Investigational New Drugs

, Volume 23, Issue 1, pp 11–20 | Cite as

Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions

  • Ephraim P. Lansky
  • Wenguo Jiang
  • Huanbiao Mo
  • Lou Bravo
  • Paul Froom
  • Weiping Yu
  • Neil M. Harris
  • Ishak Neeman
  • Moray J. Campbell
Article

Abstract

We investigated whether dissimilar biochemical fractions originating in anatomically discrete sections of the pomegranate (Punica granatum) fruit might act synergistically against proliferation, metastatic potential, and phosholipase A2 (PLA2) expression of human prostate cancer cells in vitro. Proliferation of DU 145 human prostate cancer cells was measured following treatment with a range of therapeutically active doses of fermented pomegranate juice polyphenols (W) and sub-therapeutic doses of either pomegranate pericarp (peel) polyphenols (P) or pomegranate seed oil (Oil). Invasion across Matrigel by PC-3 human prostate cancer cells was measured following treatment with combinations of W, P and Oil such that the total gross weight of pomegranate extract was held constant. Expression of PLA2, associated with invasive potential, was measured in the PC-3 cells after treatment with the same dosage combinations as per invasion. Supra-additive, complementary and synergistic effects were proven in all models by the Kruskal-Wallis non-parametric H test at p < 0.001 for the proliferation tests, p < 0.01 for invasion, and p < 0.05 for PLA2 expression. Proliferation effects were additionally evaluated with CompuSyn software median effect analysis and showed a concentration index CI < 1, confirming synergy. The results suggest vertical as well as the usual horizontal strategies for discovering pharmacological actives in plants.

botanical chaos chemoprevention complex drug complexity drug design drug discovery natural product 

