Transcript Modified Citrus Pectin & Galectin-3

Modified Citrus Pectin
& Galectin-3
The Role of Modified Citrus Pectin and
Galectin-3 in the Prevention and
Treatment of Metastatic Cancer
Galectin-3 & Disease
• Elevated Galectin-3 in the body is
directly involved in:
– Cancer
– Cardiovascular Disease
– Chronic Hepatitis
– Kidney Disease
– Diabetes
– Inflammation & Fibrosis
– Others
Galectin-3 Levels & Mortality from All Causes in the
General Population: PREVEND
Median
Galectin-3
Levels
Quintile-1
7.7
Cumulative Survival Rate (%)
100%
95%
Quintile-2
9.4
Quintile-3
10.9
90%
Quintile-4
12.6
Number of Subjects
n = 7,968
Year-11
Year-10
Year-9
Year-8
Year-7
Year-6
Year-5
Year-4
Year-3
Year-2
Year-1
Start
85%
Quintile-5
15.6
Overall
Average
11.9
Galectin-3 & Cancer
• In Cancer, Galectin-3 plays a role in:
– Cell to Cell Adhesion
– Aggregation of Cancer Cells
– Tumor Growth
– Metastasis
– Angiogenesis
– Inhibition of Apoptosis
Blood Vessel
Blood Vessel
What is Modified Citrus Pectin (MCP) ?
• MCP is derived from the pith of citrus fruit peels
• Complex polysaccharide fiber of repeating galacturonic acid groups with
neutral sugar side chains
• Unmodified citrus pectin molecular weight 50 to 300 kiloDaltons (kDa) with
esterification ~70%
• Optimal biological activity: molecular weight <13 kDa with esterification
<10%, and specific structure
Modified Citrus Pectin is a Galectin-3
Blocker
•
•
•
•
Binds to Galectin-3 molecules
Blocks aggregation of cancer cells
Blocks docking of cancer cells
Blocks interactions with endothelium
necessary for angiogenesis
Modified Citrus Pectin
Cancer Research
Benefits of MCP in Cancer Treatment
•
•
•
•
•
Anti-Cancer and Anti-Metastasis
Blocking of Galectin-3 Effects
Synergistic Effect with Chemotherapy
Protection Against Post-Radiation Damage
Improved Quality of Life
Inhibition of Spontaneous Metastasis in a Rat Prostate
Model by Oral Administration of Modified Citrus Pectin
Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle, TS, Lehr J, Donat TL, Tait L, Hogan V, Raz A
Wayne State University School of Medicine, Detroit, MI, USA
J Natl Cancer Inst 1995 87(5):348-53.
• Method: MCP’s inhibition of prostate cell adhesion to
endothelial cells. 0.1% and 1.0% MCP in rats’ drinking
water; controls had plain water
• Results: Significant reduction in lung metastases -- 50%
reduction in 0.1% group; 56% reduction in 1.0% group
(P<0.03 & P<0.001).
Inhibition of Spontaneous Metastasis in a Rat Prostate
Model by Oral Administration of Modified Citrus Pectin
Pienta KJ, Naik H, Akhtar A, Yamazaki K, Replogle, TS, Lehr J, Donat TL, Tait L, Hogan V, Raz
A Wayne State University School of Medicine, Detroit, MI, USA
J Natl Cancer Inst 1995 87(5):348-53.
• Conclusion: MCP acted as potent
inhibitor of spontaneous prostate
carcinoma metastasis.
Inhibition of Human Cancer Cell Growth & Metastasis in
Nude Mice by Oral Intake of Modified Citrus Pectin
Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A
Wayne State University, School of Medicine, Detroit, MI, USA
J Natl Cancer Inst. 2002 94(24):1854-62.
• Method: MCP’s inhibition of breast & colon cancer
progression; MCP’s interaction with Galectin-3
• Results: 70.2% Reduction in Breast Tumor Growth
– Breast Angiogenesis: 66% Reduction
– Breast to Lung Metastasis: 0% MCP v. 100% Control
– Colon to Liver Metastasis: 0% MCP v. 60% Control
– Colon to Lymph Metastasis: 25% MCP v. 100% Control
Inhibition of Human Cancer Cell Growth & Metastasis in
Nude Mice by Oral Intake of Modified Citrus Pectin
Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, Raz A
Wayne State University, School of Medicine, Detroit, MI, USA
J Natl Cancer Inst. 2002 94(24): 1854-62.
• Conclusion: MCP inhibits
carbohydrate mediated tumor
growth, angiogenesis & metastasis via
effects on Galectin-3 function
Modified Citrus Pectin Induces Cytotoxicity of Prostate
Cancer Cells in Co-Culture with Human Endothelial
Monolayers
Weiss T, McCulloch M, Eliaz I
Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA
EcoNugenics, Santa Rosa, CA, USA
Intl Conference on Diet & The Prevention of Cancer 1999, Tampere, Finland.
% Cytotoxicity
100%
76.9%
80.7%
80%
60%
40%
20%
3.8%
0%
Control
0.1%
1.0%
• Method: Human vascular
endothelial cell layer & PC-3
prostate cancer cells.
• Results: Strong tumor cell death
response with MCP, compared to
controls.
