About Author:
YOGESH KUMAR SHARMA*1, ANIL SHARMA2,
1. SIDDHI VINAK COLLEGE OF SCIENCE & HIGHER EDUCATION ALWAR,
2. GAYAN VIHAR COLLEGE OF PHARMACY JAIPUR, RAJASTHAN
Abstract
Oxidation is a natural process that occurs anytime a substance combines with oxygen like the browning of sliced apples or rusting of metals. When it occurs constantly, putting our health at risk. Antioxidants are substances that may protect cells from the damage caused by unstable molecules known as free radicals. Free radical damage may lead to cancer. Antioxidants interact with and stabilize free radicals & may prevent some of the damage free radicals otherwise might cause cancer. Antioxidants are abundant in fruits and vegetables, as well as in other foods including nuts, grains ands some meats, poultry and fish. The battle to conquer cancer is an international effort for the treatment of cancer. Currently we have about 30 chemotherapeutic agents and out of these nearly one third are natural products.The aim of this review is to know that how might antioxidants prevent cancer. So prospective study of antioxidants, & its mechanism and potential use in cancer therapy is presented.
REFERENCE ID: PHARMATUTOR-ART-1140
Introduction
A process called oxidation damages important molecules in the body and harms vital structures in our cells in the same way that rust damages the metal work of a car. This oxidation contributes to many of the degenerative diseases that are common as we age form heart disease to dementia, from cancer to cataracts. Oxidation is a natural process that occurs any time a substance combines with oxygen. Antioxidants are chemicals that may be able to block this process1.
Antioxidant can be defined as substances whose presence in relatively low concentrations significantly inhibits the rate of oxidation of the above targets. These are the substances that may protect cells from the damage caused by unstable molecules known as free radicals2a.
Scientific research now confirms that free radicals play a major role in the development of cancer, heart disease, aging, cataracts and impairment of the immune system. They are seen as molecular loose cannons involved in biological fire works. The battle to conquer cancer is an international effort for the treatment of cancer. Currently we have about 30 chemotherapeutic agents and out of these nearly one third are natural products. The use of antioxidants as an adjunct to conventional or as an integral part of alternative cancer therapy is an area of intense research.
Thus a large body of research has investigated the potential role of antioxidant nutrients; Beta carotene and other carotenoids, vitamin E, Vitamin C and selenium in the prevention of several chronic disease including cancer, cardiovascular disease, cataract, age related molecular degeneration and aging in general etc. Thus the study of antioxidant use in cancer treatment is a rapidly evolving area, which has been extensively studied for their ability to prevent cancer in humans2b.
2. Sources of antioxidants
Beta-Carotene: - It is found in many foods that are orange in colour, including sweet potatoes, carrots, squash, apricots, pumpkin and mangoes. Some green leafy vegetables e.g. Collard greens, spinach are also rich in b-carotene.
Lutein: - It is abundant in green leafy vegetables e.g. Collard greens and spinach. Lutein is best known for its association with healthy eyes.
Lycopene: -It is a potent antioxidant found in tomatoes, watermelon, guava, Papaya, apricots, blood oranges etc.
Selenium: - It is a mineral and also a component of antioxidant enzymes.Major sources of this are rice and wheat and Brazil nuts also contain large quantities of selenium.
Vitamin A: - It is found in 3 main forms- retinol (Vitamin A) 3, 4-didehydroretinol (Vitamin A2) and 3-hydroxy retinal (Vitamin A3). Foods rich in vitamin A include liver, sweet potatoes, carrots, milk, egg yolks and mozzarella cheese.
Vitamin C (Ascorbic acid): - It can be found in high abundance in many fruits and vegetables and also in cereals, beef, poultry and fish.
Vitamin E: -(a-tocopherol) It is found in many oils e.g. Almond oil, wheat germ, sunflower, corn and soybean oils and also found in mangoes, nuts and other foods2.
Antioxidants vitamins and minerals should enhance the body’s natural defense mechanisms and improve the quality and length of life. Antioxidants are abundant in fruits and vegetables, as well as in other foods including nuts, grains, and some-meats, poultry and fish. The list below describes food sources of common antioxidants.
