REVIEW

Impactul radicalilor liberi în patologia cancerului

 The impact of free radicals in oncologic pathology

Anda Crişan, Florinel Bădulescu, Adrian Săndulescu

First published: 03 martie 2017

Editorial Group: MEDICHUB MEDIA

Abstract

This article aims to show the carcinogenic effects of free radicals on human health. It is endorsed that the hypothesis of organic aging is caused by oxidative stress as a consequence of the free radicals. Furthermore, several prophylaxis methods in which the human organism can delay the oxidative stress are demonstrated, thus greatly reducing the risk of developing chronic diseases, cancer or death. 
 

Keywords
free radicals, oncology, oxidative stress

Rezumat

Scopul articolului este să prezinte efectul carcinogenic al radicalilor liberi. Este susținut de ipoteza că îmbătrânirea organică este cauzată de stresul oxidativ, ca o consecință a producerii radicalilor liberi. Mai mult, sunt demonstrate numeroase metode de profilaxie prin care organismul uman poate să atenueze stresul oxidativ, reducând astfel în mod semnificativ riscul dezvoltării bolilor cronice și a cancerului și crescând supraviețuirea. 
 

Cuvinte cheie

Free radicals

History

In 1956, dr. Denham Harman, from University of Nebraska, presented for the first time what today is known as “the theory of free radicals in the process of aging”. He demonstrated by testing on animals (mice) that free radicals actually cause aging to an organism. In 1961, he run a study in which he showed that polyunsaturated fats promote cancer growth, and in 1968 he demonstrated that antioxidants showed increased delay in organic aging by reducing the oxidative stress.

What are free radicals?(1,2,7)

  • They are highly reactive molecules with an uneven electron (or “free”) on the external orbital, which is an unbalanced situation that transforms this fragmented molecules in very unstable ones (biochemical aspect).
  • This highly unstable molecules transfer themselves an electron from the nearest stable molecules; in turn, the stable molecules will become unstable and the cycle repeats, so it begins a chain reaction.

“Nothing disappears, everything completes itself” (Antoine Laurent Lavoisier).

The medical impact(1,7,8)

Most daily meals (which contain oils, margarine etc.) that are subjected to intense oxidative process release free radicals. Such molecules affect the human organism by destroying and altering the cellular functions (an important factor in oncogenesis).

Free radicals are usually stopped by the antioxidant system of the human body. If this system is overrun by free radicals, their number being higher than the antioxidant units, the oxidative stress begins, which causes several symptoms that are usually related to organic aging, such as: skin wrinkles, pigmentation, cataract, arthritis, the swelling of arteries, heart diseases, glaucoma, Alzheimer disease, memory loss, apoplexy, dementia, cancer and other degenerative illnesses.

The most vulnerable organs for the action of free radicals are the crystalline, pancreas, neurons and blood vessels.

The analysis of the oxidative stress(1,3,7,9)

The oxidative stress can be measured by the D-Room Test in which the plasmatic level of free radicals is determined (normal values: 250-300 U.CARR; <250 U.CARR represents the optimal value for a healthy organism and >500 U.CARR represents a major health risk).

Examples and sources(1,2,7,11)

The most important free radicals are: superoxide (O2), peroxide (-O-O-), hydroxide (NO2-), nitrate (NO3-), singlet oxygen (O2), ozone (O3) etc.

  • The most wide-spread free radical is the superoxide anion (O2-). It is capable of reacting to H2O2, generating an OH- ion more reactive than the O2- ion.

The main sources of free radicals (pro-oxidative factors) are:

1. Smoking smoking a single cigarette generates aproximately 101000000000000000 of free radicals.

2. Stress.

3. Alcohol acetaldehyde.

4. Ionizing radiation/ultraviolets.

5. Radiotherapy.

6. Intense sports.

7. Being overweight type 2 diabetes.

8. Using a cellphone.

9. Acrolein by frying oils.

Oncolog-Hematolog 37 (4) 2016_mic-13
Caption


The role of free radicals(1,3,7,9)

Cancer has generated increased attention in medical fields throughout the years. There have been real progresses in uncovering the carcinogenic substances and their mechanism. A raw estimation shows that 75% of human cancers are induced by environment, by its carcinogenic factors (air, water, food etc.) and radiation. Huge efforts have been made for identifying carcinogenic factors from the environment and explaining their mechanism, the chemical factors having various structures but all having in common the following: permanent DAN alteration, activating the transduction paths of signals from the cell’s cytoplasm, mitochondria, and nucleus. Most proteins and stress genes which modulate effector genes are implicated in the cellular growth, differentiation and death.

In cancer there is a permanent oxidative stress. Oxida­tive stress, along with free radicals are known as mutagens. They are mediators in feno- and genotype changes which lead to mutations that ends with cancer.