Effect of Modified Citrus Pectin on PSA Doubling Time in
Prostate Cancer Patients:
A Pilot Clinical Trial
Strum S, Scholz M, McDermed J, McCulloch M, Eliaz, I
Prostate Oncology Specialist, Marina del Rey, CA, USA
Amitabha Medical Clinic & Healing Center, Sebastopol, CA, USA
EcoNugenics, Santa Rosa, CA, USA. International Conference on Diet & The Prevention of Cancer 1999,
Tampere, Finland.
71%
80%
% Increase in PSADT
70%
60%
50%
40%
30%
14%
14%
20%
10%
0%
No Response
Stable Disease
Response
• Method: MCP 15 g/day to
patients with biochemical
relapse post local therapy.
PSA Doubling Time
(PSADT) evaluated at
intervals.
• Results: MCP significantly
increased PSADT in
prostate cancer patients.
Pilot Clinical Results: MCP’s Effect on
PSA Doubling Time
Patient
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
MCP Use
(Months)
5
6
3
>15
6
6
5
PSADT
Change
193%
193%
80%
55%
6%
-7%
-69%
Status
Response
Response
Response
Response
P. Response
Stable Disease
No Response
Modified Citrus Pectin Increases the Prostate-Specific
Antigen Doubling Time in Men with Prostate Cancer: A
Phase II Pilot Study
Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI
Healing Touch Oncology, Marina del Rey, CA, USA
Prostate Cancer & Prostatic Disease 2003;6(4):301-4.
• Method: 10 men with biochemical
prostate cancer relapse used MCP:
15g daily for 1 year.
Modified Citrus Pectin Increases the Prostate-Specific
Antigen Doubling Time in Men with Prostate Cancer: A
Phase II Pilot Study
Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI
Healing Touch Oncology, Marina del Rey, CA, USA
Prostate Cancer & Prostatic Disease 2003;6(4):301-4.
• Results: MCP significantly increased
PSADT in 7 out of the 10 participants
(p<0.01).
Phase II Study:
PSADT Results After 1 Year
Post-MCP
500%
Pre-MCP
*
*
* P<0.01
400%
350%
*
300%
*
*
250%
*
200%
150%
*
100%
50%
Patient-10
Patient-9
Patient-8
Patient-7
Patient-6
Patient-5
Patient-4
Patient-3
Patient-2
0%
Patient-1
PSADT as % of Pre MCP
450%
968 %
Using Splines to Detect Changes in PSA Doubling
Times
Guess B, Jennrich R, Johnson H, Redheffer R, Scholz M, Healing Touch Oncology, Marin del
Ray, CA, Department of Statistics, UCLA, CA, The Prostate 2003 54:88-95.
Typical Patient Results
MCP
Clinical Benefit in Patients with Advanced Solid Tumors
Treated with Modified Citrus Pectin
Azémar M, Hildenbrand B, Haering B, Heim ME, Unger C
Albert-Ludwigs-University in Freiburg, Germany
Sonnenberg-Klinik, Bad Sooden-Allendorf, Germany
Clinical Medicine: Oncology 2007 1:73–80.
• Method: MCP 15g daily.
• Results: 49 patients with advanced solid tumors.
29 evaluated after 2 months -- 21% showed
stabilization & improvements in quality of life.
– One patient w/ metastasized prostate
carcinoma showed 50% decrease in PSA, with
significant increase in quality of life &
decrease in pain.
Clinical Benefit in Patients with Advanced Solid Tumors
Treated with Modified Citrus Pectin
Azémar M, Hildenbrand B, Haering B, Heim ME, Unger C
Albert-Ludwigs-University in Freiburg, Germany
Sonnenberg-Klinik, Bad Sooden-Allendorf, Germany
Clinical Medicine: Oncology 2007 1:73–80.
• Conclusion: MCP shows clinical
benefits & improvements in quality of
life in advanced cancer patients.
Inhibitory Effect of Modified Citrus Pectin on Liver
Metastasis in a Mouse Colon Cancer Model
Liu HY, Huang ZL, Yang GH, Lu WQ, Yu NR
Guangzhou Medical College, Guangzhou, China
World J Gastroenterol 2008 14(48): 7386-7391.
• Method: 5 groups of 15 mice.
MCP: 0.0%, 1.0%, 2.5% and 5.0%; and negative
control.
– Colon cancer cells injected into spleen except negative control - liver metastasis observed after 3 wks. ELISA used to detect
Galectin-3.
• Results: MCP groups: Metastasis 80%, 73.3% & 60%.
MCP 0.0%: Metastasis100%.
Inhibitory Effect of Modified Citrus Pectin on Liver
Metastasis in a Mouse Colon Cancer Model
Liu HY, Huang ZL, Yang GH, Lu WQ, Yu NR
Guangzhou Medical College, Guangzhou, China
World J Gastroenterol 2008 14(48): 7386-7391.
• Conclusion: MCP significantly reduced
liver metastasis.
PectaSol-C Modified Citrus Pectin Induces Apoptosis & Inhibition of
Proliferation in Human & Mouse Androgen Dependent & Independent
Prostate Cancer Cells
Yan J, Katz A
Columbia University Medical Center, New York, NY, USA
Integrative Cancer Therapies 2010 9:197-203.
