Upload
others
View
3
Download
0
Embed Size (px)
Citation preview
The Management of Estrogens, Estrogen
Receptors and Estrogen Metabolism in the Treatment
of CancersA4M – Orlando, April 8, 2011
Presented By:
Walter H. Wainright, President
Haelan Research Foundation
The Complex Relationship between the two Estrogen Receptor α and β
Fig. 3
SOY PHYTOESTROGENS ARE NOT ESTROGENS
1. There are no studies that show soy phytoestrogens are estrogens – they are anti-estrogenic
2. Estrogens are absorbed in the liver which only has alpha Estrogen Receptors
3. Estrogens have a greater affinity for ER-alpha sites and phytoestrogens have a greater affinity for ER-beta receptor sites
4. If soy phytoestrogens were estrogens
GENE Alteration with DNA-Micro-Array-Chip-Technik
Untreated
Untreated
1mg Estradiol
Soy isoflavones
1mg Estradiol +Soy isoflaovnes
20 year old womenPostmenopausal women
Soy isoflavones reduce metastasis risk of postmenopausalen women
Gene-Expression of Matrix-Metalloproteinase (9)MCF-7 Breast-Cancer Cells incubated with
Blood from postmenopausal Women
0
0,25
0,50
0,75
1,0
Relative Gene Expression of Matrixmetallo-proteinase-9-Gen
Untreated
Estradiolca. 120 x higher
Soy
Estradiol + Soy
6
Summary of Viennese GENE Investigation
Cancer risk Metastasis
risk
Untreated
Soy
Soy +Estradiol
Estradiol-intake
Quelle: Imhof et al., World Congress of Gynecological Endocrinology; Florence 2006Quelle: Imhof et al., World Congress of Gynecological Endocrinology; Florence 2006; * Alsifemin® Soja-Hormon-Balance
Hormonal Changes in Women
Quelle: Rohr, Gyne 2005
High Cancer Risk Low Cancer Risk
Puberty Menopause
Schematic Rise and Fall of Estradiol and 3ß-Adiol
unfruchtbare Phase
- 12 Yrs
fruchtbare Phase
- 40 Yrs
Perimenopause
- 55 Yrs
Hormone in BloodArbitrary units
Alter
Post-menopause
65 + Yrs
No hormonalrisks
Increasing Hormonal risks
No Hormonalrisk
Strong hormonal risks and Chronic deseases
3ß-Adiol
Estradiol
9Estrogen-Receptor -
ER-
suppresses
Estrogen-Receptor - ß
YING – YANG of Estrogen Receptors JA Gustafsson 2003
Breast Cancer Res Treat. 2009 May 12. [Epub ahead of print]
Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells.Treeck O, Lattrich C, Springwald A, Ortmann O.Department of Obstetrics and Gynecology, University of Regensburg, 93053,
Regensburg, Germany, [email protected].
Estrogen receptor beta (ERbeta) is widely expressed in mammary epithelium. ERbeta expression is reported to decline during carcinogenesis of the breast and other tissues. In this study, we examined the consequences of a loss of ERbeta expression in mammary epithelial cells. We knocked down ERbeta transcript levels in human mammary epithelial MCF-10A cells and in MCF-7 breast cancer cells by means of stable transfection with a specific shRNA plasmid. ERbeta knockdown resulted in a significant growth increase of both cell types in a ligand-independent manner. This effect was accompanied by elevated cyclin A2 expression in MCF-10A cells and by
Markus Metka : Warum nicht
2-Methoxy-Estradiol durch Ernährung erhöhen ?
Estradiol 2-hydroxy-Estradiol
COMT
2-Methoxy-Estradiol
James D.Yager et al.:Estrogen Carcinogenesis in Breast Cancer, N Engl J Med. 2006; 354: 270-82
4-Hydroxy-Estradiol
16-Hydroxy-Estradiol
Estrogen-Receptor beta Gene Expression in CTCs
Rel. Gene Expression
before treatment
Prostate Cancer Breast Cancer Ovarian Cancer
After 100 days treatment with fermented soy
Tagawa et al. 2004
Pregnancy and Immunity
non pregnant pregnancy
Trimester
Postpartum Month
1. 2. 3. 1 2-4 6-7 10-11
Adiol(pmol/L)
Invasive Carcinoma
•Chemo-Therapy•Radiation
Cancer-Stem-Cell survive
Krebs-Stamm Zellen
Normale Zellen
Nicht-kanzerogene Krebs-zellen
Nicht-kanzerogene Krebs-zellen
CANCER is spread and kept alive by
Cancer-Stem-Cell
Linheng Li and William B. NeavesCancer Res 2006; 66: (9). May 1, 2006
Chemotherapy isonly effective in Non aggressive cancer cells
aggressive cancer cellsSurvive all
Bone
Haematopoeises and cell differentiation
from stem cells in bone marrow
Leukemia Treatment by Bone Marrow Transplant
Prof. Wicha
Chemotherapy increases numbers of dangerous cancer stem cells by increasing cytokines like IL-8 so that cancer stem cell cannot differentiate *, which cause treatment resistance.
