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The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism

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Abstract

Background

Hesperidin, a flavanone present in citrus fruits, has been identified as a potent anticancer agent because of its proapoptotic and antiproliferative characteristics in some tumor cells. However, the precise mechanisms of action are not entirely understood.

Aim

The main purpose of this study is to investigate the involvement of peroxisome proliferator-activated receptor-gamma (PPARγ) in hesperidin’s anticancer actions in human pre-B NALM-6 cells, which expresses wild-type p53.

Methods

The effects of hesperidin on cell-cycle distribution, proliferation, and caspase-mediated apoptosis were examined in NALM-6 cells in the presence or absence of GW9662. The expression of peroxisome proliferator-activated receptor-gamma (PPARγ), p53, phospho-IκB, Bcl-2, Bax, and XIAP proteins were focused on using the immunoblotting assay. The transcriptional activities of PPARγ and nuclear factor-kappaB (NF-κB) were analyzed by the transcription factor assay kits. The expression of PPARγ and p53 was analyzed using the RT-PCR method.

Results

Hesperidin induced the expression and transcriptional activity of PPARγ and promoted p53 accumulation and downregulated constitutive NF-κB activity in a PPARγ-dependent and PPARγ-independent manner. The growth-inhibitory effect of hesperidin was partially reduced when the cells preincubated with PPARγ antagonist prior to the exposure to hesperidin.

Conclusions

The findings of this study clearly demonstrate that hesperidin-mediated proapoptotic and antiproliferative actions are regulated via both PPARγ-dependent and PPARγ-independent pathways in NALM-6 cells. These data provide the first evidence that hesperidin could be developed as an agent against hematopoietic malignancies.

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References

  1. Ou S (2002) Pharmacological action of hesperidin. Zhong Yao Cai 25(7):531–533

    Google Scholar 

  2. Benavente-Garcia O, Castillo J (2008) Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 56(15):6185–6205

    Article  CAS  Google Scholar 

  3. Park HJ, Kim MJ, Ha E, Chung JH (2008) Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine 15(1–2):147–151

    Article  CAS  Google Scholar 

  4. Patil JR, Chidambara Murthy KN, Jayaprakasha GK, Chetti MB, Patil BS (2009) Bioactive compounds from Mexican lime (Citrus aurantifolia) juice induce apoptosis in human pancreatic cells. J Agric Food Chem 57(22):10933–10942

    Article  CAS  Google Scholar 

  5. Salam NK, Huang TH, Kota BP, Kim MS, Li Y, Hibbs DE (2008) Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study. Chem Biol Drug Des 71(1):57–70

    CAS  Google Scholar 

  6. Vanden Heuvel JP (1999) Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. Toxicol Sci 47(1):1–8

    Article  Google Scholar 

  7. Hihi AK, Michalik L, Wahli W (2002) PPARs: transcriptional effectors of fatty acids and their derivatives. Cell Mol Life Sci 59(5):790–798

    Article  CAS  Google Scholar 

  8. Ondrey F (2009) Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention. Clin Cancer Res 15(1):2–8

    Article  CAS  Google Scholar 

  9. Agarwal ML, Agarwal A, Taylor WR, Stark GR (1995) p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc Natl Acad Sci USA 92(18):8493–8497

    Article  CAS  Google Scholar 

  10. Boland MP (2001) DNA damage signalling and NF-kappaB: implications for survival and death in mammalian cells. Biochem Soc Trans 29(Pt 6):674–678

    Article  CAS  Google Scholar 

  11. Weston VJ, Austen B, Wei W, Marston E, Alvi A, Lawson S, Darbyshire PJ, Griffiths M, Hill F, Mann JR, Moss PA, Taylor AM, Stankovic T (2004) Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-kappaB survival pathway signaling. Blood 104(5):1465–1473

    Article  CAS  Google Scholar 

  12. Burns TF, El-Deiry WS (1999) The p53 pathway and apoptosis. J Cell Physiol 181(2):231–239

    Article  CAS  Google Scholar 

  13. Leesnitzer LM, Parks DJ, Bledsoe RK, Cobb JE, Collins JL, Consler TG, Davis RG, Hull-Ryde EA, Lenhard JM, Patel L, Plunket KD, Shenk JL, Stimmel JB, Therapontos C, Willson TM, Blanchard SG (2002) Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662. Biochemistry 41(21):6640–6650

    Article  CAS  Google Scholar 

  14. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  CAS  Google Scholar 

  15. Hawkins CJ, Vaux DL (1997) The role of the Bcl-2 family of apoptosis regulatory proteins in the immune system. Semin Immunol 9(1):25–33

    Article  CAS  Google Scholar 

  16. Yang YL, Li XM (2000) The IAP family: endogenous caspase inhibitors with multiple biological activities. Cell Res 10(3):169–177

    Article  CAS  Google Scholar 

  17. Hampel JK, Brownrigg LM, Vignarajah D, Croft KD, Dharmarajan AM, Bentel JM, Puddey IB, Yeap BB (2006) Differential modulation of cell cycle, apoptosis and PPARgamma2 gene expression by PPARgamma agonists ciglitazone and 9-hydroxyoctadecadienoic acid in monocytic cells. Prostaglandins Leukot Essent Fatty Acids 74(5):283–293

