BCH 475Biochemistry of Carcinogenesis

Professor A. S. AlhomidaSummer, 2008

Part 4

BCH 475Biochemistry of Carcinogenesis

Professor A. S. AlhomidaSummer, 2008

Part 4

DisclaimerThe texts, tables and images contained in this course presentation are not my own, they can be found on: – References supplied– Atlases or– The web sites

King Saud University

College of Science

Department of Biochemistry

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Eating to Prevent Cancer

How a Healthy Diet and Physical Activity May Help

Keep You Cancer-Free

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The Relationship Between Lifestyle and cancer

A total of 60-70% of cancers may be lifestyle related!

30-40% of cancers can be prevented by a healthy diet, healthy weight, and regular physical activity

30% of cancers can be prevented by not using tobacco

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The Relationship Between Lifestyle and cancer

Many foods and nutrients have been linked to cancer prevention

For cancer prevention, focus on an overall healthy diet rather than specific foods or nutrients

Maintain a healthy weight throughout life

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The Relationship Between Lifestyle and cancer

Adopt a physically active lifestyle

Eat a variety of foods, with an emphasis on plant sources

Limit consumption of alcoholic beverages

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Maintain a Healthy Weight

Being overweight and inactive accounts for 1/3 of the worldwide cases of breast, colon, endometrial, kidney, and espophageal cancers

Balance calorie intake with physical activity

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Maintain a Healthy Weight

Avoid excessive weight gain throughout life

Achieve and maintain a healthy weight if currently overweight or obese

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Body Mass Index (BMI)

Body mass index is defined as the individual's body weight divided by the square of their height

BMI provides a reliable indicator of body fatness for most people and is used to screen for weight categories that may lead to health problems

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Body Mass Index (BMI)

It was invented between 1830 and 1850 by the Belgian polymath Adolphe Quetelet during the course of developing "social physics"

The formulas universally used in medicine produce a unit of measure of kg/m2

Body mass index may be accurately calculated using the formulas below:

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Maintain a Healthy Weight

Body Mass Index (BMI)

)(

)(22 mheight

kgweightBMI

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Maintain a Healthy Weight

Know your Body Mass Index (BMI)Below 18.5 Underweight

18.5 – 24.9 Normal weight25.0 – 29.9 Overweight30.0 and Above Obese

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Tips for Maintaining a Healthy Weight

Eat plenty of fruits and vegetables

Limit simple sugars (cakes, cookies, pies, candies, sweetened drinks)

Eat smaller portions of everything

Add physical activity to your life

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Adopt a Physically Active Lifestyle

Adults: – Get at least 30 minutes or more moderate to

vigorous physical activity five or more days of the week, 45-60 minutes if possible

Children and adolescents: – Get 60 minutes per day of moderate to

vigorous physical activity at least five days per week

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Healthy Foods

Eat a variety of healthy foods with an emphasis on plant foods

Plant foods (fruits, vegetables, whole grains, and legumes) are packed with vitamins, minerals, antioxidants, and other substances that work together to lower risks of several cancers

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Cancers Associated with Low Intake of Plant Foods

Lung cancer

Mouth cancer

Stomach cancer

Colon cancer

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Healthy Foods

Eat five or more servings of fruits and vegetables each day

Choose whole grains over processed (refined) grains and sugars

Limit consumption of processed red meats

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Healthy Foods

Fruits and vegetables are rich in fiber, vitamins, minerals, and phytochemicals

Whole grains are rich in fiber, vitamins, minerals, and phytochemicals

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Healthy Foods

They contain several substances that have been linked to lower cancer risk including fiber, antioxidants, phenols, lignans, polyestrogens, and saponins

Standard serving sizes: – One cup raw fruit or vegetable, ½ cup canned

fruit or cooked vegetable, one medium piece of fruit, ¼ cup dried fruit

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Fruits and Vegetables

Choose five or more servings of fruits and vegetables each day

Choose colorful fruits and vegetables for the most nutrient content

Choose a variety of fruits and vegetables

Enjoy fruits and vegetables prepared and served without added fat or sugar

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Fruits and Vegetables

One serving equals:– ½ cup cooked vegetables– One cup leafy vegetables– ½ cup 100% juice– One medium piece of fruit– ½ cup fresh, frozen, or canned fruit, or ¼ cup

dried fruit

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Cancers Associated with Alcohol Intake