Plants also produce their own antioxidants. These powerful plant compounds called phytochemicals can also provide us with potent antioxidant protection. Grape seed extract and pycnogenol from pine bark extract are two of the most powerful antioxidant- supplements available today. Aside from these many of several herbs which have antioxidant activity, Cayenne or chilli pepper (capsicum annuum), ginger (Zingiber officinale), garlic (Allium sativum), turmeric (curcuma longa), ginkgo biloba and bilberry (vaccinium myrtillus) etc.1
Table: - Natural and synthetic antioxidants available for therapeutic use. They are classified as follows:
Antioxidants
1. Natural antioxidants
? Enzyme antioxidants
SOD, Catalase, Glutathione, peroxidase, Preventive Antioxidants, Transferrin, Caeruloplasmin, Albumin
? Scavenging (chain-breaking) Antioxidants
Ascorbic acid (Vitamin C), Uric acid, Bilirubin, Thiols, Tocopherol, b-Carotene, Ubiquinol-Flavonoids, Estrogens
? Pharmacological antioxidants
Augmenting antioxidant enzymes -SOD, Catalase, Glutathione peroxidase
Preventive antioxidants- Deferoxamine (desfernoxamine)
Scavenging (‘chain breaking’) antioxidants - Probucol, Salicylates,‘ Lazaroids’ (21-aminosteroids) Mannitol, dimethylsulfoxide (DMSo) and dimethyl thiourea (DMTV)
Xanthine oxidase inhibitors-Allopurinol and oxypurinol
Neutrophil and macrophage inhibitors, NADPH oxidase inhibitors, Antineutrophil serum
Antiadhesion agents
Abbreviations: -
GSH = Reduced glutathione; GSSH =Oxidized glutathione,
NSAIDS = Nonsteroidal anti-inflammatory drugs;
PEG = Poly ethyleneglycol; SOD= Superoxidedismutase.
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3. ROLE OF ANTIOXIDANTS IN CANCER4,6
Research shows that 23 percent of cancer patients take antioxidants. Physicians specializing in nutritional and ortho-molecular medicine have for decades successfully employ a carefully planned protocol of natural micronutrients and antioxidants in the right dosage at the right time to reverse Cancer in its early stages and to deter cancer metastasis in advance stages.
Antioxidants in the appropriate high and repeated doses showed that they actually improve the efficacy of tumor response to chemotherapy and radiological therapy. Selectively inhibit the growth of cancer all without affect the normal cells. Normal and cancer cell respond in the same way to low dose antioxidant therapy because both cell types require antioxidant in low doses for optimum function. High dose antioxidants therefore selectively are toxic to cancer cells but not affects to normal cells.
Antioxidants neutralize free radicals as the natural by product of normal cell processes. Free radicals are molecules with incomplete electron shells, which make them more chemically reactive than those with complete electron shells. Exposure to various environmental factors, including tobacco smoke and radiation can also lead to free radicals formation.
In humans, the most common form of free radicals is O2 when an oxygen molecule (O2) becomes electrically charged or “Radicalized” it tries to steal electrons from other molecules causing damage to the DNA and other molecules. Over time, such damage may become irreversible and lead to disease including cancer. Antioxidants are often described as “mopping up” free radicals meaning they neutralize the electrical charge and prevent the free radical from taking electrons from other molecules.
Antioxidants protect against chemotherapy toxicity and local toxic effects of tumors or surrounding tissues. Antioxidant inhibits cell proliferation. One very interesting thing about cancer cells are that they lose apoptosis (programmed cell death) ability .Vitamin E saturate, inhibit growth and induce apoptosis ability of human breast cancer cell and colorectal cancer.
Important Cancer antioxidants: - The following is list of common antioxidant used in cancer programme. They should be part of a complete antioxidant; vitamin, mineral and enzymatic programme Different antioxidant works at different part of the cell.
1. Beta-carotene: - It is a form of vitamin A. vitamin is a strong immune booster. It stimulates the activity of immune cells against tumor cells. Beta-carotene inhibits the initiation of cancer. It can decrease the amount of damage free radicals do to a cells DNA. Such DNA damage is thought to be one mechanism that causes cancer and b-carotene might reduce the risk of cancer. High doses of b-carotene, even over long periods of time are not associated with serious toxicity. Cancer risk increases when our dietary intake of these nutrients is low. Women with high breast tissue concentrations. A nutrition study report found that high blood levels of b-carotene had a strong protective effect against lung cancer, melanoma, and bladder cancer. Beta-carotene is integral in directing the immune system to kill cancer cells. It increases the number of receptors on WBC for molecules known as major histo compatibility complex II (MHC II), which help in monocytes action, a type of white blood cell, and direct killer T cells to cancerous cell.