The goal is to combine chemotherapy with mechanism which prevent increase of cytokines (like IL-8) in tumors.
If the cancer stem cells would differentiate ----they would become terminal and susceptible to chemotherapy again
CYTOKINES LIKE IL-8, TNF-α inhibit Stem Cell Differentiation
CD34+ cells towards CD14+
O Berthier-Vergnes et al.. Human melanoma cells inhibit the earliest differentiation steps of human Langerhans cell precursors but failed to affect the functional maturation of epidermal Langerhans cellsBritish Journal of Cancer (2001)
Depression
Immune Cells
Tumor
Recurrence and Progression
InflammationPsychologicalDistress
Drug Resistance
SarcopeniaCachexia
Fatique Cognitive Impairment
Cytokinesfrom tumors
Stomach
Cancer StemCells leave
Metastasis
Joint
Uwe D Rohr et al. 2010Uwe D Rohr et al. 2010
Cytokines(IL-1, IL-6, IL-8, etc.) Cytokines(IL-1, IL-6, IL-8, etc.)
Note: in the Blood Circulting Tumor Cells are more aggressive than the primary tumor :
Less Differentiated !!!!!
Rohr et al 2010
Invasive Carcinoma
•Chemo-Therapy•Radiation
Cancer-Stem-Cell survive
Cancer Stem Cells Normal CellsNicht-kanzerogene Krebs-zellen
Nicht-kanzerogene Krebs-zellen
The worst case Scenario
Resistence
Cytokines which inhibit Stem Cell Differentiation are increased by doxorubicin in H460 tumor cells,
In vitro
Int J Cancer, 2009, NIH-PA
CHEMOTHERAPY INCREASE CYTOKINES IN TUMORS
Levina et al. Chemotherapeutic drugs and human tumor cells cytokine network. Int J Cancer. 2008
ADIOL AND/OR FERMENTED SOY by ER-b and NF-Kb
mechanismsMAY PREVENT TUMOR CELLS FROM SPREADING BY MAKING
THEM LESS LEAKY
•Chemo-Therapie•Radiation
Cancer-Sem Cell Normal CellNicht-kanzerogene Krebs-zellen
Nicht-kanzerogene Krebs-zellen
Fermented Soy transforms Resistant Cancer Cells into „Normal Cancer Cells“ which can then be treated with
Chemo-Therapy, which are then treatable
Invasive CarcinomaResistence
Fermented Soy
Silent Cancer – Stem
Cell
Fermented Soy
ANTI-ANGIOGENESIS
Stabilizing blood capilarities in cancer patients is the new goal in severe diseases, reducing them from being leaky to becoming stable again
Anti-Angiogenesis
Cancer cells are fast growing and stack up on top of each other - Where are the capillaries?