There are specific carcinogenic metabolic reactions of some chemicals (aromatic hydrocarbons) that react to free radicals. There are 3 stages known: initiation, advance and malignant conversion. A mutation that controls the growth and differentiation is an example of genic modification of the initiation stage. Various carcinogens, including ROS (reactive oxygen species), can produce important genetic changes.

The role of oxidative stress in cancer(2,7):

1. The main proof of ROS intervention in carcinogenesis.

2. Tumor induction by ionizing radiation.

3. Tumor induction by foreign objects.

4. Induction mediated by metal.

5. Tumor induction by food.

6. Tumor induction by chemical substances.

In the case of radiation, it is difficult to establish the exact mechanism that can explain the carcinogenic effect without the direct implication of ROS.

The activity of superoxide dismutase enzyme in plasma and in tumor tissue in breast cancer:

  • A general increase of the SDE activity has been observed in plasma and in tumor tissue (p<0.05).
  • Mn-SDE drops significantly in tumor tissue (p<0.05) and unsignificantly in plasma. EC-SDE in plasma (in benign/malign cancer) is 3.5-22.8%.
  • Decreasing of EC-SDE in tumor tissue.
  • For TBRS (tiobarbituric reactive substance) the activity is the same as SDE. Alcohol also increases the effect by being a pro-oxidative stress factor in any type of cancer and the effect is even worse in association with smoking. Another major risk factor for developing cancer is the decrease of GSH and TAA (total antioxidant activity).

The final values of fat oxidation are significantly high in the serum of patients with larynx and hypopharyngeal cancer comparing with healthy people. The total anti­oxidant capacity is also reduced in the serum of patients with the aforementioned types of cancer.

Methods of prophylaxis

Antioxidants(1,2,3,4,6)

Usually, the anti-free radicals system of the human organism is efficient as long as the body is young. As time passes, this efficiency drops.

Antioxidants are natural molecules (exogenous) or created by the human organism (exogenous), which have the possibility to reduce/annihilate the toxic effects or free radicals. They can neutralize unstable oxygen molecules, also they can protect the organism’s vital functions and decrease the risk of cancer. They are “sacrificial” substances for protecting molecules of biological importance (DNA, enzymes, membranes), such molecules being the first targets in the aggression of free radicals.

For a low oxidative stress and to delay the aging process, the human body needs a minimum of 5.000 units of antioxidants (ORAC units) in the absence of pro-oxidative factors.

At the present, there is a list of plants that have antioxidative properties according to their antioxidants units. This is called ORAC scale (oxygen absorbance capacity).

Examples: ORAC scale (units/100g product)(1,9)

314.446 - clove powder

312.400 - raw sumac bran

267.536 - cinnamon powder

240.000 - sorghum bran rich in tannin

200.129 - dried oregano powder

159.277 - turmeric powder

102.700 - freeze-dried acai beans

100.800 - black sorghum bran

91.500 - carob powder

86.800 - raw sumac

80.933 - dried cocoa powder

76.800 - dried parsley

71.000 - red sorghum bran

70.000 - Acerola cherries

67.553 - dried basil

48.504 - curry powder

45.400 - raw sorghum rich in tannin

40.200 - dutch chocolate powder

40.000 - maqui beans juice

32.004 - fresh salvia

29.257 - yellow mustard seeds

28.811 - ginger powder

27.618 - black pepper beans

27.426 - fresh marjoram

25.300 - Lycia fruit

24.700 - pollen granules

24.287 - chilly powder

21.900 - black sorghum beans

20.823 - black chocolate.

ORAC scale comments(1):

In animal foods, there are NO antioxidants! Antioxidants are found exclusively in vegetables (the only exception is salmon meat, but its amount of antioxidants is very low).

The main exogenous antioxidants(1,3,9)

  • Resveratrol
  • Carotenoids
  • Lycopene
  • Pycnogenol
  • Ascorbic acid
  • Vitamin complex E
  • Fatty acids w3
  • Fatti acids w6
  • Coenzyme Q10 (also endogenous)
  • Bioflavinoids
  • Niacin (vitamin B3 or NADp)
  • Organic germanium
  • Selenium
  • Zinc
  • Manganese
  • Copper
  • Molybdenum
  • MSM (metil-sulfonil-metan)
  • Betanin
  • Sulforaphane
  • Indole-3-carbinol
  • Capsaicin
  • Limonene
  • Anthocyanins
  • Ellagic acid
  • Sulfides
  • Tri-terpenes
  • Indole substances
  • N-acetyl-cysteine
  • EDTA
  • Hhydrogen ion (H-)
  • Lipoic acid (also endogenous).

1. Resveratrol(1,3,9)

Is the most powerful natural known antioxidant.

