An introduction to genetic and epigenetic changes in prostate gland – implications in efficacy of phytotherapy of benign prostatic hyperplasia and prostate cancer

Joanna Bartkowiak-Wieczorek, Radosław Kujawski, Anna Bogacz, Marcin Ożarowski


The usage of classical pharmacological treatment of prostate diseases causes the risk of a number of side effects therefore the researchers are looking for new pharmacologically active molecules, including those contained in the plant extracts. The most widely studied is the lipido-sterolic extract from Serenoa repens (saw palmetto), water extract from Camellia sinensis (green tea) and several cruciferous vegetables. The molecular mechanisms underlying of the development and the progression of prostate disorders, especially benign prostatic hyperplasia (BPH) and prostate cancer (PC), remain still poorly understood. The development of pathologically changed prostate cells proliferation involves many factors, including genetic alterations, such as mutations, and epigenetic changes, appear to contribute to the transformation and progression of prostate cancer. In this paper we suggest that the knowledge of epigenetic modifications presented in this paper introduces the new point of view concerning the possibility of action of plant substances used in prevention and symptomatic treatment of BPH and prostate cancer. Thus, identification of the epigenetic modifications involved on the one hand in the development and progression of BPH / PC, on the other influencing the efficacy and safety of potential phytotherapeutics will be helpful in identifying its novel therapeutic strategy.


prostate disorders; phytotherapy; epigenetic modifications

Full Text:



Cohen MB, Rokhlin OW. Mechanisms of Prostate Cancer Cell Survival After Inhibition of AR Expression. Journal of Cellular Biochemistry. 2009;106:363–371.

Delos S, Iehle C, Martin PM. Raynaud JP. Inhibition of the activity of 'basic' 5 alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol Biol. 1994;48(4):347–52.

Di Silverio F, Monti S, Sciarra A, Varasano PA, Martini C, Lanzara S, D'Eramo G, Di Nicola S, Toscano V. Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate. 1998;37(2):77–83.

Doshi T, Mehta SS, Dighe V, Balasinor N, Vanage G. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology. 2011;18;289(2–3):74–82.

Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001; 61:3225–9.

Fearnhead NS, Britton MP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001;10(7):721–33.

Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447:433–440.

Fong YK., Marihart S., Harik M., Djavan B. Preventing progression in men with mild symptoms of benign prostatic hyperplasia: a potential role for phytotherapy. Rev Urol. 2004;6(4):187–92.

Gao AC, Lou W, Dong JT, Isaacs JT. CD44 is a metastasis suppressor gene for prostatic cancer located on human chromosome 11p1. Cancer Res. 1997;57:846–849.

Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J Mol Biol. 1987;196:261–82.

Gerhauser C. Cancer chemoprevention and nutriepigenetics: state of the art and future challenges. Top Curr Chem. 2013;329:73–132.

Goessl C, Krause H, Mueller M, Heicappell R, Schrader M, Sachsinger J, Miller K. Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. Cancer Res. 2000;60:41–59.

Gravas S, Oelke M. Current status of 5alpha-reductase inhibitors in the management of lower urinary tract symptoms and BPH. World J Urol. 2010;28:9–15.

Hill B, Kyprianou N. Effect of permixon on human prostate cell growth: lack of apoptotic action. Prostate. 2004;61(1):73–80.

Ho E, Beaver LM, Williams DE, Dashwood RH. Dietary factors and epigenetic regulation for prostate cancer prevention. Adv Nutr. 2011;2(6):497–510.

Hsieh TC, Wu JM. Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol. 2002;20(3):583–8.

Chiam K, Ricciardelli C, Bianco-Miotto T. Epigenetic biomarkers in prostate cancer: Current and future uses. Cancer Lett. 2014;342(2):248–56.

Jarrard DF, Bova GS, Ewing CM, Pin SS, Nguyen SH, Baylin SB, et al. Deletional, mutational, and methylation analyses of CDKN2 (p16/MTS1) in primary and metastatic prostate cancer. Genes Chromosomes Cancer. 1997;19:90–6.