Therapeutic Dose: - 25,000 to 100,000 IU a day.
2. Vitamin C:- It is known that Vitamin C act as an antioxidant and free radical scavenger that reacts directly with superoxide, hydroxyl radicals, and singlet oxygen produced during normal cellular metabolism. Vitamin C cancer fighting process include
1. Fortifying the immune system by increased lymphocyte production.
2. Salvaging cellular free radical damage.
3. Inhibition of hyaluronidase, keeping the ground substance around the tumor infect and preventing metastasis.
4. Killing oncogenic virus through its enhancement of phagocytic activities.
5. Correction of an ascorbate deficiency commonly seen in cancer patients.
6. Stimulate collagen formation and its stabilization necessary for “walling off” tumours.
7. Neutralization of carcinogenic toxins Vitamin C has stronger antioxidant effect than vitamin A, E, or b-carotene. Diets high in vitamin decrease cancer, especially of the oesophagus and stomach, uterine cervical dysplasia, breast, larynx, oral cavity, pancreases, rectum and cervix. It is good for almost every cancer except for non-lymphocytic leukemia.
Therapeutic Dose: - Increase up to bowl tolerance from 1 gm, 2-4 time a day and gradually increase every few days by 0.5 gm. Each dose up to 3-10 Gms a day. It can be given I.V. or orally
3. Vitamin E: - For strong immune response and an important fat-soluble antioxidant vitamin E s preventive role in cancer has been well proven with cancer in remission, the use of vitamin E as a preventive nutritional agent to prevent further oxidative stress is a comer stone of any cancer remission nutritional protocol. Use only the natural vitamin E succinate form for best adsorption and therapeutic effect. In particular, women with fibrocystic breast disease can benefit from vitamin E therapy vitamin E raised blood levels of both estriol (E3) is the natural estrogen found in the body with anticancer effect. Progesterone is an opposing harmone to estrogen and counter-balances the estrogen dominance, a primary causative factor in estrogen related disease such as breast, ovarian, and uterine cancer
- Highly malignant melanoma cell in vitro has been shown to be converted into differentiated (normal) cell after 3 days of exposure to vitamin E succinate
- Calioma tumor cells (Present in the brain) are also more effective attacked by vitamin E succinate due to better penetration of blood brain barrier.
- Ovarian and cervical cancer:- Vitamin E slow downs the mitotic activity of cancer cell but normal cell don’t get affected.
- Vitamin E succinate protects the normal cell against radiation induced chromosomal damage but enhance the effect of radiation on cancer cell.
- Tamoxifen, when combined with Vitamin. E, works better than either alone in breast cancer cell.
Therapeutic Dose:- 400-800 IU a day
4. Selenium:- It is an essential trace mineral or micronutrient. It is a powerful antioxidant with a central role in the protection of tissues from the damaging effects of oxygen free radicals. The use of selenium compounds a cancer treatment predates most conventional treatments currently in use. It may play a role in reducing the risk of cancer by binding with Glutathione peroxidase (GSH-Px) to combat destruction causes by free radicals and protect cellular membranes.
Dose: - 100-200 mcg. a day. Selenium is highly toxic at concentrations of 1 milligram (1000 mcg) and selenium (200 mcg) a day has been shown to reduce cancer death by 50% and prostate cancer by 62% after 4 years. It works synergistically with Vitamin E.
5. Lipoic acid: - Called the universal antioxidant for its ability to dissolve well in water and in fat environment, Lipoic acid increase the effectiveness or potency in other antioxidants. It can cross blood brain barrier while others cannot. It has ability to regenerate other essential antioxidants such as vitamin E, coenzyme Q 10 and glutathions.
Therapeutic Dose: - 500-1000 mg a day.
5. Poly MVA: - This is an alpha lipoic acid complex with palladium. It is a non-toxic poly nucleotide reductase named polydox (USA trials), poly MVA (Canada and Mexico) or LAPD by some vitamins, and amino acids LAPD stands for Lipoic acid / palladium complex.
Poly-MVAprotects cellular DNA, carries the powerful antioxidants lipoic acid into the cell. Acts as an intracellular electron donor & generates water within the cell. Cancer cells have deranged respiration producing less water in the cell and utilizing more sugar and one-twentieth the oxygen of normal cells and no O2 radical pathways. Thus when synthetic DNA reductase enters these cells, protein radicals are formed which denatures the tumor cells proteins .The most dramatic responses were noted with brain tumors. Therapeutic dosage varies with patients. For cancer prevention, one half to one teaspoon a day is sufficient indefinitely.
