Skip to main content

Advertisement

SpringerLink
Log in

Naringenin promote apoptosis in cerebrally implanted C6 glioma cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Naringenin (NGEN), a naturally occurring citrus flavonone, has shown cytotoxicity in various human cancer cell lines as well as inhibitory effects on tumor growth. It has been also shown to access the brain and there is an increasing interest in its therapeutic applications. The up-regulated expression of Cx43 leads to the suppression of tumorigenicity with promoted apoptotic events. In this study, we investigated the in vivo effect of NGEN in fostering apoptosis in cerebrally implanted C6 glioma cells rat model. We analysed the expression of Cx43, caspase-3, caspase-9, Cyt C, Bcl-2 and Bax in vivo by immunoblot analysis and the ultra structure of brain cells by transmission electron microscopy. Supplementation of NGEN to experimental animals modulated Bcl-2/Bax ratio and up-regulation of caspase-3 and 9. NGEN was also found to up-regulate the expression of Cx43. These findings provide evidence that NGEN’s apoptotic effect, modulation of Bcl-2/Bax ratio leads to release of Cyt C from mitochondria, thereby activation of caspase-3 and caspase-9 is mediated by enhanced expression of Cx43. These observations were well supported by the transmission electron microscopic results which showed the characteristic apoptotic features. In conclusion, our findings demonstrate that NGEN promotes apoptosis in rat C6 glioma model.

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

Similar content being viewed by others

References

  1. Onda K, Davis RL, Shibuya M, Wilson CB, Hoshino T (1994) Correlation between the bromodeoxyuridine labeling index and the MIB-1 and Ki-67 proliferating cell indices in cerebral gliomas. Cancer 74:1921–1926

    Article  CAS  PubMed  Google Scholar 

  2. Cerame MA, Guthikonda M, Kohli CM (1985) Extraneural metastasis in gliosarcoma: a case report and review of the literature. Neurosurgery 17:413–418

    Article  CAS  PubMed  Google Scholar 

  3. Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas. N Engl J Med 353:811–822

    Article  CAS  PubMed  Google Scholar 

  4. Stupp R, Reni M, Gatta G, Mazza E, Vecht C (2007) Anaplastic astrocytoma in adults. Crit Rev Oncol Hematol 63(1):72–80

    Article  PubMed  Google Scholar 

  5. Lampson LA (2001) New animal models to probe brain tumor biology, therapy and immunotherapy: advantages and remaining concerns. J Neuro Oncol. 53:275–287

    Article  CAS  Google Scholar 

  6. Yamasaki H, Naus CCG (1996) Role of connexin genes in growth control. Carcinogenesis 17:1199–1213

    Article  CAS  PubMed  Google Scholar 

  7. Huang RP, Fan Y, Hossain MZ, Peng A, Zeng ZL, Boynton AL (1998) Reversion of the neoplastic phenotype of human glioblastoma cells by connexin 43 (cx43). Cancer Res 58:5089–5096

    CAS  PubMed  Google Scholar 

  8. Huang RP, Hossain MZ, Huang R, Gano J, Fan Y, Boynton AL (2001) Connexin 43 (cx43) enhances chemotherapyinduced apoptosis in human glioblastoma cells. Int J Cancer 92:130–138

    Article  CAS  PubMed  Google Scholar 

  9. Udawatte C, Ripps H (2005) The spread of apoptosis through gap-junctional channels in BHK cells transfected with Cx32. Apoptosis 10:1019–1029

    Article  CAS  PubMed  Google Scholar 

  10. Owuor ED, Kong (2002) Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 64:765–770

    Article  CAS  PubMed  Google Scholar 

  11. Vermeulen K, Van Bockstaele DR, Berneman ZN (2005) Apoptosis: mechanisms and relevance in cancer. Ann Hematol 84:627–639

    Article  CAS  PubMed  Google Scholar 

  12. Henson PM, Bratton DL, Fadok VA (2001) Apoptotic cell removal. Curr Biol 11:795–805

    Article  Google Scholar 

  13. Green DR, Evan GI (2002) A matter of life and death. Cancer Cell 1:19–30

    Article  CAS  PubMed  Google Scholar 

  14. Vincenz C, Dixit VM (1997) Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. J Biol Chem. 272:6578–6583

    Article  CAS  PubMed  Google Scholar 

  15. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312

    Article  CAS  PubMed  Google Scholar 

  16. Gayathri R, Gunadharini DN, Arunkumar A, Senthilkumar K, Krishnamoorthy G, Banudevi S, Vignesh RC, Arunakaran J (2009) Effects of diallyl disulfide (DADS) on expression of apoptosis associated proteins in androgen independent human prostate cancer cells (PC-3). Mol Cell Biochem 320:197–203