• Method: 1% MCP treatment of human
prostate cancer cell lines (LNCaP & PC3)
and mouse prostate cancer cell lines
(CASP2-1 & CASP1-1)
PectaSol-C Modified Citrus Pectin Induces Apoptosis & Inhibition of
Proliferation in Human & Mouse Androgen Dependent &
Independent Prostate Cancer Cells
Yan J, Katz A
Columbia University Medical Center, New York, NY, USA
Integrative Cancer Therapies 2010 9:197-203.
• Results: Confirmed apoptosis and inhibition
of cancer cell proliferation
4 day MCP treatment showed cytotoxicity:
–
–
–
–
52.28% in LNCaP
48.16% in PC3
23.03% in CASP2-1
49.01% in CASP1-1
Combination Effect of PectaSol and Doxorubicin on
Viability, Cell Cycle Arrest and Apoptosis in DU-145 and
LNCaP Prostate Cancer Cell Lines
Najmeh T, Houri S, Parvin M, Firouzeh B, Arash HN, Abdolfattah S, Ebrahim H
Tehran University, Tehran, Iran
Cell Biology International (2012) doi:10.1042/CBI20110309.
• Method: 48 hour effects of PectaSol on Doxorubicin (Dox) cytotoxicity, apoptosis
and cell cycle in prostate cancer cell lines.
% Viability DU-145
100
80
60
40
20
0
IC50 Decrease: 1.5 fold
Control
250nM
Dox
3mg/ml 250nM + 3
PectaSol
mg/ml
Combined
% Viability LNCaP
100
80
60
40
20
0
IC50 Decrease: 1.3 fold
Control
250nM
Dox
3mg/ml 250nM + 3
PectaSol
mg/ml
Combined
Combination Effect of PectaSol and Doxorubicin on
Viability, Cell Cycle Arrest and Apoptosis in DU-145 and
LNCaP Prostate Cancer Cell Lines
Najmeh T, Houri S, Parvin M, Firouzeh B, Arash HN, Abdolfattah S, Ebrahim H
Tehran University, Tehran, Iran
Cell Biology International (2012) doi:10.1042/CBI20110309.
Conclusion: Lower, less toxic
doses Dox needed when
combined with PectaSol.
MCP During Chemotherapy &
Radiation
• MCP can enhance therapeutic effect of
chemotherapy drugs and treatment of chemo
resistant cancers
–
Cisplatin (Platinol), Bortezomib (Velcade),
Dexamethasone (Decadron), Doxorubicin
• MCP use very important in preventing
post chemotherapy & radiation damage
– Specifically post radiation induced inflammation and
fibrosis
Summary: MCP in Cancer Treatment
• MCP Reduces:
– Primary Tumor
– Angiogenesis
– Metastatic Process
• MCP Provides:
– Blocking of Galectin-3 Effects
– Synergistic Effect with Chemotherapy
– Protection Against Post-Radiation Damage
– Improved Quality of Life
Modified Citrus Pectin
Immune Research
MCP Immune System Benefits
Modified Citrus Pectin:
• Induces NK Cell Activation
• Induces NK Cell Activity
• Activates T Cytotoxic Cells
• Increases B Cell Activation
Activation of Human T-Cytotoxic Cell, B-Cell, and Natural Killer
(NK)-Cells and Induction of NK-Cell Activity Against K562 Chronic
Myeloid Leukemia Cells with Modified Citrus Pectin
Ramachandran C, Wilk, B, Hotchkiss, A, Eliaz, I & Melnick SJ
Dharma Biomedical, Miami, FL, USA, EcoNugenics, Santa Rosa, CA, USA Eastern Regional Research Center, ARS,
USDA, Wyndmoor, PA, USA
Department of Pathology, Miami Children's Hospital, Miami, FL, USA
BMC Complementary and Alternative Medicine 2011, 11:59.
• Method (Part I):
Healthy human blood samples incubated with
increasing doses of MCP and antibodies.
• At 24 hours samples lyzed and run on a flow
cytometer. Analyzed % of activated T-cytotoxic
cell, B-cells, and NK-cells; and % increase over
untreated control.
Results Part I:
MCP Activates T-Cytotoxic Cells
Increase in T-Cytotoxic Cell Activation (%)
160%
* p < 0.05
** p < 0.01
**
140%
*
120%
*
100%
80%
60%
40%
20%
0%
MCP
50
ug/ml
MCP
100
ug/ml
MCP
200
ug/ml
MCP
400
ug/ml
MCP
800
ug/ml
CD2/CD2R
20
ul/ml
PMA
10
ng/ml
Results Part I:
MCP Increases B-Cell Activation
***
Increased B-Cell Activation (%)
1200%
1000%
**
** p<0.010
*** p<0.001
800%
600%
400%
200%
0%
MCP
10
ug/ml
MCP
20
ug/ml
MCP
50
ug/ml
MCP
100
ug/ml
MCP
200
ug/ml
MCP
400
ug/ml
MCP
800
ug/ml
PWM
10
ug/ml
PWM
25
ug/ml
Results Part I:
MCP Increases NK Cell Activation
**
Increased NK-Cell Activation (%)
1000%
900%
* p < 0.05
** p < 0.01
**
800%
700%
600%
*
500%
*
400%
300%
200%
100%
0%
MCP
10
ug/ml
MCP
20
ug/ml
MCP
50
ug/ml
MCP
100
ug/ml
MCP
200
ug/ml
MCP
400
ug/ml
MCP
800
ug/ml
IL-2
3.3
ng/ml
IL-2
6.6
ng/ml
MCP: Induction of NK-Cell Activity Against K562
Chronic Myeloid Leukemia Cells
• Method (Part II):
NK cell ability to induce leukemia cell death
analyzed by co-incubating MCP-treated
lymphocytes with K562 T-cell leukemia cells.
