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The Effects of Isoflavone Supplementation on Serum PSA, Lipid Profile, Antioxidant and Immune System in Prostate Cancer Patients

이소플라본 섭취가 전립선암환자의 Serum PSA, 지질패턴, 항산화체계 및 면역체계에 미치는 영향

  • Lee, Joo-Min (Dept. of Food and Nutrition, Yonsei University) ;
  • Hong, Sung-Joon (Dept. of Urology, College of Medicine, Yonsei University) ;
  • Lee, Min-June (Research Institute of Food and Nutritional Sciences, Yonsei University) ;
  • Yoon, Sun (Dept. of Food and Nutrition, Yonsei University)
  • 이주민 (연세대학교 식품영양학과) ;
  • 홍성준 (연세대학교 의과대학 비뇨기과학교실) ;
  • 이민준 (연세대학교 식품영양과학연구소) ;
  • 윤선 (연세대학교 식품영양학과)
  • Published : 2004.10.01

Abstract

Soy foods are a unique dietary source of isoflavones, which have effects relevant to prostate cancer prevention. The present study determines the effects of a short-term isoflavone supplement on serum PSA (prostate specific antigen), lipid profile, antioxidant status, and immune system in prostate cancer patients. Ten prostate cancer patients were supplemented daily with 150 mg of isoflavone for 2 months. Blood samples were collected baseline and 2 month after for analysis of PSA, serum lipid profiles, total antioxidant status (TAS), grade of DNA damage in lymphocytes, IL-6, VEGF and TNF -$\alpha$. After 2 month isoflavone supplementation, increased significantly a total of estimated urinary isoflavone excretion and did not change PSA. Serum lipid profiles showed significant change in serum total cholesterol level (p=0.007). However, there was no significant change in HDL- and LDL-cholesterol levels. TAS was increased but not significant after isoflavone supplementation. Tail moment (TM) was decreased and especially tail length (TL) was decreased significantly (p=0.043). IL-6 level was decreased but VEGF level and TNF -$\alpha$ level were increased. The results of the present study led to the conclusion that the isoflavone dosage (150 mg) in supplement had positive effects on the serum total cholesterol level and DNA damage.

본 연구에서는 전립선암 환자를 대상으로 이소플라본 보충제 섭취가 혈중 PSA 농도, 지질 패턴, 면역체계 및 항산화체계에 미치는 영향에 대하여 검토하고자 하였다. 전립선암환자에 게 하루 150 mg의 이소플라본을 섭취시킨 결과, 이소플라본 섭취 전에 비해 소변 내 이소플라본의 배설량이 유의적으로 증가하였다. PSA(prostate specific antigen)의 경우는 이소플라본 섭취 전보다 섭취 2달 후에 약간 증가함을 보였으나 유의적인 수준은 아니었다. 이소플라본 섭취가 전립선암 환자의 혈청 지질패턴에 미치는 영향에 대한 분석결과, 총 콜레스테롤의 경우 이소플라본 섭취 시작 전에 비해 섭취 2달 후에 유의적으로 감소되었으며, LDL 콜레스테롤의 경우 이소플라본 섭취 2달 후에 감소하는 경향을 보였으나 유의적인 차이를 보이지 않았고, HDL 콜레스테롤 수준에는 변화가 없는 것으로 나타났다. IL-6의 경우, 이소플라본 섭취 전에 비해 이소플라본 섭취 후에 수치가 감소하였고, VEGF와 TNF-$\alpha$는 이소플라본 섭취 전보다 섭취 2개월 후에 증가하였으나 유의적인 차이를 보이지는 않았다. 이소플라본 섭취전ㆍ후의 총항산화력을 TAS를 통해 측정한 결과 이소플라본 투여 전에 비 해 투여 2개월 후 수치가 증가하였으나 통계적으로 유의적인 차이는 보이지 않았다. 또한 혈액에서 분리된 임파구의 DNA 손상 정도를 측정하기 위해 comet assay를 시도한 결과 tail moment (TM)의 경우 이소플라본 섭취 2달 후에 감소하였으나 유의적인 차이는 없었으며, tail length(TL)의 경우는 유의적으로 감소하였다. 본 연구의 제한점으로는 연구 대상자의 수가 적었으며, 실험 결과를 비교할 대조군이 없었고, 연구기간이 짧다는 것을 들 수 있다. 따라서 이번 연구에서 이소플라본이 전립선암에 기대되는 효과를 보여주기엔 미비한 점이 있었다. 그러나 본 연구결과 이소플라본은 전립선암 환자의 혈중 지질 패턴과 항산화체계를 개선시키는 효과를 보였다. 따라서 이소플라본이 지질대사에 미치는 영향과 항산화작용기전에 대한 보다 심층적인 연구가 이루어져야 할 것이며, 보다 많은 전립선암 환자를 대상으로 이소플라본 섭취에 따른 장기적인 임상실험연구가 이루어져 이소플라본이 전립선암 환자의 삶의 질을 향상시킬 수 있는지에 대한 다각적인 검토가 필요하다고 본다.