    Article  CAS  PubMed  Google Scholar 

  17. Chen D, Chen MS, Cui QC, Yang H, Dou QP (2007) Structure–proteasome–inhibitory activity relationships of dietary flavonoids in human cancer cells. Front Biosci. 12:1935–1945

    Article  CAS  PubMed  Google Scholar 

  18. Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M (1999) HL-60 differentiating activity and flavonoid content of the readily extractable fraction prepared from citrus juices. J Agric Food Chem 47:128–135

    Article  CAS  PubMed  Google Scholar 

  19. Kanno S, Tomizawa A, Ohtake T, Koiwai K, Ujibe M, Ishikawa M (2006) Naringenin-induced apoptosis via activation of NF-kappaB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells. Toxicol Lett 166:131–139

    Article  CAS  PubMed  Google Scholar 

  20. Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med 36:592–604

    Article  CAS  PubMed  Google Scholar 

  21. Nobuhisa N, Hiroshi S, Masaru A, Kimiyoshi H (1993) Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol 86:117–125

    Article  Google Scholar 

  22. Fiddo RJ, Tatham AS, Shewry PR (1995) Western blotting analysis. Methods Mol Biol 49:423–437

    Google Scholar 

  23. La Vecchia C, Tavani A (1998) Fruits and vegetables, and human cancer. Eur J Cancer Prev 7:3–8

    Article  CAS  PubMed  Google Scholar 

  24. Kanno A, Ayako TA, Takako HA, Yuu OA, Ai Shouji A, Mayuko UA, Takaharu O AB, Katsuhiko KB, Masaaki ISA (2005) Inhibitory effects of Naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice. Biol Pharm Bull 28(3):527–530

    Article  CAS  PubMed  Google Scholar 

  25. Park C, Jin CY, Kim GY, Choi IW, Kwon TK, Choi BT, Lee SJ, Lee WH, Choi YH (2008) Induction of apoptosis by esculetin in human leukemia U937 cells through activation of JNK and ERK. Toxicol Appl Pharmacol 227:219–228

    Article  CAS  PubMed  Google Scholar 

  26. Vijayababu MR, Kanagaraj P, Arunkumar A, Ilangovan R, Aruldhas MM, Arunakaran J (2005) Quercetin-induced growth inhibition and cell death in prostatic carcinoma cells (PC-3) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. J Cancer Res Clin Oncol 131:765–771

    Article  CAS  PubMed  Google Scholar 

  27. Sabarinathan D, Vanisree AJ (2010) Naringenin, a flavanone alters the tumorigenic features of C6 glioma cells. Biomed Pharmacother (in press)

  28. Esposti MD, Dive C (2003) Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 304:455–461

    Article  PubMed  Google Scholar 

  29. Letai A (2005) Pharmacological manipulation of Bcl-2 family members to control cell death. J Clin Invest 115:2648–2655

    Article  CAS  PubMed  Google Scholar 

  30. Madhavi S, Moodbidri, Neelam V, Shirsat (2005) Activated JNK brings about accelerated apoptosis of Bcl-2 overexpressing C6 glioma cells on treatment with tamoxifen. J Neurochem 92:1–9

    Article  Google Scholar 

  31. Amelio MD, Tino E, Cecconi F (2008) The apoptosome: emerging insights and new potential targets for drug design. Pharm Res 25:740–751

    Article  PubMed  Google Scholar 

  32. Ramakrishnan G, Lo Muzio L, Elinos-Báez CM, Jagan S, Augustine TA, Kamaraj S, Anandakumar P, Devaki T (2009) Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell Prolif 42:229–240

    Article  CAS  PubMed  Google Scholar 

  33. Karamitopoulou E, Cioccari L, Jakob S, Vallan C, Schaffner T, Zimmermann A, Brunner T (2007) Active caspase 3 and DNA fragmentation as markers for apoptotic cell death in primary and metastatic liver tumors. Pathology 39:558–564

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, Tamilnadu, India

    Devan Sabarinathan, Palani Mahalakshmi & Arambakkam Janardhanam Vanisree

Authors
  1. Devan Sabarinathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Palani Mahalakshmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arambakkam Janardhanam Vanisree
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arambakkam Janardhanam Vanisree.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabarinathan, D., Mahalakshmi, P. & Vanisree, A.J. Naringenin promote apoptosis in cerebrally implanted C6 glioma cells. Mol Cell Biochem 345, 215–222 (2010). https://doi.org/10.1007/s11010-010-0575-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-010-0575-6

Keywords

Search

Navigation