HOW EFFECTIVE AND SAFE ARE COMPLEMENTARY AND ALTERNATIVE MEDICATIONS : AN EVIDENCE BASED ANSWER

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1 HOW EFFECTIVE AND SAFE ARE COMPLEMENTARY AND ALTERNATIVE MEDICATIONS : AN EVIDENCE BASED ANSWER Depypere HT 1,2, Bolca S3, Verstraeten W 3, Heyerick A 4, De keukeleire 4, Bracke M 2. Menopause and breast clinic (1), faculty of bioscience engineering (3), faculty of Pharmacy (4), Laboratory of experimental cancer research rch (2), University of Gent, De Pintelaan 185, 9000 Gent, Belgium.

2 Maubach J, Bracke M, Heyerick A, Depypere H, Serreyn R, Mareel M, De Keukeleire D. Quantitation of soy-derived phytoestrogens in human breast tissue and biological fluids by high-performance liquid chromatography. J Chromotography B 2003 ;784 : (I.F. = 2.085) J. Maubach, H.T. Depypere, J. Goeman, J. Van der Eycken, A. Heyerick, M.B. Bracke, P. Blondeel and D. De Keukeleire. Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids. Obstetrics and Gynecology. Obstetr Gynecol 2004; 103, (I.F. = 3.512) B. Vanhoecke, A. Heyerick, H. Depypere, F. Delporte, E. Van Braeckel, M. Nuytinck, D. De Keukeleire and M. Bracke. A safety study of oral tangeretin and xanthohumol administration to laboratory mice. Clin. Chem. Lab. Med. Vanhoecke, B.; Depypere, H.; De Keukeleire, D.; Bracke, M.; Cellular activities related to growth and invasion: Targets for flavonoids, Recent Res. Devel. Cell. Sci., 2004, 1, Familial male lethal incontinentia pigmenti: a rare cause of recurring spontaneous abortions. De Coen K., Lissens W., De Cuyper C., Depypere H., De Praeter C. Journal of Maternal-Fetal & Neonatal Medicine 2004, 16 suppl 1, p253. (peer reviewed en geïndexeerd voor Medline). M.E. Bracke, B.W. Vanhoecke, H.T. Depypere, H.J. Kloosterboer. Tibolone and its metabolites inhibit the invasion of human breast cancer cells. EJC Supplements, 2004, 2(9): Van Slambrouck S, Parmar V, Sharma S, De Bondt B, Flore F, Coopman P, Van hoecke B, Boterberg T, Depypere H, Leclercq G, Bracke M. Tangeretine inhibits extracellular-signal-regulated kinase phorphorylation. FEBS Letters, 2005, 579: (I.F. = 3.415) B. Vanhoecke, F. Delporte, E. Van Braeckel, A. Heyerick, H. Depypere, M. Nuytinck, D. De Keukeleire, and M. Bracke. A Safety study of oral tangeretin and xanthohumol administration to laboratory mice. In Vivo, 2005, 19: (I.F. = 1.037) B. Vanhoecke, H. Depypere, A. De Beyter, S. Sharma, V. Parmar, D. De Keukeleire, and M. Bracke. New anti-invasive compounds: results from the Indo-Belgian screening program. Pure Appl. Chem., 2005, 77(1): (I.F. = 1.679)