Oxygen starved cells produce VEGF (Vascular Endothelian Growth Factor)
VEGF in tissues cause blood vessels to grow to that area
Pharmaceutical product (Avastin) shut off cellular VEGF [$100k for 6 months (2 shots/mo)– lengthens life span 2 – 5 months]
Side effects – UCLA Study - endothelial cells die because they need VEGF to survive -- in addition Blood Clots
Fermented soy is anti-angiogenic but does not shut off VEGF – no side effects
Successfully Treating a Pregnant Women With Breast Cancer
Normal Breast Tissue
April 26th 2006
June 10th , 2006
H&E Ki67
Quelle: Karen McCarron and Regina Chorsky
F8
REDUKTION der ANGIOGESE und Zell-WachstumEines invasiven duktalen Brust-Karzinoms
Nach 16 Tagen mitfermentiertem Soja
April 26th 2006
June 10th , 2006
H&E Ki67
Quelle: Karen McCarron and Regina Chorsky
F8
REDUKTION der ANGIOGESE und Zell-WachstumEines invasiven duktalen Brust-Karzinoms
Nach 16 Tagen mitfermentiertem Soja
Reduction of Angiogenesis and Cell-Growthof an invasive ductal Breast Carcinoma
After 16 days of Treatment
Manage While You Treat Apoptosis – the normal death of a cell
BCL2 – Anti-apoptosis gene
BAX – Pro-apoptosis gene
MDR1 – Multi-Drug Resistance Gene
The P53 Gene – arrests cell cycle, repairs DNA, stops uncontrolled cell replication, kills cells when DNA is not repairable
Anti-Angiogenesis – cancers cannot grow larger than a pencil point without a fully functional independent blood supply
BRCA1, BRCA2, Her2, cachexia & more
Cell Differentiation induced by the management of estrogens and the
inflammatory cytokines may produce a dramatic increase in
cancer patient survival
For the First Time Ever
Fermented soy has been shown totransform circulating tumor cells In the in vivo human situation
into a more differentiated less aggressive treatable cells
May have caused dramatic increase in survival
Rohr et al. Horm Mol Biol Clin Invest 2010;3(2):391–409
GENE EXPRESSION IN CIRCULATING TUMOR CELLS WITH FERMENTED SOY
Rohr et al. Horm Mol Biol Clin Invest 2010;3(2):391–409
Fermented Soy increases ER-ß Gene Expression in dissiminated Tumor Cells
Fermented Soy increases ER-ß Gene Expression in dissiminated Tumor Cells
ER-ßGen Expression
Fold increase Single cases
300
200
100
0
300
200
100
0 Time (Month)
Time (Month)
0 1,5 30 1,5 3
Patient consumed Isoflavones regularly Patients with high GLEASON Factor(High Malignicy)
facher Anstieg
Ursula Jacob et al , 2009
Gene Expression of Cell Cycle Inhibitor p21 in CTC
rel. Gene Expression
n= 5
Prostate-Ca Patients Breast-Ca
n= 7
Ovarian Ca
n= 5
Ursula Jacob et al , 2009
SURVIVAL OF HIGHLY AGRESSIVE OVARIAN CANCER
Month
Survival
Stage III/IV
Stage IV Fermented Soy treated (n=6)
Stage III/IV
Prostate CancerSurvival
Biochemical after Biochemical Recurrence, y
Gleason Score 8-10
Gleason Score <7
Treated with fermented Soy (n=5)
Freedland SJ, et al. JAMA. 2005 Jul 27;294(4):433-9.
SURVIVAL OF HIGHLY AGRESSIVE PROSTATE CANCER
Patients with T3-T4 Breast Cancer treated with fermented Soy (n=5) Patients with T3-T4 Breast Cancer treated with fermented Soy (n=5)
SURVIVAL OF HIGHLY AGRESSIVE BREAST CANCER
The Soy Controversy – All Soy Products Are Not Equal
Fermented vs Unfermented
Selection of Soybeans
Minerals in the Soil
Age of Beans When Picked
Processing of the Beans
Estrogen Positive Breast Cancer
Liquids vs powders (pills, powders or capsules)
Poorly designed Studies (8 out of 9,000+ )
What is a soy study??? Whole soy versus components in soy
The ER Positive Breast Cancer & Fermented Soy Benefits
Lowers Total Circulating Estrogens 30 - 40% (Lu J; Univ. of Texas –Aromatase Inhibition Activity
Improves Ratio of 2/16 Hydroxyestrogens
Blocks Receptor Sites (26% for Tamoxifen vs 36% Soy) Soy +Tamoxifen is 62%)
Anti-Angiogenesis
Repairs DNA
Anti-Cancer Metabolites (Equol)
Cachexia Kills 80% of Advanced Cancer Patients – Its more than
calories! It is caused by inflammatory cytokines
Mitochondrial & Other DNA Damage
The MyoD Gene – allows rebuilding of lean muscle mass
DNA damage to MyoD by Cytokines TNF , Interferon gamma (IFN-y), and NF-Kb
Soy compounds protect MyoD DNA damage by cytokines TNF , IFN-y and NF-Kb
Fermented Soy protects MyoD Gene damage, Builds Muscles & Improves Electron Transport in the Mitochondria
Cachexia in Cancer Patients
n= 164 n= 78
%
Chemotherapy + fermented soy
Chemotherapy + Placebo
Cell Cycle Inhibitors
MDM2
Cyclin D1
CDK4
Cyclin E
CDK2
block
block
Cell cycle inhibitor
block
Fig. 3
Cell cycle inhibitor
NFκB and Apoptosis
mitogens
proliferation
apoptosisblocking
• Apoptosis is blocked by BCL2
• BAX increases Proliferation
Pro-inflammatory cytokines stimulate cell-mediated, humoral and/or allergic immunity. The major cytokine mediating cell-mediated immunity is interferon-γ (IFNγ). Humoral immunity is mediated by B cells and production of antibodies; interleukin 4 (IL4), IL10, IL13 and transforming growth factor-β (TGFβ)trigger isotype switching of antibodies. Some cytokines have predominantly anti-inflammatory and immunosuppressive effects (for example, IL10 and TGFβ) or both pro- and anti-inflammatory effects (for example, IL6). Innate immune cells are the major source of IL1, IL6 and tumour necrosis factor-α (TNFα), which direct activity of adaptive immunity and inflammation. GM-CSF, granulocyte macrophage-colony stimulating factor; IL1RA, IL1 receptor antagonist; IL1RII, IL1 receptor type II; TNF, tumour necrosis factor; SCF, stem cell factor.