•
• Healthy human lymphocyte samples treated
with increasing doses of MCP. After 24 hours,
K562 labeled. Plates returned to incubator (for 4
hrs) to induce leukemia cell death.
Results Part II:
MCP Induces NK Cell Activity
(% K562 cell death over untreated WBC)
Increase in NK Cell Activity
60%
50%
40%
30%
20%
10%
0%
MCP
10
ug/ml
MCP
20
ug/ml
MCP
50
ug/ml
MCP
100
ug/ml
MCP
200
ug/ml
MCP
400
ug/ml
MCP
800
ug/ml
Modified Citrus Pectin:
Chelation & Detoxification
Research
MCP Heavy Metal
Elimination
• Forms stacked “egg
box” structure
• Each pocket
negatively charged
• Negative charge
binds heavy metals
• Toxic metal trapped
in the “egg box”
• Safely excreted
from the body
The Effect of Modified Citrus Pectin on
Urinary Excretion of Toxic Elements
Eliaz I, Hotchkiss AT, Fishman ML, Rode D; Amitabha Medical Clinic & Healing Center,
Sebastopol, CA, USA; Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA;
UC, Davis, CA, USA Phytother Res 2006 20(10):859-64.
• Methods: MCP administered for 6 days. Baseline 24
hr urine collection before MCP, and on days 1 and 6.
Days 1 - 5: MCP 15 g/day & Day 6: MCP 20 g/day.
The Effect of Modified Citrus Pectin on
Urinary Excretion of Toxic Elements
Eliaz I, Hotchkiss AT, Fishman ML, Rode D; Amitabha Medical Clinic & Healing Center,
Sebastopol, CA, USA; Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA;
Univer. of CA, Davis, CA, USA Phytother Res 2006 20(10):859-64.
• Results: Urinary excretion of lead,
mercury, cadmium & arsenic increased.
Essential minerals not changed. No side
effects reported.
The Effect of Modified Citrus Pectin on
Urinary Excretion of Toxic Elements
Day-1
Day-6
450%
% Change from Day Zero
400%
#
* p < .05
# p < .10
350%
300%
250%
200%
150%
#
100%
50%
*
*
#
*
#
0%
Al
Sb
Aluminum Antimony
As
Arsenic
CD
Cadmium
Pb
Lead
Hg
Mercury
Sn
Tin
MCP & Urinary Excretion of Toxins
MCP Chelation:
• Increased urinary excretion of toxic metals
• Demonstrated heavy metal chelation due to
reduced molecular size & esterification
• 10% rhamnogalacturonan II -- known for
binding affinity and immune enhancement
• Does not affect essential minerals
• No side effects reported
Modified Citrus Pectin Decreases the Total Body
Burden: A Pilot Human Clinical trial
Eliaz I. Amitabha Medical Clinic & Healing Center, Sebastopol, California, USA.
EcoNugenics, Santa Rosa, California, USA.
228th ACS National Meeting, Philadelphia, PA. 2004.
• Methods: Oral intake 5 g Modified Citrus Pectin/3x
day for 4-10 months. Base line body burden and
change measured with DMPS challenge (250mg i.v.
followed by 6 hr. urine collection).
• Results: All subjects showed significant decrease in
Mercury levels. Average decrease was 62.17%,
ranging between 38.13% & 74.83% (p=0.0313).
• No significant side effects were noted.
Study Conclusion
Percent Reduction in Mercury
from Baseline
Percent Reduction in Mercury from
Baseline
80%
67.90%
74.80%
72.80%
70%
• MCP was effective in decreasing
the total body burden of Mercury
in all subjects.
60%
• MCP is a promising systemic
gentle chelator of heavy metals
that can be used on an on going
basis.
20%
57.30%
50%
38.10%
40%
30%
10%
0%
Patient A Patient B Patient C Patient D Patient E
10 months
4.5 months
4 months
6 months
6.5 months
MCP Intervention Individual Results
The Role of Modified Citrus Pectin as
an Effective Chelator of Lead in
Children Hospitalized with Toxic Lead
Levels
Zhao ZY, Liang L, Fan X, Yu Z, Hotchkiss AT, Wilk BJ, Eliaz I
Children’s Hospital, Zhejiang University, School of Medicine, Hangzhou, Republic of China
Centrax International, Inc, San Francisco, CA, USA
Eastern Regional Research Center, ARS, USDA, Wyndmoor, PA, USA
EcoNugenics, Santa Rosa, CA, USA
Altern Ther Health Med. 2008 14(4):34-8.