Keywords

References

  1. Korea National Statistical Office. 2003. Annual report on cause of death statistics
  2. Messina MJ, Persky V, Setchell KD, Barnes S. 1994. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer 21: 113-131 https://doi.org/10.1080/01635589409514310
  3. Adlercreutz H, Mazur W, Bartels P, Elomaa V, Watanabe S, Wahala K. 2000. Phytoestrogens and prostate disease. J Nutr 130: 658S-659S https://doi.org/10.1093/jn/130.3.658S
  4. DiPaola RS, Zhang H, Lambert GH, Meeker R, Licitra E, Rafi MM. 1998. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339: 785-791 https://doi.org/10.1056/NEJM199809173391201
  5. Affenito SG, Kerstetter J. 1999. Position of the American dietetic association and dietitians of Canada: women's health and nutrition. J Am Diet Assoc 99: 738-751 https://doi.org/10.1016/S0002-8223(99)00178-9
  6. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. 1987. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262: 5592-5595
  7. Davis JN, Muqim N, Bhuiyan M, Kucuk O, Pienta KJ, Sarkar FH. 2000. Inhibition of prostate specific antigen expression by genistein in prostate cancer cells. Int J Oncol 16: 1091-1097
  8. Messina MJ. 2003. Emerging evidence on the role of soy in reducing prostate cancer risk. Nutr Rev 61: 117-131 https://doi.org/10.1301/nr.2003.apr.117-131
  9. Onozawa M, Fukuda K, Ohtani M, Akaza H, Sugimura T, Wakabayashi K. 1998. Effects of soybean isoflavones on cell growth and apoptosis of the human prostatic cancer cell line LNCaP. Jpn J Clin Oncol 28: 360-363 https://doi.org/10.1093/jjco/28.6.360
  10. Twillie DA, Eisenberger MA, Carducci MA, Hseih WS, Kim WY, Simons JW. 1995. Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology 45: 542-549 https://doi.org/10.1016/S0090-4295(99)80034-X
  11. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. 1999. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 41: 127-133 https://doi.org/10.1002/(SICI)1097-0045(19991001)41:2<127::AID-PROS7>3.0.CO;2-H
  12. Ferrara N, Davis-Smith T. 1997. The biology of vascular endothelial growth factor. Endocr Rev 18: 4-25 https://doi.org/10.1210/er.18.1.4
  13. Claffey KP, Robinson GS. 1996. Regulation of VEGF/VPF expression in tumor cells: consequences for tumor growth and metastasis. Cancer Metastasis Rev 15: 165-176 https://doi.org/10.1007/BF00437469
  14. Torel J, Cillard J, Cillard P. 1986. Antioxidant activity of flavonoids and reactivity with peroxy radical. Phytochemistry 25: 383-385 https://doi.org/10.1016/S0031-9422(00)85485-0
  15. Wang W, Goodman MT. 1999. Antioxidant property of dietary phenolic agents in a human LDL-oxidation ex vivo model: interaction of protein binding activity. Nutr Res 19: 191-202 https://doi.org/10.1016/S0271-5317(98)00183-3
  16. Huang MH, Harrison GG, Mohamed MM, Gornbein JA, Henning SM, Go VLW, Greendale GA. 2000. Assessing the accuracy of a food frequency questionnaire for estimating usual intake of phytoestrogens. Nutrition and Cancer 37: 145-154 https://doi.org/10.1207/S15327914NC372_5
  17. Miller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A. 1993. A novel method for measuring antioxidant capacity and its application to monitoring the antioxidants status in premature neonates. Clin Sci 84: 407-412 https://doi.org/10.1042/cs0840407
