Amino Acids

, Volume 41, Issue 5, pp 1207–1214 | Cite as

Synergic effect of α-tocopherol and naringenin in transglutaminase-induced differentiation of human prostate cancer cells

  • Piera TorricelliEmail author
  • Pasquale Ricci
  • Bruno Provenzano
  • Alessandro Lentini
  • Claudio Tabolacci
Invited Review


Prostate cancer is the second most common cancer in men worldwide. Its prevention and treatment remain a challenge to clinicians. Thus, there is an urgent need to discover novel, less toxic, and more effective therapies for patients. Many vitamins and related chemicals, including vitamin E, (tocopherols) have shown their anti-cancer activities as anti-oxidants, activators of transcription factors or factors influencing epigenetic events. Although laboratory tests including the use of animal models showed that this vitamin may have anticancer properties, whether it can effectively prevent the development and/or progression of prostate cancer in humans remains to be intensively studied. This review provides up-to-date information regarding the recent outcomes of laboratory, epidemiology and/or clinical trials on the effects of tocopherols on prostate cancer development, along with our last observations on a combined treatment of a prostate cancer cell line (PC-3) with two natural antineoplastic compounds, naringenin (NG) and α-tocopherol (α-TOC). We report the synergic effect of α-TOC and NG in transglutaminase-induced differentiation of human PC-3 prostate cancer cells. While our results are based on one histological class of tumor, the most significant implication of this observation is that establishes a new way in the screening for detecting new differentiative antineoplastic agents.


α-Tocopherol Naringenin Transglutaminase Differentiation Apoptosis Human PC-3 prostate cancer cell 