Blood Serum Lead Concentration (ug/dL)
Lead in Blood Serum
60
Before
MCP
After
MCP
50
40
30
20
10
0
Patient-1 Patient-2 Patient-3 Patient-4 Patient-5 Patient-6 Patient-7
(MCP 5 grams, 3 times daily)
P Value = 0.0016
Lead in 24 Hour Urine Excretion
140
Lead Levels (mcg/dL)
120
Before
MCP
After
MCP
100
80
60
40
20
0
Patient-1 Patient-2 Patient-3 Patient-4 Patient-5 Patient-6 Patient-7
(MCP 5 grams, 3 times daily)
P Value = 0.0007
Synergistic Benefits of MCP
Prostate Poly Botanical Formula
Integrative blend of
33 ingredients:
Vitamins, Minerals,
Botanically Enhanced
Medicinal Mushrooms,
and Botanical Extracts
ProstaCaid Induces G2/M Cell Cycle Arrest & Apoptosis in
Human & Mouse Androgen-Dependent & -Independent
Prostate Cancer Cells
Yan J & Katz AE; Department of Urology, Columbia University Medical Center, New York,
NY, USA. Integr Cancer Ther 2010 9:186-196.
Effects on cell viability on androgendependent, LNCaP (A) & CASP 2.1 (C), &
androgen-independent PC3 (B) & CASP 1.1 (D)
Effects on long-term cell viability by
colony formation
Effect of ProstaCaid on Invasive Behavior of Prostate Cancer Cells
A
B
120
Cell migration [%]
Cell adhesion [%]
120
100
*
80
60
*
40
100
*
80
60
*
40
20
20
0
0
0
20
40
80
0
ProstaCaid ( g/ml)
20
40
80
ProstaCaid [ g/ml]
(A) Cell adhesion. PC-3 cells were treated with
ProstaCaid for 24 hours and cell adhesion to
fibronectin determined.
(B) Cell migration. Cell migration was determined
after 24 hours of incubation with ProstaCaid in
Boyden Chambers.
C
D
Cell invasion [%]
120
uPA Density
100
1.00
*
80
0.61
0.38
0.16
*
60
uPA
40
0
20
20
40
80
ProstaCaid ( mg/ml)
0
0
20
40
ProstaCaid [ g/ml]
80
(C) Cell invasion. Cell invasion was determined after
24 hours of incubation with ProstaCaid in Boyden
Chambers coated with Matrigel.
(D) uPA secretion. PC-3 cells were treated for 24 hours
and the expression of uPA detected in conditioned
media with anti-uPA antibody by Western blot. *
p<0.05
ProstaCaid Inhibits Tumor Growth in a Xenograft
Model of Human Prostate Cancer
• Results: No effect on body weight or activity of liver
enzymes (ALT, AST).
• No sign of toxicity in liver, spleen, kidney, lung and heart
Inhibition of tumor volumes (1024.6±378.6 vs.
749.3±234.3, P<0.001)
• qRT-PCR analysis showed significant up regulation of
expression of CDKN1A (p21) and inhibition of expression
of IGF2, NR2F2 and PLAU (uPA)
• Conclusion: ProstaCaid has significant anticancer activity in
vivo with no signs of toxicity.
Prostate Polybotanical Formula
Breast Polybotanical Formula
Contains botanicals,
purified biologically active
nutritional compounds
and botanically enhanced
medicinal mushrooms
Suppression of Proliferation & Invasive Behavior of
Human Metastatic Breast Cancer Cells by Dietary
Supplement BreastDefend
Jiang J, Wojnowski R, Jedinak A, Sliva D; Cancer Research Laboratory, Methodist Research Institute, Indianapolis, IN, USA
Department of Medicine, Indiana University. Cancer Center, School of Med., Indiana University, Indianapolis, IN, USA. Integr
Cancer Ther 2011; Jun 10 (2):192 – 200.
0 m g /m l
120
1 0 m g /m l
2 0 m g /m l
3 0 m g /m l
P ro life ra tio n In d e x [% ]
100
4 0 m g /m l
80
*
*
60
*
*
*
40
*
20
* *
* *
0
2 4 h o u rs
4 8 h o u rs
7 2 h o u rs
BreastDefend Suppresses MDA-MB-231 Growth and
Breast-to-Lung Metastasis in a Orthotopic Tumor
Model
Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C,
Sandusky GE, Sliva D. Oncol Rep. 2012; 28: 1139-1145.
• Method: Highly aggressive triple negative human breast cancer
cells (MDA-MB-231) implanted into the mammary gland in mice
then given the formula orally (100 mg/kg of body weight) for four
weeks.
• Results: The formula significantly decreased tumor growth and
breast to lung metastasis, and did not affect body weight or
activity of liver enzymes or show any sign of toxicity in liver
spleen, kidney, lung and heart tissues in mice.
– The cancer metastasized to the lungs in 67% of controls but only 20
percent of treated mice. The number of metastases per animal was
also significantly affected by the formula.
– Down-regulation of primary tumor genes PLAU (urokinase
plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor4).
Breast Polybotanical Formula
Synergistic and Additive Effects of
Modified Citrus Pectin with Two Novel
Polybotanical Compounds, in the
Suppression of Invasive Behavior of
Human Breast and Prostate Cancer Cells
Jiang J, Eliaz I, and Sliva D. Cancer Research Laboratory, MRI, Indiana
University Health, Indianapolis, IN, USA
Amitabha Med. Clinic & Healing Center, Sebastopol, CA, USA
Depart. of Med., and Indiana Univer. Cancer Center, Indiana Univer.
School of Med., Indianapolis, IN, USA.
Integr Cancer Ther. 2013 March 12 (2):145-52.
Proliferation Index (%) .
