Wednesday, February 19, 2014

Alternative Medications to Prevent Prostate Cancer

Many patients come to urology clinic asking about alternative medications for the prevention of prostate cancer.  Some are interested in taking a pill because other men in their families have prostate cancer and they are concerned they might be next in-line with the diagnosis.  Some men are already on alternative medications and wondering if they will actually work.  Here we review the scientific data regarding the most common supplements on the market for the prevention of prostate cancer.

Selenium and Vitamin E

Identification: Selenium - trace element and nutrient; Vitamin E - fat-soluble vitamin.  The best evidence regarding alternative medications for the prevention of prostate cancer exists for Selenium and Vitamin E.
Potential mechanism: anti-tumorigenic and antioxidant, possible effects on angiogenesis, cellular proliferation and apoptosis [1]
Preclinic evidence: numerous laboratory and epidemiologic studies indicate selenium and Vitamin E may prevent development or progression of prostate cancer [2-9]
Clinical evidence: do not prevent prostate cancer, Vit E may increase risk of prostate cancer

  • SELECT (Selenium and Vitamin E Cancer Prevention) Trial, included over 35,000 men randomized to receive supplements alone or in combination was closed early due to an increased risk of prostate cancer in the men taking Vitamin E.  In fact, starting 3 years after enrollment and at a median follow-up of 7 years, men taking Vitamin E were 17% more likely to be diagnosed with prostate cancer.  [10]
  • Another randomized, controlled trial of selenium for the prevention of prostate cancer in men at high-risk for disease failed to show any benefit for the prevention of prostate cancer. [11]

Curcumin

Identification: derived from turmeric
Potential Mechanism: anti-inflammtory, antiproliferative
Preclinical evidence: 
  • suppresses growth of androgen-dependent prostate cancer cell line LNCaP and androgen-independent DU145 [12]
  • inhibits VEGF and angiogenesis in vivo [13]
  • anti-inflammatory mediators are downregulated by curcumin [14]
  • curcumin can improve the effect of chemotherapy in prostate cancer cell lines [15]
Clinical evidence: None


Green Tea

Identification: used for centuries in Eastern culture and medicine, one of the most widely consumed beverages in the world, contains many compounds, most prominent is epigallocatachin-3-gallate
Potential Mechanism: apoptosis, cell-cycle arrest through anti-oxidant effects and androgen receptor effects
Preclinical Evidence: 40% reduction in tumor development and reduction in metastatic spread of cancer with coincident 70% improvement in survival in TRAMP mouse-model of prostate cancer [16]
Clinical Evidence: Mixed data showing both modest benefits and no benefit 
  • In a double-blind, placebo-controlled trial in 60 men with HGPIN (high-grade prostatic intraepithelial neoplasia) at high-risk for prostate cancer, only 1 man in the group getting Green Tea developed cancer while 9 in the placebo group developed cancer [17]
  • Phase II clinical trial given after prostate biopsy demonstrating cancer and before radical prostatectomy demonstrated a decrease in serum PSA and other growth factors.  [18]
  • Another Phase II trial of men with advanced prostate cancer failed to demonstrate a significant decrease in PSA while a number of patients complained of significant toxicities. [19]

PC-SPES

Identification: herbal mixture of chrysanthemum, isatis, liquorice and others [20]
Potential Mechanism: enhanced effects of multiple antioxidant components
Preclinical Evidence: activity in androgen-dependent and independent cell lines [21-24]
Clinical Evidence: Harmful medication, withdrawn from the market.  PC-SPES was withdrawn from the market in 2002 due to contamination with prescription medications including warfarin and diethylstilbestrol leading to a number of significant side effects including gynecomastia, erectile dysfunction, loss of libido and blood clots (both deep venous thromboses and pulmonary emboli). [25]

    Pomegranate Extract

    Identification: active ingredients in the naturally occurring juice are polyphenol punicalagins and ellagic acid
    Potential Mechanism: potent antioxidant, stronger than Green Tea or red wine
    Preclinical Evidence
    • inhibits nuclear factor kappa-B (NF-kB) in prostate cancer cell lines [26]
    • 12% in cell proliferation and 17% increase in apoptosis in prostate cancer cell lines [27]
    Clinical Evidence: Increased PSA doubling time in men with advanced cancer.  No data for prostate cancer prevention.  In a phase II clinical trial in men with rising PSA levels after surgery or radiation therapy, daily pomegranate juice increased the PSA doubling time from 15 months to 54 months.[27]

