Salvestrols cures Cancer
description
Transcript of Salvestrols cures Cancer
![Page 1: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/1.jpg)
Salvestrols
Professor Dan Burke
Salvestrol Natural Products, Leicester UK
and CYP1B1
A natural team fighting cancer naturally
![Page 2: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/2.jpg)
UNIVERSITY OF ABERDEEN CYP1B1
Enzyme protein very highly
over-expressed in cancer
cells (human biopsies /
immunohistochemistry)
Undetectable in most
normal cells ... trace levels
in some
1995
![Page 3: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/3.jpg)
normal cells stained purple
O CYP1B1
cancer cells stained black
P CYP1B1
oesophageal cancer
Murray, Melvin, Greenlee & Burke; Annu. Rev. Pharmacol. Toxicol. 41: 297-316 (2001)
![Page 4: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/4.jpg)
Murray, Taylor, McFadyen, McKay, Greenlee, Burke & Melvin; Cancer Res. 57: 3026-31031 (1997)
Expression of CYPIBI protein in 14 different types of cancer and normal tissue
Tissue Normal Cancer
(# positive / # tested) (# positive / # tested)
Bladder 0/8 8/8 (transitional cell carcinoma) Brain 0/12 11/l2 (astrocytoma) Breast 0/10 12/12 (invasive ductal carcinoma) Colon 0/10 11/12 (adenocarcinoma) Connective tissue 0/9 8/9 (sarcoma) Esophagus 0/9 8/8 (squamous carcinoma) Kidney 0/11 11/11 (carcinoma) Liver 0/8 Not tested Lung 0/8 7/8 (squamous carcinoma) Lymph node 0/5 9/9 (non-Hodgkin's lymphoma) Ovary 0/5 7/7 (adenocarcinoma) Skin 0/6 6/6 (squamous carcinoma) Small intestine 0/5 Not tested Stomach 0/10 9/10 (adenocarcinoma) Testis 0/8 8/8 (malignant germ cell tumor) Uterus 0/7 7/7 (adenocarcinoma)
![Page 5: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/5.jpg)
Murray, Taylor, McFadyen, McKay, Greenlee, Burke & Melvin; Cancer Res. 57: 3026-31031 (1997)
Expression of CYPIBI protein in 14 different types of cancer and normal tissue
Tissue Normal Cancer
(# positive / # tested) (# positive / # tested)
Bladder 0/8 8/8 (transitional cell carcinoma) Brain 0/12 11/l2 (astrocytoma) Breast 0/10 12/12 (invasive ductal carcinoma) Colon 0/10 11/12 (adenocarcinoma) Connective tissue 0/9 8/9 (sarcoma) Esophagus 0/9 8/8 (squamous carcinoma) Kidney 0/11 11/11 (carcinoma) Liver 0/8 Not tested Lung 0/8 7/8 (squamous carcinoma) Lymph node 0/5 9/9 (non-Hodgkin's lymphoma) Ovary 0/5 7/7 (adenocarcinoma) Skin 0/6 6/6 (squamous carcinoma) Small intestine 0/5 Not tested Stomach 0/10 9/10 (adenocarcinoma) Testis 0/8 8/8 (malignant germ cell tumor) Uterus 0/7 7/7 (adenocarcinoma)
![Page 6: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/6.jpg)
Murray, Taylor, McFadyen, McKay, Greenlee, Burke & Melvin; Cancer Res. 57: 3026-31031 (1997)
Expression of CYPIBI protein in 14 different types of cancer and normal tissue
Total 0 / 130 (0%) 122 / 127 (96%)
Tissue Normal Cancer
(# positive / # tested) (# positive / # tested)
Bladder 0/8 8/8 (transitional cell carcinoma) Brain 0/12 11/l2 (astrocytoma) Breast 0/10 12/12 (invasive ductal carcinoma) Colon 0/10 11/12 (adenocarcinoma) Connective tissue 0/9 8/9 (sarcoma) Esophagus 0/9 8/8 (squamous carcinoma) Kidney 0/11 11/11 (carcinoma) Liver 0/8 Not tested Lung 0/8 7/8 (squamous carcinoma) Lymph node 0/5 9/9 (non-Hodgkin's lymphoma) Ovary 0/5 7/7 (adenocarcinoma) Skin 0/6 6/6 (squamous carcinoma) Small intestine 0/5 Not tested Stomach 0/10 9/10 (adenocarcinoma) Testis 0/8 8/8 (malignant germ cell tumor) Uterus 0/7 7/7 (adenocarcinoma)
![Page 7: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/7.jpg)
prostate carcinoma
Carnell, Smith, Daley et al.; Int. J. Radiation Oncology Biol. Phys. 58: 500-509 (2004)
normal prostate
all cells blue:
O CYP1B1
PCYP1B1
cancer cells
stained brown
normal cells
stained blue
OCYP1B1 :
![Page 8: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/8.jpg)
CYP1B1 protein is highly overexpressed in all types of cancer* and in metastases and precancer cells
Bladder
Brain
Breast
Cervix
Colon
Connective tissue
Head & Neck
Kidney
Leukaemia
Lung
Lymphoma
Melanoma
Mesothelioma
Myeloma
Ovary
Oesophagus