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References

  1. 1.
    McKetchnie JL (ed.): Webster's NewTwentieth Century Dictionary of the English Language Unabridged. Second edition. The World Publishing Company, Cleveland, OH, 1971Google Scholar
  2. 2.
    Bolar JP, Norelli JL, Harman GE, Brown SK, Aldwinckle HS: Synergistic activity of endochitinase and exochitinase from Trichoderma atroviride (T. harzianum) against the pathogenic fungus (Venturia inaequalis) in transgenic apple plants. Transgenic Res 10: 533-543, 2001.Google Scholar
  3. 3.
    Bach LA, Bentzen SM, Alsner J, Christiansen FB: An evolutionary-game model of tumour-cell interactions: Possible relevance to gene therapy. Eur J Cancer 37: 2116-2120, 2001Google Scholar
  4. 4.
    Trapani JA: Target cell apoptosis induced by cytotoxic T cells and natural killer cells involves synergy between the pore-forming protein, perforin, and the serine protease, granzyme B. Aust N Z J Med 25: 793-799, 1995Google Scholar
  5. 5.
    Curnis F, Sacchi A, Corti A: Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Invest 110: 475-482, 2002Google Scholar
  6. 6.
    Shen F, Weber G: Synergistic action of quercetin and genistein in human ovarian carcinoma cells. Oncol Res 9: 597-602, 1997Google Scholar
  7. 7.
    Guthrie N, Carroll KK: Inhibition of mammary cancer by citrus flavonoids. Adv Exp Med Biol 439: 227-236, 1998Google Scholar
  8. 8.
    Gilbert B, Alves LF: Synergy in plant medicines. Curr Med Chem 10: 13-20, 2003Google Scholar
  9. 9.
    Williamson EM: Synergy and other interactions in phytomedicines. Phytomedicine 8(5): 401-409, 2001Google Scholar
  10. 10.
    Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K: Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 15;97: 1433-1437, 2000Google Scholar
  11. 11.
    Melgarejo P, Salazar DM, Artes F: Organic acids and sugars com-positionof harvested pomegranate fruits. Eur Food Res Technol 211: 185-190, 2000Google Scholar
  12. 12.
    Artik N: Determination of phenolic compounds in pomegranate juice by using HPLC. Fruit Processing 8: 492-499, 1998Google Scholar
  13. 13.
    Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA: Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 48: 4581-4589, 2000Google Scholar
  14. 14.
    Plumb GW, de Pascual-Teresa S, Santos-Buelga C, Rivas-Gonzalo JC, Williamson G: Antioxidant properties of gallocatechin and prodelphinidins from pomegranate peel. Redox Report 7: 41-46, 2002Google Scholar
  15. 15.
    Rosenberg Zand RS, Jenkins DJA, Diamandis EP: Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res Treat 62: 35-49, 2000Google Scholar
  16. 16.
    Mehta R, Lansky EP: Breast cancer chemopreventive properties of pomegranate (Punica granatum) in a mouse mammary organ culture (MMOC). Eur J Cancer Prev, in Press.Google Scholar
  17. 17.
    van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J: Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry. Phytochemistry 65: 233-234, 2004Google Scholar
  18. 18.
    Schubert SY, Lansky EP, Neeman I: Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J Ethnopharmacol 66: 11-17, 1999Google Scholar
  19. 19.
    Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay A, Poirier D, Nicholls P, Kirby A, Jiang W, Mansel R, Ramachandran C, Rabi T, Kaplan B, Lansky E: Chemopreventive and adjuvant therapeu-tic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat 71: 203-217, 2002Google Scholar
  20. 20.
    Abd El Wahab SM, El Fiki NM, Mostafa SF, Hassan AEB: Characterization of certain steroid hormones in Punica granatum seeds. Bull Fac Pharm Cairo University 36: 11-15, 1998Google Scholar
  21. 21.
    Suzuki R, Noguchi R, Ota T, Abe M, Miyashita K, Kawada T: Cytotoxic effect of conjugated trienoic fatty acids on mouse tu-mor and human monocytic leukemia cells. Lipids 36: 477-482, 2001Google Scholar
  22. 22.
    Nugteren DH, Christ-Hazelhof E: Naturally occurring conjugated octadecatrienoic acids are strong inhibitors of prostaglandin biosynthesis. Prostaglandins, Leukotrienes, and Essential Fatty Acids 33: 403-417, 1987Google Scholar
  23. 23.
    Hora JJ, Maydew ER, Lansky, EP, Dwivedi C: Chemopreventive effects of pomegranate seed oil on skin tumor development in CD1 mice. J Med Food 6: 157-161, 2003Google Scholar
  24. 24.
    Albrecht M, Jiang WG, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A, Mansel RE, Neeman I, Geldof AA, Campbell MJ: Pomegranate extracts potently suppress proliferation, xenograft growth and invasion of human prostate cancer cells. J Med Food 7: 274-283, 2004Google Scholar
  25. 25.
    Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, Carr RE, Oikawa T, Lansky EP: Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 6: 121-128, 2003Google Scholar
  26. 26.
    Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR: Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metallo-proteinases. Cancer Res 60: 4629-4637, 2000Google Scholar
  27. 27.
    Jiang J, Neubauer BL, Graff JR, Chedid M, Thomas JE, Roehm NW, Zhang S, Eckert GJ, Koch MO, Eble JN, Cheng L: Expression of group IIA secretory phospholipase A2 is elevated in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Pathol 160: 667-671, 2002Google Scholar
  28. 28.
    Rashid SF, Moore JS, Walker E, Driver PM, Engel J, Edwards CE, Brown G, Uskokovic MR, Campbell MJ: Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 Dihydroxyvitamin D(3) and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene 20: 1860-1872, 2001Google Scholar
  29. 29.
    Jiang WG, Hiscox S, Hallett MB: Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA). Cancer Res 55: 5043-5048, 1995Google Scholar
  30. 30.
    Kennedy BP, Soravia C, Moffat J, Xia L, Hiruki T, Collins S, Gallinger S, Bapat B: Overexpression of the nonpancreatic secretory group II PLA2 messenger RNA and protein in colorectal ade-nomas from familial adenomatous polyposis patients. Cancer Res 58: 500-503, 1998Google Scholar
