Skip to main content

Advertisement

SpringerLink
Log in

Bexarotene inhibits cell proliferation by inducing oxidative stress, DNA damage and apoptosis via PPARγ/ NF-κB signaling pathway in C6 glioma cells

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Gliomas are one of the most aggressive brain tumors with a poor prognosis in the central nervous system. Bexarotene is a third-generation retinoid X receptor agonist that is promising in the treatment of both cancer and neurodegenerative diseases. In this study, we aimed to investigate the cytotoxic and anti-proliferative effects of bexarotene in C6 glioma cells through the PPARγ/NF-κB pathway. In the study, first cytotoxic bexarotene concentrations for C6 cells were detected, and then apoptosis profile, reactive oxygen species (ROS), total antioxidant (TAS), 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nuclear factor-κB (NF-κB) levels in the cells were determined. In addition, peroxisome proliferator-activated receptor γ (PPARγ) mRNA expression analysis was carried out. As a result, we detected concentration- and time-dependent antiproliferative effects of bexarotene on C6 cells. We found that bexarotene treatment decreased NF-κB and TAS levels and increased PPARγ and 8-OHdG levels in C6 cells. Bexarotene enhanced PPARγ expression in a dose-dependent manner when compared to the control group (P < 0.01). Furthermore, we determined that bexarotene-induced apoptotic C6 cells enhanced through Annexin V-FITC/PI staining and caspase-3/-7 activation analyses since phosphatidylserine level on the outer surface of the cell membrane and caspase-3/-7 activities were increased in the cells treated with bexarotene. In conclusion, bexarotene treatment in C6 glioma cells could modulate apoptosis profile, DNA damage, ROS production, and reduction of TAS levels through inhibition of NF-κB by enhancing PPARγ expression.

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.

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

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310(17):1842–50. https://doi.org/10.1001/jama.2013.280319.

    Article  CAS  PubMed  Google Scholar 

  2. Wirsching HG, Galanis E, Weller M. Glioblastoma. Handb Clin Neurol. 2016;134:381–97. https://doi.org/10.1016/B978-0-12-802997-8.00023-2.

    Article  PubMed  Google Scholar 

  3. Lapointe S, Perry A, Butowski NA. Primary brain tumours in adults. Lancet. 2018;392(10145):432–46. https://doi.org/10.1016/S0140-6736(18)30990-5.

    Article  PubMed  Google Scholar 

  4. Grobben B, De Deyn PP, Slegers H. Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res. 2002;310(3):257–70. https://doi.org/10.1007/s00441-002-0651-7.

    Article  CAS  PubMed  Google Scholar 

  5. Farol LT, Hymes KB. Bexarotene: a clinical review. Expert Rev Anticancer Ther. 2004;4(2):180–8. https://doi.org/10.1586/14737140.4.2.180.

    Article  CAS  PubMed  Google Scholar 

  6. Qu L, Tang X. Bexarotene: a promising anticancer agent. Cancer Chemother Pharmacol. 2010;65(2):201–5. https://doi.org/10.1007/s00280-009-1140-4.

    Article  CAS  PubMed  Google Scholar 

  7. Hong F, Pan S, Guo Y, Xu P, Zhai Y. PPARs as Nuclear Receptors for Nutrient and Energy Metabolism. Molecules. 2019;24(14):2545. https://doi.org/10.3390/molecules24142545.

    Article  CAS  PubMed Central  Google Scholar 

  8. Brunmeir R, Xu F. Functional Regulation of PPARs through Post-Translational Modifications. Int J Mol Sci. 2018;19(6):1738. https://doi.org/10.3390/ijms19061738.

    Article  CAS  PubMed Central  Google Scholar 

  9. Li J, Liu YP. The roles of PPARs in human diseases. Nucleosides Nucleotides Nucleic Acids. 2018;37(7):361–82. https://doi.org/10.1080/15257770.2018.1475673.

    Article  CAS  PubMed  Google Scholar 

  10. Wang P, Li B, Cai G, Huang M, Jiang L, Pu J, Li L, Wu Q, Zuo L, Wang Q, Zhou P. Activation of PPAR-γ by pioglitazone attenuates oxidative stress in aging rat cerebral arteries through upregulating UCP2. J Cardiovasc Pharmacol. 2014;64(6):497–506. https://doi.org/10.1097/FJC.0000000000000143.

    Article  CAS  PubMed  Google Scholar 

  11. Li CC, Yang HT, Hou YC, Chiu YS, Chiu WC. Dietary fish oil reduces systemic inflammation and ameliorates sepsis-induced liver injury by up-regulating the peroxisome proliferator-activated receptor gamma-mediated pathway in septic mice. J Nutr Biochem. 2014;25(1):19–25. https://doi.org/10.1016/j.jnutbio.2013.08.010.

