Chemoprevention Flashcards
In people under 85, what is the leading cause of death?
cancer
In people over 85, what is the leading cause of death?
Cardiovascular disease
Cancer death rates have decreased slightly, what is this a result of?
The reduction in lung cancer due to anti-smoking campaigns
How do hereditary facts commonly predispose people to cancer?
Initiating mutation to all stem cells
How can phase I enzyme induce neoplasia?
They produce reactive electrophiles which instead of being conjugated by phase II enzymes, they cause damage to macromolecules such as DNA and cause neoplasia
How can you stop phase I enzymes inducing neoplasia?
By the induction of phase II and phase III enzymes so the reactive electrophiles are conjugated by phase II enzymes and then removed by phase III drugs by drug efflux
What is glutathione?
An antioxidant
What is the role of glutathione transferases?
Conjugates the electophiles with glutathiones and helps with excretion
Where is glutatione present and how much is there?
Present in every cell in the body
Have as much as ATP
What is the purpose of the Quinone Reductase assay?
To detect the enzyme activity in a cell
What vegetable family has the highest inducer activity?
Cruciferous
Give examples of cruciferous vegetables
Arabidopsis Cabbage Broccoli Kale Cauliflower Brussel sprouts Rocket Watercress
What do cruciferous vegetables contain?
Unique phytochemicals - Glucosinolates
What determines the diversity of glucosinolates?
The R group
How does the degradation of glucosinolates occur?
They are made in the plant and are stable and inert -> when the plant is damage it releases myrosinase -> myrosinase hydrolyses glucosinolate -> end product
What is the most reactive end product of glucosinolate degradation?
Isothiocyanate
What does benzyl isothocyanate inhibit?
DMBA-induced mammory tumour formation in Sprague-Dawley rats
Formation of neoplasms of the forestomach and pulmonary adenomas in ICR/Ha mice
How much do cruciferous vegetables lower the risk of colon cancer?
51%
How much do cruciferous vegetables lower the risk of prostate?
67%
how is sulforphane made?
Glucoraphanin (glucosinolate) -> Unstable Aglucon -> Sulforaphane
What are the cytoprotective actions of sulforaphane?
Induces phase II enzymes and elevates gluathione levels
Inhibits tumour development in animal models
Causes cell cycle arrest and apoptosis
Week inhibitor of CYP2E1
Not mutagenic
Protects against oxidants through induction of phase II enzymes and glutathione (indirect antioxidant)
How does sulforaphane induce an indirect antioxidant effect?
Cul3 is bound to Keap1 -> Keap1 has a highly reactive cysteine on its SH2 -> chemically modified by sulforaphane -> loses its activity and therefore Nrf2 is not degraded
What is the role of Nrf2?
When it is not degraded, it moves into the nucleus -> binds to the promoter (ARE) as a heterodimer with sMaf -> production of cytoprotective gees
What is the rate limiting factor in the Nrf2 process and why?
Nrf2 since it is less abundant than sMaf
Apart from Keap1, what does sulforaphane inhibit? And what do they all induce?
NF-kappaB
STAT3
MIF (macrophage migration inhibitory factor)
Inflammation and cell growth
When Keap1 is inhibited, what does it induce?
Redox balance
Resolution of inflammation
What cancers is sulforaphane cytoprotective in?
Breast Lung Skin CRC Stomach
What can topical addition of sulforaphane do to nude mice?
Stop them getting skin cancer
Apart from lung cancer, what else is tobacco smoke associated with?
Bladder cancer
What can you measure sulforaphane metabolites in?
urine
What does resveratrol reduce?
Carrageenan-induced inflammation in rats
Skin cancer formation in mice
Inhibits adenoma development in APCmin mice
What is resveratrol found in?
Red grapes
At what dose is resveratrol better at inhibiting adenoma development in APCmin mice?
Lower doses
In terms of lung cancer, what do antioxidants do? And why?
Accelerate lung cancer progression in mice
Appears to lower Nrf2 expression and therefore lowers cytoprotection
