DOI QR코드

DOI QR Code

Effects of Unripe Black Raspberry Extracts on Prostate Cancer Cell Line and Rat Model of Benign Prostatic Hyperplasia

복분자 미숙과 추출물이 전립선암 세포주와 전립선비대 백서모델에 미치는 영향

  • Received : 2013.12.23
  • Accepted : 2014.03.10
  • Published : 2014.04.30

Abstract

Benign prostatic hyperplasia (BPH), which is commonly found in aging men, is characterized by hyperplasia of prostatic stromal and epithelial cells beginning in the periurethral zone of the prostate. The prevalence of BPH increases in an age-dependent manner. Here, we investigated the protective effects of unripe Rubus occidentalis extracts (UROE) on BPH development using a prostate cancer cell line and testosterone-induced BPH rat model. Experiments using an established hormone-dependent prostate cancer cell line (LNCaP) showed that UROE treatment significantly decreased expression of androgen-related genes, including androgen receptor (AR), prostate specific antigen (PSA), and 5-alpha reductase 2, but not 5-alpha reductase 1, which was also observed in flutamide-treated cells. Further, AR and PSA gene expression was reduced by UROE treatment under androgen-stimulated conditions using dihydrotestosterone (DHT). BPH animals displayed elevated prostate weights. However, UROE as well as finasteride treatment significantly reduced prostate weights and DHT levels compared to testosterone-induced BPH animals. Histopathological analysis also showed that UROE treatment suppressed testosterone-induced prostatic hyperplasia. Taken together, the results suggest that UROE may effectively inhibit the development of BPH and thus may be a useful agent in BPH treatment.

본 연구는 전립선암세포주인 LNCaP 세포주와 테스토스테론으로 유도된 전립선비대 백서모델에서 복분자 추출물의 전립선비대 억제 효과를 조사하였다. 첫째, 전립선암 세포주(LNCaP)에서 복분자 미숙과 추출물의 안드로겐 관련 전립선비대 유전자 억제 효과를 조사한 결과 미숙과 50% 에탄올 추출물은 안드로겐 수용체(AR)뿐만 아니라 전립선특이항원(PSA)과 5-알파 환원 효소 type 2(5AR2)의 발현을 가장 높게 억제하였다. 또한 LNCaP 세포에 DHT로 안드로겐 관련 유전자를 유도한 후 복분자 미숙과 50% 에탄올 추출물을 처리한 결과 AR과 PSA mRNA의 발현이 억제됨을 확인하였다. 둘째, 테스토스테론을 이용하여 전립선비대를 유도한 동물모델에서 복분자 미숙과 50% 에탄올 추출물을 6주간 투여한 후 전립선비대 개선 효과를 조사한 결과, 전립선비대유발군에 복분자 미숙과 추출물을 투여한 군에서 전립선 무게, 전립선 소포의 상피세포 두께 및 면적이 감소함을 확인할 수 있었고, 전립선비대 유발 호르몬인 DHT level이 감소함을 확인할 수 있었다.