    Article  CAS  PubMed  Google Scholar 

  12. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18(5):309–24. https://doi.org/10.1038/nri.2017.142.

    Article  CAS  PubMed  Google Scholar 

  13. Chen GG, Lee JF, Wang SH, Chan UP, Ip PC, Lau WY. Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci. 2002;70(22):2631–46. https://doi.org/10.1016/s0024-3205(02)01510-2.

    Article  CAS  PubMed  Google Scholar 

  14. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99. https://doi.org/10.1016/j.cell.2010.01.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B, Pestell RG. NF-kappaB and cell-cycle regulation: the cyclin connection. Cytokine Growth Factor Rev. 2001;12(1):73–90. https://doi.org/10.1016/s1359-6101(00)00018-6.

    Article  CAS  PubMed  Google Scholar 

  16. Janssens S, Tschopp J. Signals from within: the DNA-damage-induced NF-kappaB response. Cell Death Differ. 2006;13(5):773–84. https://doi.org/10.1038/sj.cdd.4401843.

    Article  CAS  PubMed  Google Scholar 

  17. Shen D, Yu X, Wu Y, Chen Y, Li G, Cheng F, Xia L. Emerging roles of bexarotene in the prevention, treatment and anti-drug resistance of cancers. Expert Rev Anticancer Ther. 2018;18(5):487–99. https://doi.org/10.1080/14737140.2018.

    Article  CAS  PubMed  Google Scholar 

  18. Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR, and the Big Bang. Cell. 2014;157(1):255–66. https://doi.org/10.1016/j.cell.2014.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang L, DeMarco SS, Chen J, Phillips CM, Bridges LC. Retinoids Bias Integrin Expression and Function in Cutaneous T-Cell Lymphoma. J Invest Dermatol. 2015;135(8):2102–8. https://doi.org/10.1038/jid.2015.122.

    Article  CAS  PubMed  Google Scholar 

  20. Wu K, DuPre E, Kim H, Tin-U CK, Bissonnette RP, Lamph WW, Brown PH. Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade. Breast Cancer Res Treat. 2006;96(2):147–57. https://doi.org/10.1007/s10549-005-9071-1.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang C, Hazarika P, Ni X, Weidner DA, Duvic M. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer. 2002;8(5):1234–40.

    CAS  Google Scholar 

  22. Huuskonen MT, Loppi S, Dhungana H, Keksa-Goldsteine V, Lemarchant S, Korhonen P, Wojciechowski S, Pollari E, Valonen P, Koponen J, Takashima A, Landreth G, Goldsteins G, Malm T, Koistinaho J, Kanninen KM. Bexarotene targets autophagy and is protective against thromboembolic stroke in aged mice with tauopathy. Sci Rep. 2016;6:33176. https://doi.org/10.1038/srep33176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ai X, Mao F, Shen S, Shentu Y, Wang J, Lu S. Bexarotene inhibits the viability of non-small cell lung cancer cells via slc10a2/PPARγ/PTEN/mTOR signaling pathway. BMC Cancer. 2018;18(1):407. https://doi.org/10.1186/s12885-018-4224-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Heo JC, Jung TH, Lee S, Kim HY, Choi G, Jung M, Jung D, Lee HK, Lee JO, Park JH, Hwang D, Seol HJ, Cho H. Effect of bexarotene on differentiation of glioblastoma multiforme compared with ATRA. Clin Exp Metastasis. 2016;33(5):417–29. https://doi.org/10.1007/s10585-016-9786-x.

    Article  CAS  PubMed  Google Scholar 

  25. Hanafi R, Anestopoulos I, Voulgaridou GP, Franco R, Georgakilas AG, Ziech D, Malamou-Mitsi V, Pappa A, Panayiotidis MI. Oxidative stress based-biomarkers in oral carcinogenesis: how far have we gone? Curr Mol Med. 2012;12(6):698–703. https://doi.org/10.2174/156652412800792598.

    Article  CAS  PubMed  Google Scholar 

  26. Klaunig JE. Oxidative Stress and Cancer. Curr Pharm Des. 2018;24(40):4771–8. https://doi.org/10.2174/1381612825666190215121712.

    Article  CAS  PubMed  Google Scholar 

  27. Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50–64. https://doi.org/10.1016/j.semcdb.2017.05.023.

    Article  CAS  PubMed  Google Scholar 

  28. Storz P. Reactive oxygen species in tumor progression. Front Biosci. 2005;10:1881–96. https://doi.org/10.2741/1667.

    Article  CAS  PubMed  Google Scholar 

  29. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47. https://doi.org/10.1038/nrd4002.