Prostate
Stomach
Testis
Uterus
* confirmed by Dana-Farber Cancer Institute, Boston, USA
![Page 9: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/9.jpg)
cancer cell
ribosome
nucleus
CYP1B1 gene
normal cell
nucleus
CYP1B1 gene
CYP1B1 protein
mRNA
cancer cell CYP1B1 mRNA and CYP1B1 protein
normal cell
CYP1B1 mRNA but no CYP1B1 protein
mRNA
ribosome μRNA
1. Tsuchiya, Y. et al., Cancer Res. 66: 9090-98 (2006) 2. Devlin, A. et al., Mol. Carcin. 49: 190-99 (2010)
CYP1B1 protein expression controlled by microRNA 1 and untranslated region DNA interactions 2
DNA interactions
![Page 10: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/10.jpg)
CYP1B1 in plasma as cancer biomarker CYP1B1 as imaging tool for cancer in surgery Lung cancer patient plasma sample no.
CYP1B1 peptide level x higher than pooled normal plasma
0016005001 6291
0016003001 1234
0016005002 1207
0016001001 799
0016002002 279
0016003002 276
0016004001 222
0016002001 214
0016004002 162
0016006002 148
0016009001 135
0016006001 134
0016009002 124
0016001002 121
0016008002 119
0016007001 118
0016007002 97
0016008001 93
CYP1B1 in pooled normal plasma:
< 10 amol/μl inactive
CYP1B1 peptide measured in plasma using SISCAPA absolute quantitation mass spectrometry
![Page 11: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/11.jpg)
The majority of anticancer drugs are not truly
selective for cancer cells.
Their efficacy is limited by the damage they also
cause to normal cells.
Prof. Bill Denny, University of Auckland, NZ
Cancer Investigation 22: 604-619 (2004)
---------------------------------------------------------------------------------------------
The anticancer drug targets not just in cancer cells
but also in many critically important normal cells
![Page 12: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/12.jpg)
UNIVERSITY OF ABERDEEN
CYP1B1
Protein present virtually
only in cancer cells
Cytochrome P450 enzyme
that can alter chemical
structure of drugs
Change drug's structure ...
change its effects
Activate prodrug – new
type of anticancer drug
1995
![Page 13: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/13.jpg)
Gerry Potter
Professor of Medicinal Chemistry
To design anticancer prodrug
to be activated by CYP1B1
had invented Abiraterone
Designed anticancer prodrug
activated by CYP1B1
Pharmacophore
Theorized also in natural
phytochemical compounds
e.g. in oranges
2002 - SALVESTROLS
![Page 14: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/14.jpg)
Unique mechanism of action
Activated by CYP1B1 in cancer cells
Stimulate apoptosis
Kill cancer cells without harming
normal cells
In fruits, vegetables and herbs in diet
Historically Salvestrols probably
helped protect against cancer
Now grossly deficient in diet
natural
phytochemical
anticancer
prodrugs
2002
15+ years university
research
Salvestrols
![Page 15: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/15.jpg)
CYP1B1
Salvestrols
natural
anticancer
prodrugs
cancer cell normal cell
drug target
drug target
active Salvestrol metabolite
unharmed
no CYP1B1
initially
inactive and
innocuous
not activated
enzyme only in cancer
cells
![Page 16: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/16.jpg)
Natural Sources of Salvestrols
Sources of Salvestrols
FRUIT
Apples
Blackcurrants
Cranberries
Grapes
Oranges
Strawberries
VEGETABLES
Avocados
Brussels Sprouts
Capsicums
Cabbage
Cauliflower
Olives
HERBS
Artichoke
Basil
Dandelion
Milk Thistle
Parsley
Thyme
![Page 17: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/17.jpg)
0.1 1 10
Dose-response curve for a Salvestrol with human cells in culture
% cells killed at each dose
0
25
50
75
100
mean ± sem
cancer cells have CYP1B1
normal cells lack CYP1B1 unharmed
killed : higher dose – more killed
: at any dose
Salvestrol dose ( μM ) Log dose scale
Salvestrols kill cancer cells while
sparing normal cells
![Page 18: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/18.jpg)
0.1 1 10
Salvestrol dose-response curve with specific chemical inhibitor of CYP1B1
% cells killed at each dose
0
25
50
75
100
mean ± sem