  31. 31.
    Poch, G, Vychodil-Kahr S, Petru E: Sigmoid model versus median-effect analysis for obtaining dose-response curves for in vitro chemosensitivity testing. Int J Clin Pharmacol Ther 37: 189-192, 1999Google Scholar
  32. 32.
    Viant MR: Improved methods for the acquisition and interpretation of NMR metabolomic data. Biochem Biophys Res Commun 310: 943-948, 2003Google Scholar
  33. 33.
    Lindon JC, Holmes E, Nicholson JK: Metabonomics and its role in drug development and disease diagnosis. Expert Rev Mol Diagn 4: 189-199, 2004Google Scholar
  34. 34.
    Baker ME: Endocrine activity of plant-derived compounds: An evolutionary perspective. Proc Soc Exp Biol Med 208: 131-138, 1995Google Scholar
  35. 35.
    Oberdorster E, Clay MA, Cottam DM: Common phytochemicals are ecdysteroid agonists and antagonists: A possible evolutionary link between vertebrate and invertebrate steroid hormones. J Steroid Biochem Mol Biol 77: 229-238, 2001Google Scholar
  36. 36.
    Tang BY, Adams NR: Oestrogen receptors and metabolic activity in the genital tract after ovariectomy of ewes with permanent infertility caused by exposure to phytoestrogens. J Endocrinol 89: 365-370, 1981Google Scholar
  37. 37.
    Gadgeel SM, Shields AF, Heilbrun LK, Labadidi S, Zalupski M, Chaplen R, Philip PA: Phase II study of paclitaxel and carboplatin in patients with advanced gastric cancer. Am J Clin Oncol 26: 37-41, 2003Google Scholar
  38. 38.
    Harris NM, Anderson WR, Lwaleed BA, Cooper AJ, Birch BR, Solomon LZ: Epirubicin and meglumine gamma-linolenic acid: A logical choice of combination therapy for patients with superficial bladder carcinoma. Cancer 97: 71-78, 2003.Google Scholar
  39. 39.
    Nair S, Boczkowski D, Moeller B, Dewhirst M, Vieweg J, Gilboa E: Synergy between tumor immunotherapy and antiangiogenic therapy. Blood 102: 964-971, 2003Google Scholar
  40. 40.
    Schwab ED, Pienta KJ: Cancer as a complex adaptive system. Med Hypotheses 47: 235-241, 1996Google Scholar
  41. 41.
    Waliszewski P, Molski M, Konarski J: On the holistic approach in cellular and cancer biology: Nonlinearity, complexity, and quasi-determinism of the dynamic cellular network. J Surg Oncol 68: 70-78, 1998Google Scholar
  42. 42.
    Regalado A: A gentle scheme for unleashing chaos. Science 268: 1848, 1995Google Scholar
  43. 43.
    Cerda B, Llorach R, Ceron JJ, Espin JC, Tomas-Barberan FA: Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice. Eur J Nutr 42: 18-28, 2003Google Scholar
  44. 44.
    Cerda B, Ceron JJ, Tomas-Barberan FA, Espin JC. Repeated oral administration of high doses of the pomegranate ellagitannin puni-calagin to rats for 37 days is not toxic. J Agric Food Chem 51: 3493-3501, 2003Google Scholar
  45. 45.
    Perez-Vicente A, Gil-Izquierdo A, Garcia-Viguera C. In vitro gastrointestinal digestion study of pomegranate juice phenolic com-pounds, anthocyanins, and vitamin C. J Agric Food Chem 50: 2308-2312, 2002Google Scholar
  46. 46.
    Longtin R: The pomegranate: Nature's power fruit? J Natl Cancer Inst 95: 346-348, 2003Google Scholar
  47. 47.
    Aviram M, Dornfeld L, Rosenblat M, Volkova N, Kaplan M, Coleman R, Hayek T, Presser D, Fuhrman B. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: Studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr 71: 1062-1076, 2000Google Scholar
  48. 48.
    Kaplan M, Hayek T, Raz A, Coleman R, Dornfeld L, Vaya J, Aviram M: Pomegranate juice supplementation to atherosclerotic mice re-duces macrophage lipid peroxidation, cellular cholesterol accumu-lation and development of atherosclerosis. J Nutr 131: 2082-2089, 2001Google Scholar
  49. 49.
    Aviram M, Dornfeld L, Kaplan M, Coleman R, Gaitini D, Nitecki S, Hofman A, Rosenblat M, Volkova N, Presser D, Attias J, Hayek T, Fuhrman B: Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: Studies in atherosclerotic mice and in humans. Drugs Exp Clin Res 28: 49-62, 2002Google Scholar
  50. 50.
    Langley P: Why a pomegranate? BMJ 321: 1153-1154, 2000Google Scholar
  51. 51.
    Heftmann E, Ko ST, Bennet RD: Identification of estrone in pomegranate seeds. Phytochemistry 5: 1337, 1966Google Scholar
  52. 52.
    Moneam NMA, El Sharaky AS, Badreldin MM: Oestrogen content of pomegranate seeds. J Chromatography 438: 438-442, 1988Google Scholar
  53. 53.
    Lei F, Xing DM, Xiang L, Zhao YN, Wang W, Zhang LJ, Du LJ: Pharmacokinetic study of ellagic acid in rat after oral administration of pomegranate leaf extract. Chromatogr B Analyt Technol Biomed Life Sci 796: 189-194, 2003Google Scholar
  54. 54.
    Amakura Y, Okada M, Tsuji S, Tonogai Y: High-performance liquid chromatographic determination with photodiode array detection of ellagic acid in fresh and processed fruits. J Chromatogr A 896: 87-93, 2000Google Scholar

Copyright information

© Kluwer Academic Publishers 2005

Authors and Affiliations

  • Ephraim P. Lansky
    • 1
  • Wenguo Jiang
    • 2
  • Huanbiao Mo
    • 3
  • Lou Bravo
    • 3
  • Paul Froom
    • 4
  • Weiping Yu
    • 5
  • Neil M. Harris
    • 6
  • Ishak Neeman
    • 7
  • Moray J. Campbell
    • 8
  1. 1.Rimonest Ltd., Horev Center, BoxIsrael
  2. 2.University Department of SurgeryUniversity of Wales College of MedicineUK
  3. 3.Department of Nutrition and Food ScienceTexas Women's UniversityDentonUSA
  4. 4.Department of Epidemiology and Preventive MedicineSackler Medical School, Tel Aviv UniversityIsrael
  5. 5.School of Biological SciencesUniversity of Texas at AustinAustinUSA
  6. 6.Department of UrologyRoyal Bournemouth HospitalUK
  7. 7.Department of Food Engineering and BiotechnologyTechnion—Israel Institute of TechnologyIsrael
  8. 8.Division of Medical SciencesUniversity of Birmingham Medical SchoolUK

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