-Fang Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Lu-Rong Shao
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Jing-Yi Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Bao-Liang Sun
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Jing Zhai
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Cun-Dong Fan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Bao-Liang Sun, Jing Zhai or Cun-Dong Fan.

    Ethics declarations

    Conflict of interest

    The authors declare that there is no conflict of interest for all the authors.

    Additional information

    S.-J. Zhao and X.-J. Wang have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhao, SJ., Wang, XJ., Wu, QJ. et al. Induction of G1 Cell Cycle Arrest in Human Glioma Cells by Salinomycin Through Triggering ROS-Mediated DNA Damage In Vitro and In Vivo. Neurochem Res 42, 997–1005 (2017). https://doi.org/10.1007/s11064-016-2132-5

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11064-016-2132-5

    Keywords

    Search

    Navigation