Breakthroughs in the Breakthroughs in the Quest to Cure Cancer Quest to Cure Cancer Professor Gerry Potter Professor Gerry Potter Founder of the Founder of the Cancer Drug Discovery Group Cancer Drug Discovery Group Leicester School of Pharmacy Leicester School of Pharmacy De Montfort University, Leicester, UK De Montfort University, Leicester, UK
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Breakthroughs in the Breakthroughs in the Quest to Cure CancerQuest to Cure Cancer
Professor Gerry PotterProfessor Gerry Potter
Founder of the Founder of the
Cancer Drug Discovery GroupCancer Drug Discovery Group
Leicester School of PharmacyLeicester School of Pharmacy
De Montfort University, Leicester, De Montfort University, Leicester, UKUK
Early DaysEarly Days
University of ManchesterUniversity of Manchester1983-19861983-1986
““Mechanism of Action of Anticancer Agents”Mechanism of Action of Anticancer Agents”
- Most are generally toxic (cytotoxic)Most are generally toxic (cytotoxic)- Toxic to liver, kidneys, heart, white blood Toxic to liver, kidneys, heart, white blood
cellscells- Many are highly mutagenic & carcinogenicMany are highly mutagenic & carcinogenic- Key Issue is SelectivityKey Issue is Selectivity
Chemotherapy Agents Mutate DNA and are Highly Carcinogenic
Institute of Cancer Institute of Cancer ResearchResearch
1987 - 19941987 - 1994Drug Development Section, CRC Drug Development Section, CRC
LaboratoryLaboratory
developed new selective agents fordeveloped new selective agents for
Breast & Prostate CancerBreast & Prostate Cancer Tamandron (Antiandrogen)Tamandron (Antiandrogen) Idoxifene (An Improved Tamoxifen Idoxifene (An Improved Tamoxifen
Salvestrol Activase is a Salvestrol Activase is a Tumour Suppressor EnzymeTumour Suppressor Enzyme Works as a cancer preventing enzyme acting via Works as a cancer preventing enzyme acting via
natural prodrug bioactivation, i.e. salvestrol natural prodrug bioactivation, i.e. salvestrol activationactivation
Expressed in a variety of tumoursExpressed in a variety of tumours Generic Rescue MechanismGeneric Rescue Mechanism Irrespective of tumour type or oncogenic originIrrespective of tumour type or oncogenic origin Cancers arise from many different mutagenic originsCancers arise from many different mutagenic origins
Induction tightly regulatedInduction tightly regulated Induced by various cellular damaging effectsInduced by various cellular damaging effects
G.A. Potter, British Journal of CancerG.A. Potter, British Journal of Cancer, , 8686 (Suppl 1), S12, (Suppl 1), S12, 20022002
Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour
Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed
Shows very exciting tumour selective activityShows very exciting tumour selective activity No toxic effectsNo toxic effects Development to clinical use taking many yearsDevelopment to clinical use taking many years
Realised molecular relationship to natural compoundsRealised molecular relationship to natural compoundsthat have cancer preventative propertiesthat have cancer preventative properties Could have a natural version of this drugCould have a natural version of this drug Could explain link between diet and cancerCould explain link between diet and cancer
Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), (Suppl 1), S117, 2002S117, 2002
Designed Prodrugs Designed Prodrugs Activated by a Tumour Activated by a Tumour
Specific EnzymeSpecific Enzyme Synthetic Prodrugs DesignedSynthetic Prodrugs Designed
Shows very exciting tumour selective activityShows very exciting tumour selective activity(10,000-fold selective)(10,000-fold selective) No toxic effects observedNo toxic effects observed Currently Undergoing Pre-clinical development at the Currently Undergoing Pre-clinical development at the
Gray Cancer Institute, LondonGray Cancer Institute, London Phase I Clinical Studies being planned in the USPhase I Clinical Studies being planned in the US Results look very promisingResults look very promising Drug has real potential as a non-toxic tumour selective Drug has real potential as a non-toxic tumour selective
anticancer agentanticancer agent
Potter et al, British Journal of CancerPotter et al, British Journal of Cancer, , 8686 (Suppl 1), S117, (Suppl 1), S117, 20022002
ResveratrolResveratrolThe First Salvestrol to be The First Salvestrol to be
DiscoveredDiscovered Resveratrol is a natural molecule found in Resveratrol is a natural molecule found in
grapesgrapes
(a phytoestrogen, polyphenol, and antioxidant)(a phytoestrogen, polyphenol, and antioxidant) Cancer preventative (unknown mechanism)Cancer preventative (unknown mechanism)
Tumour CYP enzyme catalyses the Tumour CYP enzyme catalyses the bioactivation of resveratrol to generate bioactivation of resveratrol to generate piceatannolpiceatannol
PiceatannolPiceatannol Known anticancer activityKnown anticancer activity TK Inhibitor (src, MAPK, tubulin)TK Inhibitor (src, MAPK, tubulin)Potter et al, British Journal of Cancer, 86, 774, 2002
HO
OH
OH
Resveratrol