    Resveratrol

    Identification: compound found in the skin of grapes
    Potential Mechanism: inhibits prostate cancer cell growth
    Preclinical Evidence: regulates androgen receptor gene transcription, expression and degradation through a variety of mechanisms [28-31]
    Clinical Evidence: None


    Silbinin

    Identification: natural phenol from milk thistle plant
    Potential Mechanism: decreased angiogenesis, proliferation and increased apoptosis
    Preclinical Evidence: decreases incidence of tumors, size of tumors and progression of tumors in TRAMP mouse model [32-33]
    Clinical Evidence: None


    Zyflamend

    Identification: herbal blend of extracts from rosemary, turmeric, ginger, holy basil, green tea and others
    Potential Mechanism: cell growth suppression and apoptosis through COX-inhibition [34]
    Preclinical Evidence: inhibits androgen-dependent and independent tumor growth in mouse models [35]
    Clinical Evidence: Early phase data may indicate a benefit in men at higher than normal risk to develop prostate cancer.  Phase I clinical trial in men with HGPIN at risk for developing prostate cancer demonstrated a 50% reduction in PSA levels in 50% of the men taking the medication with a lower than expected rate of progression to prostate cancer [36]


    Summary

    There is much pre-clinical data that alternative medications and supplements may affect the ability of prostate cancer cells to grow and flourish.  However, there is little evidence that any supplement will prevent or alter the course of prostate cancer in humans.  In fact, a number of studies have demonstrated significant detriments to taking supplements specifically for prostate cancer.  

    Alluding to the fact that they are often health conscious and more likely to undergo screening, Dr. Patrick Walsh often says, 
    "Men who take more than one supplement are more likely to be diagnosed with prostate cancer."  
    In fact, the data may show that supra-physiologic levels of alternative medications, even if naturally occurring or based on organic compounds, may be harmful.  


    For more details, two great resources for this entry and your reading are:
    Klempner SJ, Bubley G.Complementary and alternative medicines in prostate cancer: from bench to bedside?  Oncologist. 2012;17(6):830-7. doi: 10.1634/theoncologist.2012-0094. Epub 2012 May 22.
    Philippou Y, Hadjipavlou M, Khan S, Rane A.Complementary and alternative medicine (CAM) in prostate and bladder cancer.  BJU Int. 2013 Dec;112(8):1073-9. doi: 10.1111/bju.12062.