Salvestrol dose ( μM )
Tan H. et al. J. Pharm. Pharmacol. 59: S158 (2007)
ability of Salvestrols to kill cancer cells while
sparing normal cells
is due to CYP1B1 in cancer cells
cancer cells
normal cells cancer cells with inhibitor not killed when CYP1B1 is blocked
cancer cells without inhibitor
plus CYP1B1 inhibitor
![Page 19: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/19.jpg)
Dose-response curve for a Salvestrol with human cells in culture
mean ± sem
% cells killed at each dose
0
25
50
75
100
Salvestrol dose ( μM )
0.0001 0.001 0.01 0.1 1.0 10 100
Salvestrol with high potency
and very high selectivity
breast cancer cancer cells have CYP1B1
breast non-cancer cells lack CYP1B1
therapeutic index
= 25,000
0.0011 μM 28.000 μM
![Page 20: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/20.jpg)
Cancer cells treated with Salvestrol
cell succumbing to Salvestrol
cancer cells not yet affected
nucleus
cytoplasm
![Page 21: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/21.jpg)
Cancer cells treated with Salvestrol
DNA (blue)
CYP enzyme (red)
condensed DNA ... cell death by apoptosis
tyrosine kinase inhibition →
apoptosis stimulation
not antioxidant
![Page 22: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/22.jpg)
Salvestrols should contribute to
protection
by fruit & vegetables
against cancer
![Page 23: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/23.jpg)
Salvestrols – enough bioavailability for protection
0 12 24 36 time of day (h)
8 am next day 8 am
3.5 x Palaeolithic
daily diet level
as 1x daily supplement
20 x Palaeolithic daily diet level as 2x daily supplement : used by many cancer patients
Salvestrol blood level
10% cancer cell kill
50%
![Page 24: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/24.jpg)
Salvestrols should contribute to
protection
by fruit & vegetables against cancer
but …
Modern diet very deficient in Salvestrols
Why?
![Page 25: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/25.jpg)
Main reason for Salvestrol deficiency
Agricultural spraying with synthetic fungicides
Salvestrols ... phytoalexins ...
... produced in response to fungal attack
Spraying eliminates all fungi ...
... removes stimulus for Salvestrol synthesis
Organic has 30x more Salvestrols
![Page 26: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/26.jpg)
Other reasons for Salvestrol deficiency
Salvestrols taste bitter
Debittering of manufactured fruit juices
Modern sweeter varieties of fruit
Salvestrols readily dissolve in boiling water
Boiling vegetables extensively in lots of water
Solution to problem - Salvestrol supplement
![Page 27: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/27.jpg)
Salvestrols and dogs
CYP1B1 in dogs
Amino acid sequence 84% similar to human
Over-expressed in dog cancer ? ... don't know yet
Dog drug metabolism pathways similar to human
Expect Salvestrols to be bioavailable &
metabolized in dogs similar to in humans
Expect Salvestrols to be anticancer prodrugs in
dogs as in humans
![Page 28: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/28.jpg)
Mrs K : standard poodle - lower leg tumour – predicted 4 weeks to live
– given Salvestrol supplement for 7 months - although leg eventually
amputated, cancer did not spread and dog remained bright and active -
vet said to continue with Salvestrols because they prevented a normally
very aggressive type of cancer from spreading beyond the leg.
YR : dog had bladder cancer – given Salvestrol supplement for some
months - cancer no longer detectable.
DB : dog has liver cancer –being given Salvestrol supplement daily –
" doing well " at this point.
MM : dog has sarcoma – predicted 6-12 months to live – being given
Salvestrol supplement daily – initially kept having to have surgery but
after Salvestrols tumours reduced from fist size to size of Canadian
dollar coin (2.6 cm dia.) - so at six month check up no surgery required.
![Page 29: Salvestrols cures Cancer](https://reader030.fdocuments.in/reader030/viewer/2022020715/5533575a550346457f8b487b/html5/thumbnails/29.jpg)
Thank You
for listening