Jarrard DF, Kinoshita H, Shi Y, Sandefur C, Hoff D, Meisner LF, Chang C, Herman JG, Isaacs WB, Nassif N. Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells. Cancer Res. 1998;58:5310–15.

Kang GH, Lee S, Lee HJ, Hwang KS. Aberrant CpG island hypermethylation of multiple genes in prostate cancer and prostatic intraepithelial neoplasia. J Pathol 2004;202:233–40.

Karr JP, Wajsman Z, Madajewicz S, Kirdani RY, Murphy GP, Sandberg AA. Steroid hormone receptors in the prostate. J Urol 1979;122:170–5.

Koh J, Enders GH, Dynlacht BD, Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 1995;375:506–10.

Konishi N, Nakamura M, Kishi M, Nishimine M, Ishida E, Shimada K. Heterogeneous methylation and deletion patterns of the INK4a/ARF locus within prostate carcinomas. Am J Pathol 2002;160:1207–14.

Konishi N, Nakamura M, Kishi M, Nishimine M, Ishida E, Shimada K. DNA hypermethylation status of multiple genes in prostate adenocarcinomas. Jpn J Cancer Res 2002;93:767–73.

Kujawski R, Bartkowiak-Wieczorek J. Wybrane właściwosci biologiczne surowców zielarskich z rodzaju Epilobium z uwzglednieniem zagadnień profilaktyki schorzeń prostaty w okresie andropauzy. Postep. Farm. 2012;1:16–22.

Kujawski R, Bartkowiak-Wieczorek J, Bogacz A, Karasiewicz M, Mikołajczak PŁ, Czerny B, Mrozikiewicz PM. SRC kinase mRNA transcription changes in testosterone-induced rat ventral prostate lobes under the influence of Epilobium angustifolium extract. Herba Pol. 2013;59(4):60–71.

Kujawski R, Bartkowiak-Wieczorek J, Karasiewicz M, Bogacz A, Mikołajczak P, Czerny B, Mrozikiewicz PM. Influence of Epilobium angustifolium extract on 5α-reductase type 2 and MAPK3 kinase gene expression in rats prostates. Herba Pol. 2013;59(4):72–85.

Kujawski R, Bogacz A, Bartkowiak-Wieczorek J, Karasiewicz M, Mikołajczak PŁ, Mrozikiewicz-Rakowska B, Wolski H, Czerny B, Grześkowiak E, Mrozikiewicz PM. Effect of Epilobium angustifolium and Serenoa repens extracts on regulation of non-genomic signaling pathway of kinases. Ginek Pol. 2014;85:278–282.

Kujawski R, Mrozikiewicz PM, Bogacz A, Cichocka J, Mikołajczak PŁ, Czerny B, Bobkiewicz-Kozłowska T, Grześkowiak E. Influence of standardized extract of Epilobium angustifolium on estrogen receptor alpha and beta expression in in vivo model. Ginekol Pol. 2010;81(8):600–5.

Lee WH, Bookstein R, Hong F, Young LJ, Shew JY, Lee EY. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 1987;235:1394–9.

Lepor H. Medical Treatment of Benign Prostatic Hyperplasia. Rev Urol. 2011;13(1):20–33.

Li LC, Carroll PR, Dahiya R. Epigenetic Changes in Prostate Cancer: Implication for Diagnosis and Treatment. Journal of the National Cancer Institute, 2005, Vol. 97, No. 2, January 19.

Li LC, Chui R, Nakajima K, Oh BR, Au HC, Dahiya R. Frequent methylation of estrogen receptor in prostate cancer: correlation with tumor progression. Cancer Res. 2000;60:702–706.

Lowe FC. The Role of Serenoa repens in the Clinical Management of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia. Eur Urol Suppl. 2009;8:894–7.

Luo J, Dunn TA, Ewing CM, Walsh PC, Isaacs WB. Decreased Gene Expression of Steroid 5 Alpha-Reductase 2 in Human Prostate Cancer: Implications for FinasterideTherapy of Prostate Carcinoma. The Prostate. 2003;57: 134 –139.