  • It is found in 50-100 mg/g in grape skin, that is double than in any other fruit or vegetable.
  • Usually, is found in fruits colored in black or violet: black grape juice, grape kernels, mulberries, blackbe­rries, plums, gooseberries, brussel cabbage, strawberries, wall nuts.
  • Its direct effect is tumor destruction, acting on tumor despite its localization, even on hormone-dependent ones (breast, ovary, testicle, liver, stomach).
  • Its antioxidant potential is 50 times greater than vitamins C+E all together!
  • It has an anti-AIDS effect and on some viruses (including hepatitis viruses), it has anti-allergies (histamine inhibition), anti-bacterial and anti-swelling effects.

2. Lycopene(1,3,9)

  • This is the only antioxidant that can boost its effect by 4-6 times when boiling.
  • Lycopene can be found in any red colored foods: tomato, strawberries, red grapes, jalapeno, pimiento, pepper, guava, sea buckthorn oil.
  • Olive oil can amplify lycopene absorption. Lycopene is rather inefficient in water, so it requires a fatty environment to be absorbed.
  • With vitamins C and E, lycopene can prevent macular degeneration and lowers the risk of developing cataract by 50%.
  • Its main role is the prevention of cancer, degenerative diseases and Alzheimer disease.

3. ß-Carotene(1,3)

  • It is apocarotenal and not ß-carotene that is responsible for the yellow-orange color of carrots!
  • Sources (mg/100 g product): lucerne (4.818), carrot (3-9), almonds (5-6), lettuce (4-8), rosehip (5), peanut (3.6), spinach (2.5), cabbage (2), red beetroot (1.78), mango (1.454), papaya (1.25), parsley and nuts (1.2), yellow melon (1.03), apricot (0.606), olives (0.2), tomato (0.133), sea buckthorn oil, wheat germ, roots, plums, garlic, onion, beans, mulberry, raspberry, pear, cherry, apple, banana, nap, cucumber, pineapple, gooseberry, oat, rice, dandelion, grapes, celery, aloe.

4. Lutein(1,3)

  • Sources: loboda, lettuce, spinach, pumpkin, red cabbage, rebarbarum, leek, peas, any green vegetable and any intense colored fruit.
  • It acts on the yellow spot of the retina and on the crystalline.
  • Cataract can be prevented using antioxidants, but the best effect is by consuming lutein (risk decreased by one-third).
  • Fat oxidation is inhibited by lutein, therefore it lowers the cholesterol values!
  • The lutein effect is amplified by lycopene.

The main endogenous antioxidants(1):

  • SOD (superoxide-dismutase)
  • Glutathione
  • Catalase
  • DHEA (dehydroepiandrosterone)
  • Melatonin
  • Lipoic acid
  • Ceruloplasmin
  • Cytochrome P 450
  • Metallothionein (MT)
  • 2,3-diphosphoglycerate
  • Uric acid
  • Albumin
  • Some amino acids
  • Bilirubin
  • Coenzyme Q10.

1. Superoxide-dismutase (SOD)(1,3,9)

  • SOD is found in the mucus surrounding every cell in the organism; it destroys FR (free radicals) before they enter the cells.
  • It is one of the most powerful known antioxidant; after the age of 25, the SOD genesis decreases, every organ reduces its volume and density (the average brain of a 80-year-old person is 30% smaller than the brain of a 25-year-old person).
  • The use of purified SOD is helpful in: cataract, bronchopulmonary dysplasia, chemical intoxications, rheumatoid arthritis, and the secondary effect of radiotherapy or cytostatics.

2. Glutathione(1,3,9)

  • The most powerful antioxidant made by the human organism.
  • It is more effective than vitamin C in keeping the oxidation state of iron 2, and it has an anti-methemoglobin effect.
  • A major anti-AIDS factor (inhibits HIV multiplication by 10 fold).
  • It helps in the regeneration of the liver and prevents the excessive alcohol consumption consequences. It lowers the risk of hepatitis B disease and liver cancer.
  • It neutralizes the toxic effects of: nitrates, nitrites, chlorine, benzene derivatives, toluene, aniline etc.

3. Melatonin(1,3,9)

  • It is a natural hormone produced by the pineal gland and its secretion decreases throughout the lifetime.
  • Some studies show that the well-functioning of the pineal gland can delay the aging process.
  • The epiphysis can be protected by indirectly restoring the natural youth hormones rhythm (ingestion of pills that contain melatonin). If melatonin is deficient, the aging process will accelerate.
  • It is produced during night sleep by the pineal gland (during the day by other tissues), having a nocturnal spike almost constantly at the same hour, each night between 10 p.m. and 2 a.m.
  • It is used to cure insomnia.

Conclusion

This article focuses on the harmful effects of free radicals; it explains their mechanism and their effect on the human body and describes the main pro-oxidative factors and their carcinogenic effect on the human organism.

Furthermore, it details the main effect of free radicals: oxidative stress, its implications on human health, and analyses this effect on the main organs.

Last but not least, it describes the main methods of prophylaxis: endogenous/exogenous antioxidants, ORAC scale, the roles of antioxidants in cancer control. 

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