Keywords

References

  1. Carson C 3rd, Rittmaster R. 2003. The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61: 2-7.
  2. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, Mc- Connell JD, Russell DW. 1993. Tissue distribution and ontogeny of steroid 5alpha-reductase isozyme expression. J Clin Invest 92: 903-910. https://doi.org/10.1172/JCI116665
  3. Asada Y, Sonoda T, Ojiro M, Kurata S, Sato T, Ezaki T, Takayasu S. 2001. 5alpha-reductase type 2 is constitutively expressed in the dermal papilla and connective tissue sheath of the hair follicle in vivo but not during culture in vitro. J Clin Endocrinol Metab 86: 2875-2880.
  4. Steers WD. 2001. 5alpha-reductase activity in the prostate. Urology 58: 17-24. https://doi.org/10.1016/S0090-4295(01)01299-7
  5. Nixon P. 1997. New clinical trial of medical therapy for benign prostatic hyperplasia. Drug Benefit Trends 9: 44-45.
  6. Lazier CB, Thomas LN, Douglas RC, Vessey JP, Rittmaster RS. 2004. Dutasteride, the dual 5alpha-reductase inhibitor, inhibits androgen action and promotes cell death in the LNCaP prostate cancer cell line. Prostate 58: 130-144. https://doi.org/10.1002/pros.10340
  7. Angwafor F 3rd, Anderson ML. 2008. An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males. J Int Soc Sports Nutr 5: 12. https://doi.org/10.1186/1550-2783-5-12
  8. Dreikorn K. 2005. Complementary and alternative medicine in urology. BJU Int 96: 1177-1184. https://doi.org/10.1111/j.1464-410X.2005.05931.x
  9. Fagelman E, Lowe FC. 2002. Herbal medications in the treatment of benign prostatic hyperplasia (BPH). Urol Clin North Am 29: 23-29. https://doi.org/10.1016/S0094-0143(02)00015-0
  10. Ahn DK. 1998. Illustrated book of Korea medicinal herbs. Kyohak Publishing Co, Seoul, Korea. p 946-947.
  11. Boivin D, Blanchette M, Barrette S, Moghrabi A, Beliveau R. 2007. Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice. Anticancer Res 27: 937-948.
  12. Seeram NP. 2008. Berry fruits for cancer prevention: current status and future prospects. J Agric Food Chem 56: 630-635. https://doi.org/10.1021/jf072504n
  13. Jeong J, Jung H, Lee S, Lee H, Hwang KT, Kim T. 2010. Anti-oxidant, anti-proliferative and anti-inflammatory activities of the extracts from black raspberry fruits and wine. Food Chem 123: 338-344. https://doi.org/10.1016/j.foodchem.2010.04.040
  14. Pieters R, Huismans DR, Leyva A, Veerman AJ. 1998. Adaptation of the rapid automated tetrazolium dye based (MTT) assay for chemosensitivity testing in childhood leukemia. Cancer Lett 41: 323-332.
  15. Shin IS, Lee MY, Jung DY, Seo CS, Ha HK, Shin HK. 2012. Ursolic acid reduces prostate size and dihydrotestosterone level in a rat model of benign prostatic hyperplasia. Food Chem Toxicol 50: 884-888. https://doi.org/10.1016/j.fct.2012.01.007
  16. Babinski MA, Chagas MA, Costa WS, Sampaio FJ. 2003. Prostatic epithelial and luminal area in the transition zone acini: morphometric analysis in normal and hyperplastic human prostate. BJU Int 92: 592-596. https://doi.org/10.1046/j.1464-410X.2003.04433.x
  17. Scheinfeld NA. 2008. review of hormonal therapy for female pattern (androgenic) alopecia. Dermatol Online J 14: 1.
  18. Kim JM, Shin MS. 2011. Characteristics of Rubus coreanus Miq. fruits at different ripening stages. Korean J Food Sci Technol 43: 341-347. https://doi.org/10.9721/KJFST.2011.43.3.341
  19. Kwon JW, Lee HK, Park HJ, Kwon TO, Choi HR, Song JY. 2011. Screening of biological activities to different ethanol extracts of Rubus coreanus Miq. Korean J Medicinal Crop Sci 19: 325-333. https://doi.org/10.7783/KJMCS.2011.19.5.325
  20. Richard A, Hiipakka RA, Zhong HZ, Dai W, Dai Q, Liao S. 2002. Structure-activity relationships for inhibition of human 5${\alpha}$-redutases by polyphenols. Biochem Pharmacol 63:1165-1176. https://doi.org/10.1016/S0006-2952(02)00848-1
  21. Ren F, Zhang S, Mitchell SH, Butler R, Young CY. 2000. Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells. Oncogene 19: 1924-1932. https://doi.org/10.1038/sj.onc.1203511
  22. Siddiqui IA, Asim M, Hafeez BB, Adhami VM, Tarapore RS, Mukhtar H. 2011. Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB J 25:1198-1207. https://doi.org/10.1096/fj.10-167924
  23. Kim SD, Lee BH, Sohn DW, Cho YH, Lee SM, Kim JO, Lim SW. 2008. The effect of herbal formulation KH-305 mainly consisted of Rubus coreanus on benign prostatic hyperplasia-induced rat. Kor J Pharmacogn 39: 80-85.
  24. Peters DH, Sorkin EM. 1993. Finasteride. A review of its potential in the treatment of benign prostatic hyperplasia. Drugs 46: 177-208.
  25. Bisson JF, Hidalgo S, Rozan P, Messaoudi M. 2007. Therapeutic effect of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats. J Med Food 10: 628-635. https://doi.org/10.1089/jmf.2006.242
  26. Aleksandra K, Katarina S, Gordana Z, Teodora J, Zorica J, Nebojsa M, Ivan S. 2011. Biological activity and chemical composition of different berry juices. Food Chem 125:1412-1417. https://doi.org/10.1016/j.foodchem.2010.10.018

Cited by

  1. Anti-microbial, Anti-oxidant, and Anti-thrombosis Activities of the Lees of Bokbunja Wine (Rubus coreanus Miquel) vol.25, pp.7, 2015, https://doi.org/10.5352/JLS.2015.25.7.757
  2. Characteristics of Lactic Acid Fermentation of Black Raspberry Juice Using the Lactobacillus plantarum GBL17 Strain vol.31, pp.6, 2015, https://doi.org/10.9724/kfcs.2015.31.6.773
  3. Characterization of Lactobacillus plantarum strains isolated from black raspberry and their effect on BALB/c mice gut microbiota pp.2092-6456, 2018, https://doi.org/10.1007/s10068-018-0420-3
  4. Amelioration of Benign Prostatic Hyperplasia by Costunolide and Dehydrocostus Lactone in Wistar Rats vol.39, pp.2, 2021, https://doi.org/10.5534/wjmh.190053