Prostate Polybotanical Formula
Effect on Proliferation of Human Prostate Cancer Cells
120
100
*
80
60
*
40
*
20
0
0
10
20
40
80
PC3 growth measured using MTT assay. Cells incubated for 24 hrs
with ProstaCaid (ug/ml). *P < .05
Prostate Formula & MCP
Effect on Migration of Human Prostate Cancer Cells
120
The invasive behavior of PC3 evaluated using migration assay in the presence of (A)
MCP (mg/mL) & (B) MCP (mg/mL) plus Prostacaid (10 ug/mL).
% M igration
100
P < 0 .0 1
80
P < 0 .0 1
60
40
P < 0 .0 1
A
20
B
0
MCP
P r o s ta C a id
0
0 .2 5
0 .5
1 .0
0
10
0 .2 5
10
0 .5
10
1 .0
10
m g /m l
m g /m l
Breast Polybotanical Formula
Proliferation Index (%)
Effect on Proliferation of Human Breast Cancer Cells
120
100
*
80
60
*
40
*
20
0
0
5
10
20
40
Growth of MDA-MB-231 measured using MTT assay. MDA-MB-231 cells incubated
for 24 hrs with BreastDefend (ug/mL) at the indicated concentrations. *P < .05
Breast Formula & MCP
Invasive behavior of MDA-MB-231 evaluated using migration assay in the presence of (A)
MCP (mg/mL) & (B) MCP (mg/mL) plus BreastDefend (20 ug/mL).
120
100
% M igration
P < 0 .0 1
80
P < 0 .0 1
60
P < 0 .0 1
40
20
0
MCP
0
B re a s tD e fe n d
0 .2 5
A
0 .5
1 .0
0
20
0 .2 5
B
20
0 .5
20
1 .0
20
m g /m l
m g /m l
Modified Citrus Pectin
Published Data Summary
Preclinical and Clinical Research
Highlights on Modified Citrus Pectin
Preclinical Studies with MCP
(17 Published Articles)
In vitro (Type of Cancer)
In vivo (Type of Cancer)
5 (Prostate*)
2 (Prostate) including 1 Lung Metastasis Study
2 (Breast*,**)
2 (Breast*,**) including 1 Lung Metastasis
Study
1 (Melanoma***) including 1 Lung Metastasis
Study
3 (Colon**) including 1 Lymph and 1 Liver
Metastasis Study
2 (Non Cancer; Kidney Injury, Arteriole Fibrosis)
1 (Melanoma***)
1 (Non Cancer; Small Intestine
Permeability)
9 Total
10 Total
Ex vivo (Type of
Cancer)
1 (Immune;
Leukemia)
1 (Angiosarcoma &
Hemangiosarcom)
2 Total
*One in vitro study reported on both prostate and breast cancer (Glinskii OV, Huxley
VH, Glinsky GV. et al. Neoplasia. 2005;7(5):522-527). **One article reported two in
vivo studies and one in vitro study (Nangia-Makker P, Hogan V, Honjo Y, et al. J Natl
Cancer Inst. 2002 Dec 18;94(24):1854-62). ***One articles reported both an in vivo
and an in vitro study (Platt D, Raz A. J Natl Cancer Inst. 1992 Mar;84(6):438-42)
Seven Clinical Studies with MCP
Human Clinical Study
Type of Trial
(Number of Participants)
Zhoa, et al., Altern Ther
Pilot trial: Lead toxicity in
Health Med. 2008. (n = 7) hospitalized children ages 512
Results
Very significant decrease in blood serum
levels of lead (P = .0016) and very
significant increase in 24-hour urine
collection (P = .0007). No adverse effects.
22.5% patients showed a stable disease
(SD) and 12.3% patients had a SD for a
period longer than 24 weeks. One patient
with metastasized prostate carcinoma
showed a 50% decrease in serum PSA
level after 16 weeks of treatment
associated with a significant increase of
clinical benefit, quality of life and decrease
in pain. 20.7% patients had an overall
clinical benefit response associated with a
stabilization or improvement of life quality.
All patients tolerated the therapy well
without any severe adverse events.
5 case studies presented show reduction
Eliaz, et al. Forsch
Case studies: Involving
Komplementmed. 2007. (n lowering of lead and mercury in toxic heavy metals was achieved
without side effects. Gradual decrease of
= 5)
body burden
total body burden is believed to have
played an important role in recovery and
health maintenance.
Azémar, et al., Clinical
Pilot trial: To assess the
Medicine: Oncology. 2007. quality of life, clinical benefit
(n = 49)
and antitumoral efficacy in
advanced stage solid tumors
(colorectal, prostate, breast,
kidney, cervix/uterine, liver,
pharynx, pancreatic,
melanoma, stomach, bile
duct carcinoma and
chondrosarcoma)
Human Clinical Study
(Number of Participants)
Eliaz, et al. Phytother Res.
2006. (n = 8)
Type of Trial
Results
Pilot trial: Toxic
heavy metal
removal in healthy
population
In the first 24 hours the urinary excretion of arsenic
increased significantly (p < 0.05). On day 6, urinary
excretion was increased significantly for cadmium (p <
0.05). Lead showed a dramatic increase in excretion (p <
0.08), and mercury approached significance on day six.
Other elements analyzed including essential elements
did not show any significant change in excretion.
Eliaz. 228th Annual American
Chemistry Meeting. August
2004. (n = 5)
Pilot trial:
Decrease total
body burden of
mercury
A significant decrease in total body mercury burden was
seen in all participants. The decrease was found more
significant over time. The mercury burden for the group
dropped 68.32% (p=0.0313). All individual completed the
study, and there were no side effects reported.