    [1] Chan JM, Gann PH, Giovannucci EL. Role of diet in prostate cancer development and progression. J Clin Oncol 2005; 23: 8152–8160
    [2] Fleshner N, Fair WR, Huryk R, Heston WD. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice.  J Urol. 1999;161(5):1651-1654
    [3] Ip C, Thompson HJ, Zhu Z, Ganther HE. In vitro and in vivo studies of methylseleninic acid: evidence that a monomethylated selenium metabolite is critical for cancer chemoprevention.  Cancer Res. 2000;60(11):2882-2886
    [4] Jiang C, Wang Z, Ganther H, Lu J. Caspases as key executors of methyl selenium-induced apoptosis (anoikis) of DU-145 prostate cancer cells.  Cancer Res. 2001;61(7):3062-3070
    [5] Menter DG, Sabichi AL, Lippman SM. Selenium effects on prostate cell growth.  Cancer Epidemiol Biomarkers Prev. 2000;9(11):1171-1182
    [6] Redman C, Scott JA, Baines AT,  et al.  Inhibitory effect of selenomethionine on the growth of three selected human tumor cell lines.  Cancer Lett. 1998;125(1-2):103-110
    [7] Taylor PR, Albanes D. Selenium, vitamin E, and prostate cancer–ready for prime time?  J Natl Cancer Inst. 1998;90(16):1184-1185
    [8] Yoshizawa K, Willett WC, Morris SJ,  et al.  Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer.  J Natl Cancer Inst. 1998;90(16):1219-1224
    [9] Zhong W, Oberley TD. Redox-mediated effects of selenium on apoptosis and cell cycle in the LNCaP human prostate cancer cell line.  Cancer Res. 2001;61(19):7071-7078
    [10] Klein EA, Thompson IM Jr, Tangen CM et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306: 1549–1556
    [11] Marshall JR. Randomized phase III trial of selenium supplementation to prevent prostate cancer among men with high grade prostatic intraepithelial neoplasia. Paper presented at the 2010 American Urological Association (AUA) Annual Meeting; June 1, 2010; San Francisco, USA
    [12] Aggarwal BB. Prostate cancer and curcumin: add spice to your life. Cancer Biol Ther 2008; 7: 1436–1440
    [13] Gururaj AE, Belakavadi M, Venkatesh DA, Marme D, Salimath BP. Molecular mechanisms of anti-angiogenic effect of curcumin. Biochem Biophys Res Commun 2002; 297: 934–942
    [14] Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockade of NF kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion and metastasis. Oncogene 2001; 20: 4188–4197
    [15] Hour TC, Chen J, Huang CY et al. Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21WAF1/CIPI and C/EBP expressions and suppressing NF-kB activation. Prostate 2002; 51: 211–218
    [16] Gupta S, Hastak K, Ahmad N, Lewin JS, Mukhtar H. Inhibition of prostate carcinogenesis in TRAMP mice by oral infusion of green tea polyphenols. Proc Natl Acad Sci USA 2001; 98: 10350–10355
    [17] Brausi M, Rizzi F, Bettuzzi S. Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 2008; 54: 472–473
    [18] McLarty J, Bigelow RL, Smith M, Elmajian D, Ankem M, Cardelli JA. Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res (Phila) 2009; 2: 673–682
    [19] Jatoi A, Ellison N, Burch PA et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 2003; 97: 1442–1446
    [20] DiPaola RS, Zhang H, Lambert GH et al. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 1998; 339: 785–791
    [21] de la Taille A, Buttyan R, Hayek O, et al. Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 2000;164:1229-1234.
    [22] Halicka H, Ardelt B, Juan G, et al. Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC-SPES. Int J Oncol 1997;11:437-448. 
    [23] Oh WK, George DJ, Hackmann K, et al. Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen independent prostate cancer. Urology 2001;57:122-126. 
    [24] Tiwari RK, Geliebter J, Garikapaty VP, et al. Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 1999;14:713-719. 
    [25] Sovak M, Seligson AL, Konas M et al. Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 2002; 94: 1275–1281
    [26] Rettig MB, Heber D, An J et al. Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-KB-dependent mechanism. Mol Cancer Ther 2008; 7: 2662–2671
    [27] Pantuck AJ, Leppert JT, Zomorodian N et al. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 2006; 12: 4018–4026
    [28] Athar M, Back JH, Tang X et al. Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharmacol 2007; 224: 274–283
    [29] Harada N, Murata Y, Yamaji R et al. Resveratrol down-regulates the androgen receptor at the post-translational level in prostate cancer cells. J Nutr Sci Vitaminol (Tokyo) 2007; 53: 556–560
    [30] Niu Y, Yeh S, Miyamoto H et al. Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. Cancer Res 2008; 68: 7110–7119
    [31] Shi WF, Leong M, Cho E et al. Repressive effects of resveratrol on androgen receptor transcriptional activity. PLoS One 2009; 4: e7398
    [32] Raina K, Rajamanickam S, Singh RP, Deep G, Chittezhath M, Agarwal R. Stage-specific inhibitory effects and associated mechanisms of silibinin on tumor progression and metastasis in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2008; 68: 6822–6830
    [33] Singh RP, Raina K, Sharma G, Agarwal R. Silibinin inhibits established prostate tumor growth, progression, invasion and metastasis, and suppresses tumor angiogenesis and epithelial-mesenchymal transition in transgenic adenocarcinoma of the mouse prostate model mice. Clin Cancer Res 2008; 14: 7773–7780
    [34] Bemis DL, Capodice JL, Anastasiadis AG, Katz AE, Buttyan R. Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 2005; 52: 202–212
    [35] Huang EC, McEntee MF, Whelan J. Zyflamend, a combination of herbal extracts, attenuates tumor growth in murine xenograft models of prostate cancer. Nutr Cancer 2012; 64: 749–760
    [36] Capodice JL, Gorroochurn P, Cammack AS et al. Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 2009; 7: 43–51



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