Macdonald R, Tacklind JW, Rutks I, Wilt TJ. Serenoa repens monotherapy for benign prostatic hyperplasia (BPH): an updated Cochrane systematic review. BJU Int. 2012;109(12):1756–61.

Nakayama T, Watanabe M, Suzuki H, Toyota M, Sekita N, Hirokawa Y, Mizokami A, Ito H, Yatani R, Shiraishi T. Epigenetic Regulation of Androgen Receptor Gene Expression in Human Prostate Cancers. Laboratory Investigation. 2000, Vol. 80, No. 12, p. 1789.

Naor D, Sionov RV, and Ish-Shalom D. CD44: Structure, function, and association with the malignant process. Adv Cancer Res. 1997;71:241–319.

Nguyen TT, Nguyen CT, Gonzales FA, Nichols PW, Yu MC, Jones PA. Analysis of cyclin-dependent kinase inhibitor expression and methylation patterns in human prostate cancers. Prostate 2000;43:233–42.

Nickel JC, Méndez-Probst CE, Whelan TF, Paterson RF, Razvi H. 2010 Update: Guidelines for the management of benign prostatic hyperplasia. Can Urol Assoc J. 2010;4(5):310–6.

Peedicayil J. Epigenetic therapy – a new development in pharmacology. Indian J. Med. Res. 2006;123(1):17–24.

Richiardi L, Fiano V, Vizzini L, De Marco L, Delsedime L, Akre O, Tos AGMerletti F. Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients. JCO. 2009;27(19):3161–3168.

Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 1991;48:880–8.

Sasaki M, Tanaka Y, Perinchery G, Dharia A, Kotcherguina I, Fujimoto S, Dahiya R. Methylation and Inactivation of Estrogen, Progesterone, and Androgen Receptors in Prostate Cancer. Journal of the National Cancer Institute. 2002, Vol. 94, No. 5, March 6.

Steenkamp V. Phytomedicines for the prostate.Fitoterapia. 2003 Sep;74(6):545–52.

Stirzaker C, Millar DS, Paul CL, Warnecke PM, Harrison J, Vincent PC, et al. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Res 1997;57:2229 –37.

Takahashi S, Inaguma S, Sakakibara M, Cho YM, Suzuki S, Ikeda Y, Cui L, Shirai T. DNA methylation in the androgen receptor gene promoter region in rat prostate cancers. Prostate. 2002 Jun 1;52(1):82–8.

Tsuchiya T, Tamura G, Sato K, Endoh Y, Sakata K, Jin Z, Motoyama T, Usuba O, Kimura W, Nishizuka S, Wilson KT, James SP, Yin J, Fleisher AS, Zou T, Silverberg SG, Kong D, Meltzer SJ. Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia. Oncogene. 2000 Jul 27;19(32):3642–6.

Verkaik NS, van Steenbrugge GJ, van Weerden WM, Bussemakers MJ, van der Kwast TH. Silencing of CD44 expression in prostate cancer by hypermethylation of the D44 promoter region. Lab Invest. 2000;80:1291–1298.

Yamanaka M, Watanabe M, Yamada Y, Takagi A, Murata T, Takahashi H, Suzuki H, Ito H, Tsukino H, Katoh T, Sugimura Y, Shiraishi T. Altered methylation of multiple genes in carcinogenesis of the prostate. Int J Cancer. 2003 Sep 1;106(3):382–7.

Yang Y, Ikezoe T, Zheng Z, Taguchi H, Koeffler HP, Zhu WG. Saw Palmetto induces growth arrest and apoptosis of androgen-dependent prostate cancer LNCaP cells via inactivation of STAT 3 and androgen receptor signaling. Int J Oncol. 2007;31(3):593–600.


  • There are currently no refbacks.

Copyright (c) 2016 Journal of Medical Science

Copyright 2018 by Journal of Medical Sciences