  18. Miller NJ, Castellucio C, Tijburg L, Rice-Evans C. 1996. The antioxidant properties of theaflavins and their gallate esters-radical scavengers or metal chelators. FEBS Letters 392: 40-44 https://doi.org/10.1016/0014-5793(96)00780-6
  19. Rice-Evans C, Miller NJ. 1994. Total antioxidant status in plasma and body fluids. Methods Enzymol 234: 279-293 https://doi.org/10.1016/0076-6879(94)34095-1
  20. Sachez-Rodriguez M, Mendoza-Nunez VM, Vargas-Guadarrama LA. 1998. Niveles de antioxidantes totales en una muestra de la poblaci?n gerontol?gica de la ciudad de Mexico. Bioquimia 23: 848-855
  21. Hansen MB, Svenson M, Diamant M, Bendtzen K. 1993. High-affinity IgG autoantibodies to IL-6 in sera of normal individuals are competitive inhibitors of IL-6 in vitro. Cytokine 5: 72-80 https://doi.org/10.1016/1043-4666(93)90026-2
  22. MacEwan DJ. 2002. TNF ligands and receptors - a matter of life and death. British J Pharmacology 135: 855-875 https://doi.org/10.1038/sj.bjp.0704549
  23. Cao Y, Chen H, Zhou L, Chiang MK, Anand-Apte B, Weatherbee JA, Wang Y, Fang F, Flanagan JG, Tsang ML. 1996. Heterodimers of placenta growth factor/vascular endothelial growth factor. J Biol Chem 271: 3154-3162 https://doi.org/10.1074/jbc.271.6.3154
  24. Rojas E, Lopez MC, Valverde M. 1999. Single cell gel electrophoresis assay: methodology and applications. J Chromatography B 722: 225-254 https://doi.org/10.1016/S0378-4347(98)00313-2
  25. King RA, Bursill DB. 1998. Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 67: 867-872 https://doi.org/10.1093/ajcn/67.5.867
  26. Jarred RA, Keikha M, Dowling C. 2002. Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev 11: 1689-1696
  27. Urban D, Irwin W, Kirk M, Markiewicz MA, Myers R, Smith M, Weiss H, Grizzle WE, Barnes S. 2001. The effects of isolated soy protein in plasma biomarkers in elderly men with elevated serum prostate specific antigen. J Urol 165: 294-300 https://doi.org/10.1097/00005392-200101000-00082
  28. Jenkins DJ, Kendall CW, D'Costa MA, Jackson CJ, Vidgen E, Singer W, Silverman JA, Koumbridis G, Honey J, Rao AV, Fleshner N, Klotz L. 2003. Soy consumption and phytoestrogens: effect on serum prostate specific antigen when blood lipids and oxidized low-density lipoprotein are reduced in hyperlipidemic men. J Urol 169: 507-511 https://doi.org/10.1016/S0022-5347(05)63944-4
  29. Kirk EA, Sutherland P, Wang SA, Chait A, LeBoeuf RC. 1998. Dietary isoflavones reduce plasma cholesterol and atherosclerosis in C57BL/6 mice but not LDL receptor- deficient mice. J Nutr 128: 954-959 https://doi.org/10.1093/jn/128.6.954
  30. Kapiotis S, Hermann M, Held I, Seelos C, Ehringer H, Gmeiner BM. 1997. Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL. Arterioscler Thromb Vasc Biol 17: 2868-2674 https://doi.org/10.1161/01.ATV.17.11.2868
  31. Ruiz-Larrea MB, Mohan AR, Paganga G, Miller NJ, Bolwell GP, Rice-Evans CA. 1997. Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res 26: 63-70 https://doi.org/10.3109/10715769709097785
  32. Sargeant P, Farndale RW, Sage SO. 1993. The tyrosine kinase inhibitors methyl 2,5-dihydroxycinnimate and genistein reduce thrombin-evoked tyrosine phophorylation and $Ca^2^+$ entry in human platelets. FEBS Letters 315: 242 -246 https://doi.org/10.1016/0014-5793(93)81172-V
  33. Wilcox JN, Blumenthal BF. 1995. Thrombotic mechanisms in atherosclerosis: potential impact of soy protein. J Nutr 125: 631S-638S