Guess, et al. Prostate Cancer
Prostatic Dis. 2003. (n = 13)
Phase II pilot trial:
Lengthening of
PSA doubling time
in biochemical
relapsed prostate
cancer patients.
There were no serious side effects in any patient, but
three patients withdrew from the study due to abdominal
cramping or diarrhea. MCP was well tolerated by the
remaining 10 evaluable patients. Seven (70%) of these
evaluable patients had a significantly increased doubling
time of PSA compared with their times before the
treatment.
Strum, et al. International
Conference on Diet and
Prevention of Cancer. May
1999. (n = 7)
Pilot Study:
Lengthening of
prostate-specific
antigen doubling
time in biochemical
relapsed prostate
cancer patients.
PSA doubling time was lengthened by more than 30% in
4/7 (57%) of patients. One patient had a partial
response, one patient had stable disease, and one
patient did not respond. No adverse effects were
reported.
Galectin-3 Research
The role of active biomarker galectin-3 in
chronic disease progression
The PREVEND Study
(Prevention of Renal and
Vascular End-stage Disease)
de Boer RA, van Veldhuisen DJ, R. T. Gansevoort RT, et al. The fibrosis marker
Galectin-3 and outcome in the general population. J Intern Med. 2012 doi:
10.1111/j.1365-2796.2011.02476.x. University of Groningen, Groningen, The
Netherlands
Galectin-3 Levels & Mortality from All Causes in the
General Population: PREVEND
Median
Galectin-3
Levels
Quintile-1
7.7
Cumulative Survival Rate (%)
100%
95%
Quintile-2
9.4
Quintile-3
10.9
90%
Quintile-4
12.6
Number of Subjects
n = 7,968
Year-11
Year-10
Year-9
Year-8
Year-7
Year-6
Year-5
Year-4
Year-3
Year-2
Year-1
Start
85%
Quintile-5
15.6
Overall
Average
11.9
Galectin-3 in General Population: PREVEND
(number of subjects = 7,968)
CHARACTERISTIC
TOTAL
QUINTILE-1
QUINTILE-2
QUINTILE-3
QUINTILE-4
QUINTILE-5
11.9
7.7
9.4
10.9
12.6
15.6
DM%
3.6
2.3
2.3
3.1
4.3
6.1
0.000
MI
3.7
1.8
2.4
2.7
4.2
7.4
0.000
Hypertension
33.4
22.2
26.6
31.1
39.7
47.9
0.000
Stroke %
0.9
0.8
0.6
0.6
1.3
1.6
0.004
Systolic BP
129.2±20.2
125.0±18.1
126.6±19.0
128.6±19.6
131.3±20.6
134.9±22.5
0.000
Diastolic BP
74.0±9.7
72.1 ±9.4
73.3±9.8
74.1±9.6
75.2±9.8
75.4±9.8
0.000
Median Gal3
P
Galectin-3 in General Population: PREVEND
(number of subjects = 7,968)
CHARACTERISTIC
TOTAL
QUINTILE-1
QUINTILE-2
QUINTILE-3
QUINTILE-4
QUINTILE-5
11.9
7.7
9.4
10.9
12.6
15.6
CRP
1.29
[0.56-3.00]
0.89
[0.39-2.16]
1.04
[0.49-2.40]
1.33
[0.58-2.92]
1.53
[0.71-3.42]
1.98
[0.85-4.28]
0.000
Cholesterol
5.66±1.12
5.41±1.05
5.56±1.10
5.68±1.11
5.79±1.11
5.91±1.17
0.000
LDL
3.69±1.05
3.47±1.00
3.60±1.01
3.71±1.04
3.77±1.05
3.90±1.06
0.000
HDL
1.27
[1.03+1.56]
1.32
[1.07-1.62]
1.28
[1.04-1.57]
1.25
[1.03+1.55]
1.24
[1.03-1.53]
1.24
[0.99-1.52]
0.000
Triglycerides
1.16
[0.85-1.68]
1.02
[0.75-1.43]
1.11
[0.82-1.59]
1.17
[0.86-1.69]
1.23
[0.89-1.78]
1.31
[0.95-1.92]
0.000
Median Gal3
P
The COACH (Coordinating Study on
Outcomes of Advising and
Counseling in Heart Failure)
Multicenter, randomized, controlled trial conducted in The Netherlands. A
prospective sub-study was designed to evaluate Galectin-3 in patients
with chronic heart failure and define cut-off levels for subsequent
validation studies.
Galectin-3 levels were measured in 582 banked EDTA-plasma samples.
COACH Galectin-3 Sub-Study Mortality from All
Causes at 1 Year in Patients with CHF
40%
36.51%
% Died within 365 Days
35%
30%
25%
19.69%
20%
15%
12.57%
10%
5%
0%
< 17.8
17.8 - 25.9
Galectin-3 Levels (ng/mL)
> 25.9
% Death or HF Hospitalization within 365 Days
COACH Galectin-3 Sub-Study Cardiovascular Mortality or
Heart Failure-Related Hospitalization at 1 Year in
Patients with CHF
60%
52.38%
50%
40%
33.51%
30%
20%
18.85%
10%
0%
< 17.8
17.8 - 25.9
Galectin-3 Levels (ng/mL)
> 25.9
Galectin-3 and Cardiovascular Health
•
•
•
•
•
DeFillipi et al, U.S. Cardiology, 7,1, 3–6 (2010) clearly indicate that circulating
Galectin-3 is an important factor in fibrosis of many organs and organ systems, and
that reducing circulating Galectin-3 may have an important role in remediating
cardiac injury and progression to heart failure (HF).