3 Derycke L, Van Marck V, Depypere H, Bracke M. Molecular targets of growth, differentiation, tissue integrity and ectopic cell dath in cancer cells. Cancer Biother Radiopharmac. 2005, 20: (I.F. = 1.669) B. Vanhoecke, L. Derycke, V. Van Marck, H. Depypere, D. De Keukeleire, and M. Bracke. The anti-invasive effect of xanthohumol, a prenylated chalcone present in hops (Humulus lupulus L.) and beer. Int. J. Cancer 2005, (I.F. = 4.700) Depypere, H., Bracke, M., Vanhoecke, B., De Keukeleire, D., Heyerick, A., Bolca, S., Verstraete W. Are phytoestrogens of any help? International Journal of Gynecological Cancer, 2006; 16[S2], B.W. Vanhoecke, M.E. Bracke, H.J. Kloosterboer en H.T. Depypere. Tibolone and its metabolites inhibit invasion of human mammary carcinoma cells in vitro. Maturitas 2006; 54: (I.F = 2.004) Heyerick A, Vervacke S, Depypere H, Bracke M, De keukeleire D. A first prospective, randomized, double-blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2005; 54: (I.F = 2.004) Bolca, S., Possemiers, S., Maervoet, V., Huybrechts, I., Heyerick, A., Vervarcke, S., Depypere, H., De Keukeleire, D., Bracke, M., De Henauw, S., Verstraete, W., Van de Wiele, T. Microbial and dietary factors associated with the 8- prenylnaringenin producer phenotype: a dietary intervention trial with fifty healthy post-menopausal. British Journal of Nutrition, 2007; 98[5], Bolca, S., Possemiers, S., Herregat, A., Huybrechts, I., Heyerick, A., De Vriese, S., Verbruggen, M., Depypere, H., De Keukeleire, D., Bracke, M., De Henauw, S., Verstraete, W., Van de Wiele, T. Microbial and dietary factors are associated with the equol producer phenotype in healthy postmenopausal women. Journal of Nutrition, 2007; 137[10], Possemiers, S., Bolca, S., Eeckhaut, E., Depypere, H., Verstraete, W. Metabolism of isoflavones, lignans and prenylflavonoids by intestinal bacteria: producer phenotyping and relation with intestinal community. FEMS Microbiology Ecology, 2007; 61; Bracke, M., Vanhoecke, B., Dercycke, L., Bolca, S., Possemiers, S., Heyerick, A., Stevens, C.V., De Keukeleire, D., Depypere, H.T., Verstraete, W., Williams, C.A., McKenna, S.T., Tomar, S., Sharma, D., Prasad, A.K., DePass, A.L., Parmar, V.S. Plant polyphenolics as anti-invasive cancer agents. Anti-Cancer Agents in Medicinal Chemistry, 2008; 8[3],

4 BOLCA, S., Possemiers, S., Herregat, A., Huybrechts, I., Heyerick, A., Debeuf, C., Verbruggen, M., Depypere, H., De Keukeleire, D., Bracke, M., De Henauw, S., Verstraete, W., and Van de Wiele, T.: Microbial and dietary factors associated with the equal producer phenotype: a dietary intervention trial with 100 healthy postmenopausal women. (in Press). VANHOECKE, B., Van Gele, M., Vercoutter-Edouart, A.S., Dollé, L., Boelens, J., Lust, S., Martinet, W., Depypere, H., De Keukeleire, D., Offner, F., and Bracke, M.: Xanthohumol induces apoptosis via endoplasmic reticulum stress in human breast cancer cells. (Submitted)

5 Phytoestrogens are a diverse group of polyphenolic non steroidal plant compounds

6 12 Ǻ 17 -Estradiol Daidzein Genistein Equol Coumestrol Secoisolariciresinol 8-prenylnaringenin

7 Influence of phyto estrogens : On vasomotor symptoms : Studies were grouped into broad categories:. Five trials used Promensil (Novogen, Sydney, Australia), a red clover extract; these trials were combined in a meta-analysis, and summary effect measures were calculated. There is no evidence of effectiveness in the alleviation of menopausal symptoms with the use of phytoestrogen treatments (dietary soy, soy extracts, red clover extracts, and other types of phytoestrogen). Cohrane Update (maart 2008, obst Gyn vol 111, 3) On the cardiovascular system : no evidence On the breast :

8 ETIOPATHOGENESIS BREASTCANCER

9 DUCTLOBULAR UNIT

10 Mareel en Bracke

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16 P-1 breast cancer prevention trial van de National Surgical Adjuvant Breast and Bowel Project NSABP results : in the tamoxifen arm there was a reduction of 49 % of invasive breastcancer.