Oral (mouth)

Pharyngeal (throat)

Esophageal

Laryngeal (voice box)

Breast

Liver– Use of tobacco at the same time as alcohol

increases your risk for developing these cancers

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Dietary Factors Associated with Reduced Cancer Risk

Dietary fiber– Colorectal, pancreas, breast

Folic acid– Cervix, colorectal

Vitamin D and calcium – Colorectal, breast

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Dietary Factors Associated with Reduced Cancer Risk

Vitamin C from foods – Oral cavity, esophagus, lung, stomach,

pancreas, cervix

Tea (flavonoids)Lung, colorectal

α-tocopherolLung

Soy isoflavones?Breast

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Dietary Factors Associated with Reduced Cancer Risk

Antioxidants (nutrient and non-nutrient) from foods– Colorectal, lung, breast, cervix, prostate,

esophagus, stomach

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Food Components that May Prevent Cancer

Antioxidants – Vitamins A, C, E, cartenoids, selenium– There is no evidence to support taking

antioxidant supplements to prevent cancer

Dietary fiber– The link between fiber and cancer is weak– Foods that contain fiber are high in other

nutrients that may prevent cancer

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Food Components that May Prevent Cancer

Phytochemicals– Compounds made by plants that may prevent

cancer (e.g., lycopene in tomato)– There is no evidence that phytochemical

supplements prevent cancer– Lycopene is a phytochemical (red-orange

carotene pigment found in tomatoes and other pink and red fruits and vegetables)

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Food Components that May Prevent Cancer

Phytochemicals– Several studies report that consuming tomato

products reduces the risk of some cancers but the link with lycopene is uncertain

– This has been highly touted as preventing prostate cancer based on one study

– Further studies are in process

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Food Components that May Prevent Cancer

Vitamin D– There is growing evidence that vitamin D may

help prevent colon, prostate, and breast cancer

– In some cases supplements are recommended

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Food Components that May Prevent Cancer

Vitamin D– Research is needed to determine how much

vitamin D is needed by different populations, but it appears to current Dietary Reference Intakes’ (DRI) may be inadequate to prevent cancer

– A balanced diet, moderate supplementation, and frequent sun exposure (small amounts) are preferred method to obtain Vitamin D

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Do These Foods Prevent Cancer?

Cruceriferous vegetables (broccoli, cauliflower, cabbage)

These vegetables may contain phytochemicals that reduce cancer risk

Eat a wide variety of vegetables, not just cruceriferous vegetables

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Cruceriferous Vegetables

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Cruceriferous Vegetables

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Do These Foods Prevent Cancer?

Soy foods– Contain phytochemicals that may fight cancer

(based on animal studies)– Soy supplements should not be taken to

reduce cancer risk– Women with breast cancer should consume

only moderate amounts of soyHigh doses of soy could increase the risk of estrogen-responsive cancers, such as breast or endrometrial cancer

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Do These Foods Prevent Cancer?

Tea – Some research (animal studies) suggests that

tea may have antioxidant properties and prevent cancer

– Studies in humans have been less conclusive

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Do These Foods Prevent Cancer?

Garlic– The health benefits of garlic have been widely

publicized– There is not enough evidence to support

garlic as a food to prevent cancer at this time

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Things That Don’t Cause Cancer

Food additives

Irridiated foods

Bioengineered foods

Aspartame

Coffee

Dietary fat

Pesticides and herbicides (wash thoroughly)

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Things That Don’t Cause Cancer

Based on information provided by the American Cancer Society, there is not evidence to tie any of these items with cancer

The low doses of pesticides and herbicides in food do not appear to increase the risk of cancer

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Dietary Factors Inversely Related to Cancer Risk

Alcohol– Mouth, pharnyx, larnyx, esophagus, liver-

convincing– Breast, colon, rectum- probable

Salt– Stomach- probable

Sucrose– Colon, rectum

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Dietary Factors Inversely Related to Cancer Risk