    Article  CAS  Google Scholar 

  18. Bonofiglio D, Aquila S, Catalano S, Gabriele S, Belmonte M, Middea E, Qi H, Morelli C, Gentile M, Maggiolini M, Ando S (2006) Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells. Mol Endocrinol 20(12):3083–3092

    Article  CAS  Google Scholar 

  19. Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 18:621–663

    Article  CAS  Google Scholar 

  20. Zhou M, Gu L, Zhu N, Woods WG, Findley HW (2003) Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: interaction of IkBm and p53. Oncogene 22(50):8137–8144

    Article  CAS  Google Scholar 

  21. Beecher GR (2003) Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 133(10):3248S–3254S

    CAS  Google Scholar 

  22. Fresco P, Borges F, Diniz C, Marques MP (2006) New insights on the anticancer properties of dietary polyphenols. Med Res Rev 26(6):747–766

    Article  CAS  Google Scholar 

  23. Shinjyo T, Kurosawa H, Miyagi J, Ohama K, Masuda M, Nagasaki A, Matsui H, Inaba T, Furukawa Y, Takasu N (2008) Ras-mediated up-regulation of survivin expression in cytokine-dependent murine pro-B lymphocytic cells. Tohoku J Exp Med 216(1):25–34

    Article  CAS  Google Scholar 

  24. Sarkar FH, Li Y, Wang Z, Kong D (2009) Cellular signaling perturbation by natural products. Cell Signal 21(11):1541–1547

    Article  CAS  Google Scholar 

  25. Xu L, Zhang L, Bertucci AM, Pope RM, Datta SK (2008) Apigenin, a dietary flavonoid, sensitizes human T cells for activation-induced cell death by inhibiting PKB/Akt and NF-kappaB activation pathway. Immunol Lett 121(1):74–83

    Article  CAS  Google Scholar 

  26. Khan N, Afaq F, Syed DN, Mukhtar H (2008) Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 29(5):1049–1056

    Article  CAS  Google Scholar 

  27. Li Y, Wang Z, Kong D, Li R, Sarkar SH, Sarkar FH (2008) Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells. J Biol Chem 283(41):27707–27716

    Article  CAS  Google Scholar 

  28. Gaetano C, Colussi C, Capogrossi MC (2007) PEDF, PPAR-gamma, p53: deadly circuits arise when worlds collide. Cardiovasc Res 76(2):195–196

    Article  CAS  Google Scholar 

  29. Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP (2007) PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res 76(2):213–223

    Article  CAS  Google Scholar 

  30. Sarkar FH, Li Y (2008) NF-kappaB: a potential target for cancer chemoprevention and therapy. Front Biosci 13:2950–2959

    Article  CAS  Google Scholar 

  31. Horie R, Watanabe T, Umezawa K (2006) Blocking NF-kappaB as a potential strategy to treat adult T-cell leukemia/lymphoma. Drug News Perspect 19(4):201–209

    Article  CAS  Google Scholar 

  32. Bremner P, Heinrich M (2002) Natural products as targeted modulators of the nuclear factor-kappaB pathway. J Pharm Pharmacol 54(4):453–472

    Article  CAS  Google Scholar 

  33. Ringseis R, Gahler S, Eder K (2008) Conjugated linoleic acid isomers inhibit platelet-derived growth factor-induced NF-kappaB transactivation and collagen formation in human vascular smooth muscle cells. Eur J Nutr 47(2):59–67

    Article  CAS  Google Scholar 

  34. Ohga S, Shikata K, Yozai K, Okada S, Ogawa D, Usui H, Wada J, Shikata Y, Makino H (2007) Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation. Am J Physiol Renal Physiol 292(4):F1141–F1150

    Article  CAS  Google Scholar 

  35. Eligini S, Banfi C, Brambilla M, Camera M, Barbieri SS, Poma F, Tremoli E, Colli S (2002) 15-deoxy-delta12, 14-prostaglandin J2 inhibits tissue factor expression in human macrophages and endothelial cells: evidence for ERK1/2 signaling pathway blockade. Thromb Haemost 88(3):524–532

    CAS  Google Scholar 

Download references

Acknowledgments

This article is based in part on a thesis made possible by Master research grants from National Institute of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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Authors and Affiliations

  1. National Institute and Faculty of Nutrition and Food Technology, Department of Basic Medical Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19395-4741, Tehran, Iran

    Asghar Ghorbani, Maryam Nazari & Hamid Zand

  2. Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

    Mahmood Jeddi-Tehrani

Authors
  1. Asghar Ghorbani
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  2. Maryam Nazari
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  3. Mahmood Jeddi-Tehrani
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  4. Hamid Zand
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Correspondence to Hamid Zand.

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Ghorbani, A., Nazari, M., Jeddi-Tehrani, M. et al. The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism. Eur J Nutr 51, 39–46 (2012). https://doi.org/10.1007/s00394-011-0187-2

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  • DOI: https://doi.org/10.1007/s00394-011-0187-2

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