  34. Akiyama T, Ishida J, Nakagava S, Ogawara S, Watanabe S, Itoh N, Shiyba M, Fukami Y. 1987. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262: 5592-5595
  35. Smith PC, Hobisch A, Lin DL, Culig Z, Keller ET. 2001. Interleukin-6 and prostate cancer progression. Cytokine & Growth Factor Reviews 12: 33-40 https://doi.org/10.1016/S1359-6101(00)00021-6
  36. Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. 1999. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 161: 182-187 https://doi.org/10.1016/S0022-5347(01)62092-5
  37. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. 1999. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 41: 127-133 https://doi.org/10.1002/(SICI)1097-0045(19991001)41:2<127::AID-PROS7>3.0.CO;2-H
  38. Jones A, Fujiyama C, Turner K, Fuggle S, Cranston D, Bicknell R, Harris AL. 2000. Elevated serum vascular endothelial growth factor in patients with hormone-escaped prostate cancer. BJU Int 85: 276-280 https://doi.org/10.1046/j.1464-410x.2000.00432.x
  39. Duque JLF, Loughlin KR, Adam RM. 1999. Plasma levels of vascular endothelial growth factor are increased in patients with metastatic prostate cancer. Urology 54: 523- 527 https://doi.org/10.1016/S0090-4295(99)00167-3
  40. Turner K, Jones A. 2000. Vascular endothelial growth factor in prostate cancer. Urology 56: 183
  41. Kollermann J, Helpap B. 2001. Expression of vascular endothelial growth factor (VEGF) and VEGF receptor Flk-1 in benign, premalignant, and malignant prostate tissue. Am J Clin Pathol 116: 115-121 https://doi.org/10.1309/1LBM-6X32-JH6W-ENUD
  42. Lucia MS, Torkko KC. 2004. Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale. J Urol 171: S30-S35 https://doi.org/10.1097/01.ju.0000108142.53241.47
  43. Davis JN, Kucuk O, Djuric Z, Sarkar FH. 2001. Soy isoflavone supplementation in healthy men prevents NF- kappa B activation by TNF-alpha in blood lymphocytes. Free Radic Biol Med 30: 1293-1302 https://doi.org/10.1016/S0891-5849(01)00535-4
  44. Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. 1999. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18: 3166-3172 https://doi.org/10.1038/sj.onc.1202650
  45. Morris SM, Chen JJ, Domon OE, McGarrity LJ, Bishop ME, Manjanatha MG, Casciano DA. 1998. P53, mutation and apoptosis in genistein-exposed human lymphoblastoid cells. Mutat Res 405: 41-56 https://doi.org/10.1016/S0027-5107(98)00126-2
  46. Salti GI, Grewal S, Mehta RR, Das Gupta TK, Boddie AW, Constantinou AI. 2000. Genistein induces apoptosis and topoisomerase Π-mediated DNA breakage in colon cancer cells. Eup J Cancer 36: 796-802 https://doi.org/10.1016/S0959-8049(00)00017-4
  47. Traganos F, Ardelt B, Halko N, Bruno S, Darzynkiewicz Z. 1992. Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res 52: 6200- 6208
  48. Miltyk W, Craciunescu CN, Fischer L, Jeffcoat RA, Koch MA, Lopaczynski W, Mahoney C, Jeffcoat RA, Crowell J, Paglieri J, Zeisel SH. 2003. Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J Clin Nutr 77: 875-882 https://doi.org/10.1093/ajcn/77.4.875
  49. Mitchell JH, Collins AR. 1999. Effects of a soy milk supplement on plasma cholesterol levels and oxidative DNA damage in men-a pilot study. Eur J Nutr 38: 143-148 https://doi.org/10.1007/s003940050055
  50. Djuric Z, Chen G, Doerge DR, Heilbrun LK, Kucuk O. 2001. Effect of soy isoflavone supplementation on markers of oxidative stress in men and women. Cancer Letters 172: 1-6 https://doi.org/10.1016/S0304-3835(01)00627-9