Similarly, Psarras et al, Eur. Heart J., April 26 (2011) demonstrate that reduction in
Galectin-3 levels in the myocardium may reduce fibrosis in the heart and improve
outlook.
De Boer et al, Ann. Med., 43,1, 60–68 (2011) identify Galectin-3 as a key indicator
in cardiac health.
Shash et al, Eur J. Heart Fail., 12,8, 826–32 (2011) identify Galectin-3 levels as a
key agent in heart failure through fibrosis.
De Boer et al. Eur. J. Heart Fail., 11, 9, 811-817 (2009) link an increase in Galectin-3
expression and presence to heightened fibrosis, and heart failure. The same
article links Galectin-3 to inflammation. Inflammation is the hallmark of
arteriosclerosis, therefore Galectin-3 levels also contribute to coronary artery
disease, peripheral artery disease, strokes, and vascular dementia.
Modified Citrus Pectin Reduces Galectin3 Expression and Disease Severity in
Experimental Acute Kidney Injury
Kolatsi-Joannou M, Price KL, Winyard PJ, Long DA. NephroUrology Unit, UCL Institute of Child Health, London, UK
PLoS ONE 2011 April 6(4): e18683.
MCP & Kidney Injury Study
• Background: Folic acid (FA)-induced acute kidney
injury model
• Method: Mice given 1% MCP-supplemented water, or
plain water, 1 week before FA injection
• Results: During initial injury phase, all FA treated mice
lost weight while their kidneys enlarged secondary to
renal insult
– Gross changes significantly lessened in MCP group
– MCP clearly reduced renal cell proliferation
– Recovery phase:
MCP group showed decreased Galectin-3 expression
with decreased renal fibrosis, macrophages, proinflammatory cytokine expression, and apoptosis
Galectin-3 Mediates AldosteroneInduced Vascular Fibrosis
Calvier L, Miana M, Reboul P, et al.
Arterioscler Thromb Vasc Biol. 2013 Jan;33(1):67-75.
Aldosterone Galectin-3 MCP Vascular
Fibrosis Study
• Background: Aldosterone is involved in arterial stiffness and heart
failure. Galectin-3 plays an important role in inflammation,
fibrosis, and heart failure. MCP blocks Galectin-3
• Methods and Results: Rats were treated with aldosterone
combined with MCP for 3 weeks. Hypertensive aldosteronetreated rats presented vascular hypertrophy, inflammation,
fibrosis, and increased aortic Gal-3 expression. Those also treated
with MCP treatment abolished all the above effects.
• Conclusion: Galectin-3 is required for inflammatory and fibrotic
responses to aldosterone in vascular smooth muscle cells in vitro
and in vivo. By inhibiting Galectin-3, MCP prevents vascular
fibrosis.
Elevated Galectin-3:
What can we do?
• Test for Galectin-3 levels
• Address general inflammation &
hyperviscosity
• Use MCP at appropriate dosages by:
– Condition
– Galectin-3 levels
– Therapeutic goal
Serum Galectin-3
Testing
USFDA approved blood test that
measures Galectin-3 for Cardiovascular
Disease
Galectin-3 Levels:
Reference Ranges
•
Galectin-3 levels > 17.8 ng/ml are considered
to be an extreme risk factor of mortality.
•
Ideal levels are < 14 ng/ml in the
general population.
•
For cancer and cardiac patients,
ideal levels are < 12 ng/ml.
•
Galectin-3 levels change in 20% of population
every 3 months.
• Repeated testing is important.
Galectin-3 Levels:
Cancer
• Desired levels <12.0 ng/ml
• Follow up on Galectin-3 levels routinely
every 3-6 months
Active Cancer
• Levels <17.8, or not tested
MCP 15g daily
• Levels >17.8
MCP 20 - 25g daily
Cancer Long Term Maintenance
(3 years post therapy)
• Levels < 12.0 ng/ml
MCP 5g daily
• Levels = 12.0 – 14.0 ng/ml
MCP 10g daily
• Levels = 14.0 – 17.8 ng/ml
MCP 15g daily
• Levels >17.8 ng/ml
MCP 20 – 25g daily
Galectin-3 Levels:
MCP Dosage (grams)
Galectin-3 Test
Results
(ng/ml)
No Known
Medical
Conditions
Cardiovascular,
Inflammation,
Fibrosis, Hepatitis
Active
Cancer
Post
Cancer
(3 years)
<12
5
5
15
5
12.0 – 14.0
5
10
15
10
14.0 – 17.8
10
15
15
15
> 17.8
15
20
20 - 25
20 - 25
Not Tested
5
15
15
5 -10
In Conclusion:
Galectin-3 and Modified Citrus Pectin
• Galectin-3 is a novel, active biomarker
that is both a cause of multiple diseases
and a diagnostic and prognostic biomarker.
• Modified Citrus Pectin is a proven natural
Galectin-3 blocker.