salvestrols cures cancer

Salvestrols

Professor Dan Burke

Salvestrol Natural Products, Leicester UK

and CYP1B1

A natural team fighting cancer naturally

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

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)

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)

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)

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 :

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

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

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

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

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

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

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

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

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

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

0.1 1 10

Salvestrol dose-response curve with specific chemical inhibitor of CYP1B1


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

Dose-response curve for a Salvestrol with human cells in culture

mean ± sem


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

Cancer cells treated with Salvestrol

cell succumbing to Salvestrol

cancer cells not yet affected

nucleus

cytoplasm

Cancer cells treated with Salvestrol

DNA (blue)

CYP enzyme (red)

condensed DNA ... cell death by apoptosis

tyrosine kinase inhibition →

apoptosis stimulation

not antioxidant

Salvestrols should contribute to

protection

by fruit & vegetables

against cancer

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%

Salvestrols should contribute to

protection

by fruit & vegetables against cancer

but …

Modern diet very deficient in Salvestrols

Why?

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

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

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

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.

Thank You

for listening

salvestrols cures cancer

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