We thanks Prof. Salvatore Passarella for assistance and helpful discussion.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Ablin RJ, Whyard TC (1991) Identification and biological relevance of spermatozoal transglutaminase. Experientia 47:277–279PubMedCrossRefGoogle Scholar
  2. Adlercreutz H (2002) Phyto-oestrogens and cancer. Lancet Oncol 3(6):364–373PubMedCrossRefGoogle Scholar
  3. Ahlbom A, Lichtenstein P, Malmström H, Feychting M, Hemminki K, Pedersen NL (1997) Cancer in twins: genetic and nongenetic familial risk factors. J Natl Cancer Inst 89(4):287–293PubMedCrossRefGoogle Scholar
  4. An G, Meka CS, Bright S, Veltri RW (1999) Human prostate-specific transglutaminase gene: promoter cloning, tissue-specific expression, and down-regulation in metastatic prostate cancer. Urology 54:1105–1111PubMedCrossRefGoogle Scholar
  5. Ablin RJ, Bartkus JM, Gonder MJ, Polgar J (1987) In: Cimino F, Birkmayer CD, Pimental E, Klavins JV, Salvatore F (eds) Factors contributing to suppression of tumor–host responsiveness. Human tumor markers–biology and clinical applications. Walter de Gruyter, Berlin, pp 279–299Google Scholar
  6. Beninati S, Abbruzzese A, Cardinali M (1993) Differences in the post-translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells. Int J Cancer 53:792–797PubMedCrossRefGoogle Scholar
  7. Bhat R (1986) Serum, retinal, choroidal vitreal vitamin E concentrations in human infants. Pediatrics 78:866–870PubMedGoogle Scholar
  8. Birt DF (1986) Update on the effects of vitamins A, C, and F and selenium on carcinogenesis. Proc Soc Exp Biol Med 183:311–320PubMedGoogle Scholar
  9. Breslow N, Chan CW, Dhom G, Drury RA, Franks LM, Gellei B, Lee YS, Lundberg S, Sparke B, Sternby NH, Tulinius H (1977) Latent carcinoma of prostate at autopsy in seven areas. The international agency for research on cancer, Lyons, France. Int J Cancer 20(5):680–688PubMedCrossRefGoogle Scholar
  10. Brigelius-Flohe R, Traber MG (1999) Vitamin E: function and metabolism. FASEB J 13:1145–1155PubMedGoogle Scholar
  11. Campbell SE, Stone WL, Lee S, Whaley S, Yang H, Qui M, Goforth P, Sherman D, McHaffie D, Krishnan K (2006) Comparative effects of RRR-∝ and RRR-γ-tocopherol on proliferation and apoptosis in human colon cancer cell lines. BMC Cancer 6:13PubMedCrossRefGoogle Scholar
  12. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572PubMedCrossRefGoogle Scholar
  13. Chan JM, Stampfer MJ, Giovannucci EL (1998) What causes prostate cancer? A brief summary of the epidemiology. Semin Cancer Biol 8(4):263–273PubMedCrossRefGoogle Scholar
  14. Chan R, Lok K, Woo J (2009) Prostate cancer and vegetable consumption. Mol Nutr Food Res 53(2):201–216PubMedCrossRefGoogle Scholar
  15. Chen LH, Boissonneault GA, Glauert HP (1988) Vitamin C, vitamin F and cancer. Anticancer Res 8:739–748PubMedGoogle Scholar
  16. Clarke DD, Mycek MJ, Neidle A, Waelsch H (1957) The incorporation of amines into proteins. Arch Biochem Biophys 79:338–354CrossRefGoogle Scholar
  17. Davies G, Ablin RJ, Mason MD, Jiang WG (2007) Expression of the prostate transglutaminase (TGase-4) in prostate cancer cells and its impact on the invasiveness of prostate cancer. J Exp Ther Oncol 6(3):257–264PubMedGoogle Scholar
  18. Dubbink HJ, Verkaik NS, Faber PW, Trapman J, Schroder FH, Romijn JC (1996) Tissue-specific and androgen-regulated expression of human prostate-specific transglutaminase. Biochem J 315:901–908PubMedGoogle Scholar
  19. Dubbink HJ, Hoedemaeker RF, van der Kwast TH, Schroder F, Romijn JC (1999) Human prostate-specific transglutaminase: a new prostatic marker with a unique distribution pattern. Lab Invest 79:141–150PubMedGoogle Scholar
  20. Eichholzer M, Stahelin HB, Gey KF, Ludin E, Bernasconi F (1996) Prediction of male cancer mortality by plasma levels of interacting vitamins: 17-year follow-up of the prospective Basel study. Int J Cancer 66:145–150PubMedCrossRefGoogle Scholar
  21. Fesus L, Piacentini M (2002) Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci 27(10):534–539PubMedCrossRefGoogle Scholar
  22. Fitzpatrick JM (2008) Management of localized prostate cancer in senior adults: the crucial role of comorbidity. BJU Int 101(Suppl. 2):16–22PubMedCrossRefGoogle Scholar
  23. Folk JE, Finlayson JS (1977) The ε-(γ-glutamyl)lysine crosslink and the catalytic role of transglutaminase. Adv Prot Chem 31:1–133CrossRefGoogle Scholar
  24. Gábor M (1986) Anti-inflammatory and anti-allergic properties of flavonoids. Prog Clin Biol Res 213:471–480PubMedGoogle Scholar
  25. Gao K, Henning SM, Niu Y, Youssefian AA, Seeram NP, Xu A, Heber D (2006) The citrus flavonoid naringenin stimulates DNA repair in prostate cancer cells. J Nutr Biochem 17(2):89–95PubMedCrossRefGoogle Scholar
  26. Geng H, Rademacher BL, Pittsenbarger J, Huang CY, Harvey CT, Lafortune MC, Myrthue A, Garzotto M, Nelson PS, Beer TM, Qian DZ (2010) ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. Cancer Res 70:3239–3248PubMedCrossRefGoogle Scholar
  27. Gopalakrishnan A, Xu CJ, Nair SS, Chen C, Hebbar V, Kong AN (2006) Modulation of activator protein-1 (AP-1) and MAPK pathway by flavonoids in human prostate cancer PC3 cells. Arch Pharm Res 29(8):633–644PubMedCrossRefGoogle Scholar