GADPH: Cancer cell killing was measured by the GAPDH gene expression. Only live cells have GAPDH gene expression. The GAPDH chart in the study measures cancer cell kill and survival by the agent being tested:
Results: Breast Cancer - Cancer Cell Survival DOXORUBICIN CHEMOTHERAPY FERMENTED SOY TREATMENT: ` Cells ` Surviving Doxorubicin : Surviving(%) BAX BCL2 Fermented Soy Cells(%) BAX BCL2 .5 % Strength 82% 1.05 .4575 .5%^Strength 58% 2.55 1.2468 1.5% Strength 56 % 1.09 .2222 2.5 % Strength 14 % 1.91 .1163 1.5 % Strength 20 % 2.94 .4675 3.75 % Strength 2.3 % .98 .0693 5.0 % Strength 4.6 % .71 .051 3.0 % Strength 4.8 % 3.97 .026 Combined Treatment: .5% Doxorubicin + 3 % Fermented Soy 14% NOTE: HIGHER BAX (PRO APOPTOSIS GENE EXPRESSION) IS BETTER THAN LOWER BAX LOWER BCL2 (ANTI-APOPTOSIS GENE EXPRESSION) IS BETTER THAN HIGHER BCL2
Platinum Chemotherapy Resistant Ovarian Cancer
Does Femented Soy Reduce The Effectiveness of
Chemotherapy Treatments ?
National Cancer Institute (US), Office of Cancer, Complementary and Alternative Medicine: Best Case Series Program –Fermented Soy Program
.
Relapse of Breast Cancer Cases under different Adjuvant Therapy Regimens
Untreated
Tamoxifen Tamoxifen + Arimidex®
Tamoxifen + Soy
Tamoxifen + Soy
Tamoxifen + Soy
Relapse(100% = 1,0)
0,2
0,4
0,0
ER+, after 8 years, menopausal Women
Fig. 1
Why Fermented Soy?Because it is synergistic with chemotherapy
treatments and has positive effects on NF-kB, MDR1, BAX, BCL2, BRCA1 & BRCA2 , Her2,
address the cachexia problem, reduces stress and depression, improves quality of life ----AND
IT DOES A LOT MORE
Results of a $20 Million U.S. Government Study on anti-cancer compounds in fruits and vegetables
Five Super Stars – all in Soy
1. Isoflavones
2. Protease Inhibitors
3. Saponins
4. Phytosterols
5. Phytic Acid Compounds
(Journal of the National Cancer Institute April 17,1991)
PROPERTIES OF THE WHOLE SOYBEAN
ANTI-ALLERGY
ANTI-VIRAL
ANTI-INFLAMMATORY
VASODILATOR
ANTI-CANCER
Mechanisms of Action That Help The Physician Manage Disease
While Treating It With IPT
MDR1 Apoptosis
DNA Repair P21 Increased
Anti-angiogenesis Estrogen Metabolism
Reduces Estrogen Levels Increased ER-beta receptors
Decreased ER-alpha receptors Produces Anti-Cancer metabolites
Prevents Protein Calorie Malnutrition Shuts Down NF-kB Mutation Pathway Decreases Viral and Bacterial Burdens
Non-Specific Immune Stimulation Increased 700%
Thank you for your attention
Walter H. Wainright
Haelan Research Foundation
Cell tel: (425) 269-7798
Haelanresearch.org
Woodinville, WA