HO
OH
OH
OH
Piceatannol
CYP1B1
HO
HO
OH
OH
OH
HO
OH
HO
OH
Estradiol 4-Hydroxyestradiol
OH
a
b
c
CYP1B1
Bioactivation of Resveratrol by CYP1B1
SalvestrolsSalvestrols New class of molecule with very important New class of molecule with very important
activity in removing diseased cells from the activity in removing diseased cells from the human bodyhuman body((salvesalve = to save) = to save)
Defined as natural dietary prodrugs that are Defined as natural dietary prodrugs that are bioactivated in diseased cellsbioactivated in diseased cells
Present in cancer preventative foods and dietsPresent in cancer preventative foods and diets
Higher levels found in traditional medicinal Higher levels found in traditional medicinal plantsplants
Anti-salvestrols also identifiedAnti-salvestrols also identified- inhibit the positive action of salvestrols- inhibit the positive action of salvestrols
Relationship of Salvestrols to Relationship of Salvestrols to Antioxidants, Polyphenols & Antioxidants, Polyphenols &
PhytoestrogensPhytoestrogens
Antioxidants
PolyphenolsSalvestrols
Salvestrols are a new class of natural productSome are antioxidantsSome are polyphenolsSome are phyoestrogens
- others are not
However…Some Anti-salvestrols are alsoantioxidants, polyphenols and phytoestrogens
A model of CYP1B1 A model of CYP1B1 Activation Activation
of a Salvestrol in a of a Salvestrol in a Tumour Tumour
•Most are equally toxic to normal and tumour cells•Some are actually more toxic to normal cells than tumours
(e.g. Taxol, Doxorubicin, 5-FU)•Many are carcinogenic tumour promoters (Chlorambucil etc)
Tumour Specific ActivationTumour Specific Activationof Salvestrol Q40of Salvestrol Q40
Salvestrols in Natural Salvestrols in Natural FoodsFoods
(Fruits & Vegetables)(Fruits & Vegetables)
Natures Way of Eliminating Cancer Cells as they form
– Disease Prevention
Hippocrates “Let food be your medicine
and medicine be your food”
- referring to foods rich in salvestrol Q40
Salvestrol Q40
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=2 M
Normal breastIC50=21 M
concentration (M)
surv
ival
(%
)
sem
Resveratrol Bioactivation
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
control
Normal BreastIC50=60 MIC25=30 M
Breast TumourIC50=60 MIC25=0.003 M
concentration (M)
surv
ival
(%
)
sem
Salvestrols in Medicinal Salvestrols in Medicinal HerbsHerbs
Salvestrol P52
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=0.5 M
Normal breastIC50=16 M
concentration (M)
surv
ival
(%
)
sem
Salvestrol P54
0
25
50
75
100
125
10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2control
Breast cancerIC50=0.08 M
Normal breastIC50>100 M
concentration (M)
surv
ival
(%
)
sem
Ancient Cancer Cures used herbs rich in Salvestrols
Culpeper (1653) - This herb is under the celestial sign of Cancer
“It healeth tough tumours of the breast, and for this I hold it inferior to but few herbs that grow”
Dioscorides – “this is marvellous good for the joints, and for Cancers which cannot be healed by any other meanes”
Depletion of SalvestrolsDepletion of Salvestrolsin the Modern Dietin the Modern Diet
Depleted by Modern Agricultural MethodsDepleted by Modern Agricultural Methods- Use of fungicides depletes plants - Use of fungicides depletes plants salvestrolssalvestrols- Much Higher levels in Organic produce- Much Higher levels in Organic produce
Removed by Food ProcessingRemoved by Food Processing- Fruit Juice Extraction- Fruit Juice Extraction- Filtering- Filtering
Only really present in wholefoodsOnly really present in wholefoods Modern processed foods have no Modern processed foods have no
Need for a SalvestrolNeed for a SalvestrolFood SupplementFood Supplement
Specialist knowledge of SalvestrolsSpecialist knowledge of Salvestrols Modern diet seriously depleted in Modern diet seriously depleted in
SalvestrolsSalvestrols Dietary intake randomDietary intake random
-food source, growing conditions-food source, growing conditions No need for exotic foods or specialist dietNo need for exotic foods or specialist diet Guaranteed intake of essential SalvestrolsGuaranteed intake of essential Salvestrols Convenient source of SalvestrolsConvenient source of Salvestrols
Formation of Natures Formation of Natures Defence LtdDefence Ltd
Linked up with The Herbal ApothecaryBased in Syston, Leicestershire
Cancer Cure Cases & Cancer Cure Cases & ResponsesResponses
using Salvestrol Therapyusing Salvestrol TherapyTerminally Ill people with Advanced Metastatic DiseaseTerminally Ill people with Advanced Metastatic Disease(relapsed after chemotherapy and radiotherapy failed)(relapsed after chemotherapy and radiotherapy failed)
Have made truly remarkable recoveries after taking salvestrol food Have made truly remarkable recoveries after taking salvestrol food supplementssupplements
Salvestrol supplements have exciting anticancer activity against:Salvestrol supplements have exciting anticancer activity against:
•Breast CancerBreast Cancer•Prostate CancerProstate Cancer•Ovarian CancerOvarian Cancer•Testicular CancerTesticular Cancer