Meat (especially charbroiled)– Colon and rectum- probable

Total and saturated fat– Lung, colon, rectum, breast, prostate-

possible

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Chemopreventive Non-nutritiveDietary Factors

Compound Food SourceCinnamic acid Fruit, vegetables, coffee beans

Flavonoids (catechins, quercitin, isoflavones, anthocyanins)

vegetables, fruit, citrus fruit, celery, parsley,onions, grains, tea, soybean

Indoles Cruciferous vegetables

Isothiocyanates Cruciferous vegetables

Lignans Whole grains, flax

Organosulfur Garlic, Onion

Terpenes Citrus, spices

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Role of Dietary Factors in Carcinogenesis

Neoplastic Manifestation

DNA Binding

Reaction with Cellular TargetsDNA Damage, Mutagenesis

Inhibitors of Activation

Blocking Agents

Suppressing Agents

Exposure to Carcinogen

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Inhibitors of Activation

Inducers of Phase I Biotransformation Enzymes– Cytochrome P450 mono-oxygenase system– Converts hydrophobic to hydrophilic

compounds for elimination by forming reactive intermediate

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Phase I Activation and Phase II Detoxification Reactions

Carcinogen PrimaryMetabolite

SecondaryMetabolite

Reactive Intermediate

Covalent Binding

Acute CellularInjury

DelayedToxicity

Mutations & Cancer

Excretion

Bioactivation Detoxification

Phase I Phase II

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Blocking Agents

Inducers of phase II detoxification Enzymes– Glutathione S-transferases, sulfotransferases,

UDP-gluronosyltransferases– Phenols, isothiocyanates, flavones, and

coumarins– Affect gene expression at transcriptional level

Binders of free radical intermediates– Antioxidants

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Suppressing Agents

Inhibit development of cancer subsequent to administration of carcinogen– Retinoids and carotenoids– Protease inhibitors– Phenols and polyphenols– Selenium

Antioxidant protection

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Role of Antioxidants in Carcinogenesis

Reactive O2

+O2-Derived

Free Radicals

Oxidized basesin DNA

Normal cell

Lipid peroxidationin cell membranes

Cell repairExposure of DNACell DeathLipid Peroxides

DNA Repair

Normal Cell

Mutations Cell DeathNo Repair

CompensatoryCellularHypoproliferation

Less regulation of cellgrowth & differentiation

Cell Hyperproliferation

Exposure of DNA

Further Mutations

Antioxidant Scavengers &

Enzyme Systems

Antioxidant Protection

C ata laseP eroxid ase

G lu ta th ion eP eroxid ase

S u p eroxid eD ism u tase

E n zym e S ys tem sM in era ls

M em b ran eL ip id

P ro tec tion

A q u eou sC om p tm ts

L ip idC om p tm ts

S caven g ersV itam in s

C e llu la rA n tioxid an ts

Non-nutrient Plant Chemicals

Cu/Mn E C CarotenoidsSe, AAFe

PolyphenolsIsothiocyanates

CoQ10

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Other Protective Effects: Folic Acid

Thymidine synthesis inhibited

Lack of methyl donor from methylene-THF

or S-adenosyl-methionine

DNA hypomethylation

Uracil misincorporation

DNA repair by excision

Increase in fragile sites and chromosomal breaks

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Folate Deficiency and DNA Stability

single strandbreak

double strandbreak

DNA TMP dUMP

CH3

X

DNA repair removesmisincorporated

uracil

Chromosomal damage

U A

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Moderators of Insulin Sensitivity and Resistance

Moderators of insulin and insulin-like growth factor (IGF-1)– IGF-1 protects against apoptosis– Insulin and IGF-1 increase aberrant crypt foci

growthPrecursor of colorectal tumors

– Insulin resistance associated with increased tumor promotion in animal models (r = 0.67)

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Insulin Resistance and Relative Risk of Colon Cancer

PhysicalActivity

Dietary Glycemic Index

Low Medium High

High 1.0 1.3 1.4

Medium 1.6 1.8 2.1

Low 1.5 1.9 3.5

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Other Protective Effects

Inhibitors of invasive processes – Stimulate plasminogen activator inhibitors

Reduces plasmin-stimulated degradation of extracellular membrane

Dietary fiber, low glycemic index sugars