17 BORSTCANCER Total Cases = 77 *P<.001 RR = 0.38 (95% CI = )* Placebo 5.3 per 1000 woman-years 0.0 Raloxifene 1.9 per 1000 woman-years

18 PARTIAL AGONIST O OH HO O Genistein OH

19 Relative affinity for the alfa and beta receptor

20 GENISTEIN, DAIDZEIN, AND EQUOL AND CELL-CELL ADHESION IN MCF- 7/6 CELLS SLOW AGGREGATION ASSAY DMSO Equol Equol + MB2 Equol + ICI 182,780

21 FAST AGGREGATION ASSAY

22 The major problem is the large variation in results in studies with phyto estrogens due the large variation in resorption in human.

23 WORK PACKAGE I Daidzein Isoxanthohumol O-desmethylangolensin Equol 8-prenylnaringenin Secoisolariciresinol Enterodiol (END) Enterolactone (ENL) Large interindividual variation Agreement Nr. RT-05/02-FYTOES-1 Ghent, January12 th 2009

24 MIX H 3 CO OR OH O HO OR Daidzein O OH OMe IX OH OCH 3 R: H SECO GUT MICROBIOT A OH O Equol OH OH 8-PN ENL Agreement Nr. RT-05/02-FYTOES-1 Ghent, January12 th 2009

25 WORK PACKAGE I Individual phytoestrogens SHIME run Agreement Nr. RT-05/02-FYTOES-1 Ghent, January12 th 2009

26 WORK PACKAGE I Individual phytoestrogens SHIME run Daidzein metabolism (Decroos et al. (2006) J Nutr 136, ) Weak equol-producing inoculum + EPC4 Standard SHIME feed µm M daidzein aglycon eq. Stable EQUOL production in colon transversum IX metabolism (Possemiers et al. (2006) J Nutr 136, ; Possemiers et al. (2008) J Nutr 138, ) Strong 8-PN8 PN-producing inoculum Weak 8-PN8 PN-producing inoculum + E. limosum Standard SHIME feed + 70 µm M IX Stable 8-PN production in colon transversum Agreement Nr. RT-05/02-FYTOES-1 Ghent, January12 th 2009

27 BREAST TISSUE HOMOGENATE Group Genistein Daidzein Equol SOY Median Minimum Maximum N Nd Nd Nd 9 Nd Nd Nd PLACEBO Median Minimum Maximum N Nd Nd Nd Nd Nd Concentration (nmol/l) G enis tein Daidzein E quol Active group Placebo group

28 MATERIAL & METHODS - BREAST AESTHETIC BREAST SURGERY R Breath methane GC-FID WASHOUT FFQ, BMI, age, antibiotic use, TREATMENT spot urine Breast biopsies blood Enzymatic deconjugation Extraction HPLC-UV-MS Bio-activity biodistribution concentration molecular form

29 WP 2 Distribution in breast tissue Molecular form Aglycones or conjugated? (Gu et al. 2005) ISOLATION HYDROLYSIS Biodistribution Glandular or adipose tissue? Concentration EXTRACTION KWANTIFICATION

30 Soy products could be used as an alternative to classical hormonal therapy if the resorpion problem could be solved. Adding strains of bacteria can improve absoption in vitro to 100 %. In vivo studies need to prove safety of these bacteria in all circumstances. Gut bacteria play an important role in the absorption and metabolisation of phyto estrogens. 8-PN is by far the most potent phyto estrogen. Xanthohumol has antitumoral properties. Iso xanthohumol can be a precursor of 8-PN. The ultimate goal is to obtain sufficient fyto estrogen concentration in target tissues such as breast, brain, cardiovascular system and the bone.