  28. Gunawardena K, Murray DK, Meikle AW (2000) Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis. Prostate 44:287–295PubMedCrossRefGoogle Scholar
  29. Hamalainen E, Adlercreutz H, Puska P, Pietinen P (1983) Decrease of serum total and free testosterone during a low-fat high-fibre diet. J Steroid Biochem 18:369–370PubMedCrossRefGoogle Scholar
  30. Iemelynova AA, Grygorenko VM, Cheremuha SV, Romanenko AM (2009) Correlation between histological type and immunohistochemical profile of prostate cancer and gleason scale gradation. Exp Oncol 31:246–249PubMedGoogle Scholar
  31. Israel K, Sanders BG, Kline K (1995) RRR-alpha-tocopheryl succinate inhibits the proliferation of human prostatic tumor cells with defective cell cycle/differentiation pathways. Nutr Cancer 24:161–169PubMedCrossRefGoogle Scholar
  32. Jimenez JJ, Yunis AA (1987) Tumor cell rejection through terminal cell differentiation. Science 238:1278–1280PubMedCrossRefGoogle Scholar
  33. Knekt P (1988) Serum alpha-tocopherol, the risk of cancer, vol 83. Publications of the Social Insurance Institution, Helsinki, pp 1–148Google Scholar
  34. Knekt P, Aromaa A, Maatela J, Aaran RK, Nikkari T, Hakama M, Hakulinen T, Peto R, Teppo L (1991) Vitamin E and cancer prevention. Am J Clin Nutr 53(1 Suppl):283S–286SPubMedGoogle Scholar
  35. Lentini A, Forni C, Provenzano B, Beninati S (2007) Enhancement of transglutaminase activity and polyamine depletion in B16–F10 melanoma cells by flavonoids naringenin and hesperitin correlate to reduction of the in vivo metastatic potential. Amino Acids 32:95–100PubMedCrossRefGoogle Scholar
  36. Lentini A, Provenzano B, Tabolacci C, Beninati S (2009) Protein–polyamine conjugates by transglutaminase 2 as potential markers for antineoplastic screening of natural compounds. Amino Acids 36(4):701–708PubMedCrossRefGoogle Scholar
  37. Lentini A, Tabolacci C, Provenzano B, Rossi S, Beninati S (2010) Phytochemicals and protein-polyamine conjugates by transglutaminase as chemopreventive and chemotherapeutic tools in cancer. Plant Physiol Biochem 48(7):627–633PubMedCrossRefGoogle Scholar
  38. Leszczyniecka M, Roberts T, Dent P, Grant S, Fisher PB (2001) Differentiation therapy of human cancer: basic science and clinical applications. Pharm Therap 90:105–156CrossRefGoogle Scholar
  39. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873PubMedCrossRefGoogle Scholar
  40. Nakamura A, Shirai T, Takahashi S, Ogawa K, Hirose M, Ito N (1991) Lack of modification by naturally occurring antioxidants of 3, 2’-dimethyl-4-aminobiphenyl-initiated rat prostate carcinogenesis. Cancer Lett 58:241–246PubMedCrossRefGoogle Scholar
  41. Ni J, Chen M, Zhang Y, Li R, Huang J, Yeh S (2003) Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery. Biochem Biophys Res Commun 300:357–363PubMedCrossRefGoogle Scholar
  42. Packer L (1991) Protective role of vitamin E in biological systems. Am J Clin Nutr 53:1050S–1055SPubMedGoogle Scholar
  43. Sies H, Murphy ME (1991) Role of tocopherols in the protection of biological systems against oxidative damage. J Photochem Photobiol B 8:211–218PubMedCrossRefGoogle Scholar
  44. Spina AM, Esposito C, Pagano M, Chiosi E, Mariniello L, Cozzolino A, Porta R, Illiano G (1999) GTPase and transglutaminase are associated in the secretion of the rat anterior prostate. Biochem Biophys Res Commun 260:351–356PubMedCrossRefGoogle Scholar
  45. Stangelberger A, Waldert M, Djavan B (2008) Prostate cancer in elderly men. Rev Urol 10:111–119PubMedGoogle Scholar
  46. Thiele CJ, Gore S, Collins S, Waxman S, Miller W (2000) Differentiate or die: the view from Montreal. Cell Death Differ 7:1014–1017PubMedCrossRefGoogle Scholar
  47. Venkateswaran V, Fleshner NE, Klotz LH (2002) Modulation of cell proliferation and cell cycle regulators by vitamin E in human prostate carcinoma cell lines. J Urol 168:1578–1582PubMedCrossRefGoogle Scholar
  48. Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH (2004) Antioxidants block prostate cancer in lady transgenic mice. Cancer Res 64:5891–5896PubMedCrossRefGoogle Scholar
  49. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert P (2003) Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 290:476–485PubMedCrossRefGoogle Scholar
  50. Williams-Ashman HG (1984) Transglutaminases and the clotting of mammalian seminal fluids. Mol Cell Biochem 58:51–61PubMedCrossRefGoogle Scholar
  51. Yin M, Bastacky S, Chandran UE, Becich MJ, Dhir R (2008) Prevalence of incidental prostate cancer in the general population: a study of healthy organ donors. J Urol 179:892–895PubMedCrossRefGoogle Scholar
  52. Zu K, Ip C (2003) Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res 63:6988–6995PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Piera Torricelli
    • 1
    Email author
  • Pasquale Ricci
    • 1
  • Bruno Provenzano
    • 2
  • Alessandro Lentini
    • 2
  • Claudio Tabolacci
    • 2
  1. 1.Department SPESUniversity of MoliseCampobassoItaly
  2. 2.Department of BiologyUniversity of Rome “Tor Vergata”RomeItaly

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