    Article  CAS  PubMed  Google Scholar 

  30. Khoo NK, Hebbar S, Zhao W, Moore SA, Domann FE, Robbins ME. Differential activation of catalase expression and activity by PPAR agonists: implications for astrocyte protection in anti-glioma therapy. Redox Biol. 2013;1(1):70–9. https://doi.org/10.1016/j.redox.2012.12.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Valavanidis A, Vlachogianni T, Fiotakis C. 8-hydroxy-2’ -deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009;27(2):120–39. https://doi.org/10.1080/10590500902885684.

    Article  CAS  PubMed  Google Scholar 

  32. Al Mamun Bhuyan A, Bissinger R, Cao H, Lang F. Triggering of Suicidal Erythrocyte Death by Bexarotene. Cell Physiol Biochem. 2016;40(5):1239–51. https://doi.org/10.1159/000453178.

    Article  CAS  PubMed  Google Scholar 

  33. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6. https://doi.org/10.1038/35037710.

    Article  CAS  PubMed  Google Scholar 

  34. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205–19. https://doi.org/10.1016/s0092-8674(04)00046-7.

    Article  CAS  PubMed  Google Scholar 

  35. Zander T, Kraus JA, Grommes C, Schlegel U, Feinstein D, Klockgether T, Landreth G, Koenigsknecht J, Heneka MT. Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. J Neurochem. 2002;81(5):1052–60. https://doi.org/10.1046/j.1471-4159.2002.00899.x.

    Article  CAS  PubMed  Google Scholar 

  36. Liu Y, Meng Y, Li H, Li J, Fu J, Liu Y, Chen XG. Growth inhibition and differentiation induced by peroxisome proliferator activated receptor gamma ligand rosiglitazone in human melanoma cell line A375. Med Oncol. 2006;23(3):393–402. https://doi.org/10.1385/mo:23:3:393.

    Article  PubMed  Google Scholar 

  37. Gretskaya NM, Gamisonia AM, Dudina PV, Zakharov SS, Sherstyanykh G, Akasov R, Burov S, Serkov IV, Akimov MG, Bezuglov VV, Markvicheva E. Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models. Eur J Pharmacol. 2020;883:173346. https://doi.org/10.1016/j.ejphar.2020.173346.

    Article  CAS  PubMed  Google Scholar 

  38. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409–35. https://doi.org/10.1146/annurev.med.53.082901.104018.

    Article  CAS  PubMed  Google Scholar 

  39. Delerive P, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol. 2001;169(3):453–9. https://doi.org/10.1677/joe.0.1690453.

    Article  CAS  PubMed  Google Scholar 

  40. Hwang JK, Yu HN, Noh EM, Kim JM, Hong OY, Youn HJ, Jung SH, Kwon KB, Kim JS, Lee YR. DHA blocks TPA-induced cell invasion by inhibiting MMP-9 expression via suppression of the PPAR-γ/NF-κB pathway in MCF-7 cells. Oncol Lett. 2017;13(1):243–9. https://doi.org/10.3892/ol.2016.5382.

    Article  CAS  PubMed  Google Scholar 

  41. Kiekow CJ, Figueiro F, Dietrich F, Vechia LD, Pires EN, Jandrey EH, Gnoatto SC, Salbego CG, Battastini AM, Gosmann G. Quercetin derivative induces cell death in glioma cells by modulating NF-κB nuclear translocation and caspase-3 activation. Eur J Pharm Sci. 2016;84:116–22. https://doi.org/10.1016/j.ejps.2016.01.019.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry, Faculty of Medicine, Düzce University, Düzce, Turkey

    Ceyhan Hacioglu

  2. Department of Medical Services and Techniques, Vocational School of Health Services, Kütahya Health Science University, Kütahya, Turkey

    Fatih Kar

  3. Department of Histology and Embryology, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey

    Sedat Kacar & Varol Sahinturk

  4. Department of Medical Biochemistry, Faculty of Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey

    Gungor Kanbak

Authors
  1. Ceyhan Hacioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fatih Kar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sedat Kacar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Varol Sahinturk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gungor Kanbak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by CH, FK and SK. The first draft of the manuscript was written by CH and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ceyhan Hacioglu.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hacioglu, C., Kar, F., Kacar, S. et al. Bexarotene inhibits cell proliferation by inducing oxidative stress, DNA damage and apoptosis via PPARγ/ NF-κB signaling pathway in C6 glioma cells. Med Oncol 38, 31 (2021). https://doi.org/10.1007/s12032-021-01476-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-021-01476-z

Keywords

Search

Navigation