7. Bioflavanoides: - These are compounds that occur naturally in many plants. They can be divided with their occurrence into six groups:-
(i) Isoflavones (Soy)
(ii) Flavonols (onions & broccali)
(iii) Flavones (In greens, include thyme & parsley).
(iv) Flavonones (citrus fruits.)
(v) Catechins (Tea and apples)
(vi) Proanthocyanidins (grapes & cherries.).
Green teashowed tumor regression patterns as the chemotherapeutic agent’s effectiveness appears to be increased. A cup of green tea contains about 50 mg of caffeine, a stimulate cancer-patients should avoid. In therapeutic dosage 4-10 decaffeinated green tea extracts capsules a day. High doses of 20 mg/kg are needed
- Quercetin flavonoid damages cancer cells only and leaves normal cells intact food sources include onion and apples. It is anti-angiogenesis and enhances apoptosis.
- The role of tomato based products may have in preventing the formation of prostate cancer. It contains the antioxidant lycopene (such as tomato sauce) may also benefit patients already suffering from the disease.
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- Wine contains resveratrol, which helps suppress cancer. The red grapes that go into red wine also have bioflavonoid, which are antioxidants and help prevent cancer to begin with. Wine as a stress fighter help cancer patients by relaxing them and helping them fight their disease.
The cautions and judicious use of a number of important antioxidants can be helpful in the treatment of cancer either as sole agents or as adjuncts to standard radiation and chemotherapy protocols. A large bode of evidence is available to show a positive effects of high dose repeated use of antioxidants in the period before, during and after conventional
Enzyme antioxidants catalyse the breakdown of radical species usually in the intracellular environment preventive antioxidants bind transition metal ions such as iron and copper, preventing their interaction with hydrogen peroxide and superoxide to produce highly reactive hydroxyl radicals. Sacrificial (“chain-breaking”) antioxidants are powerful electron.donors and react preferentially with free radicals before more important target molecules are damaged. In doing so the antioxidant is sacrificed (oxidized) and must be regenerated or replaced. By definition, the antioxidant radical is relatively unreactive and unable to attack further molecules.
RECENT ADVANCES & FUTURE ASPECTS
Epidemiological data showing ethnic and geographic variations in the incidence of, and mortality from prostate cancers have suggested that the consumption of certain dietary factors particularly anti-oxidants may be protective. These factors include the vitamins D and E, Soy, lycopene and selenium. The antioxidant treatment was found to have an effect both on reactive oxygen species levels and glutathione peroxidase activity. The antioxidant treatment also reduced serum levels of IL-6 and TNF7.
Recently, the application of genomic tools to study the antioxidant responses of E. coli has both confirmed previous observations and provided evidence for a wealth of putative new anti-oxidant functions8.
Antioxidants when added adjunctively, to first line chemotherapy, may improve the efficacy of chemotherapy and may prove to be safe. Because of the positive results found in patients, a randomized controlled trial is now underway, evaluating safety and efficacy of antioxidants when added to chemotherapy in newly diagnosed ovarian cancer9. The patient treated for early-stage oral cavity carcinoma, at risk for second primary cancers have a statistically significant deficiency in dietary (food) sources of antioxidant nutrients when compared with body historic control subjects and current recommendation physicians may consider recommending at least 5 daily serving of fruits and vegetable as an alternative to vitamin supplementation10.
Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage11.
Our findings don’t provide consistent support for an inverse association between supplemental Vitamin E and colon cancer risk. Considering the purity of epidemiological data on this association, further studies of Vitamin E and colon cancer are warranted12.
Data shows a positive association between b-cryptoxanthin and prostate cancer risk. Our study also shows inverse associations for retinol, a-carotene, and b-carotene, among nondrinkers; this suggests an interaction between vitamins and alcohol consumption, which needs confirmation13.
Antioxidants have a beneficial effect on reducing extraneous oxidative damage so, based on what is known to date, an antioxidant-rich diet seems to be the most prudent advice when confronted with the advisability of supplementation during cancer therapy. In the near future, it is hoped that studies will further define the relationship between the many different cancer diseases, treatments, and supplemental antioxidants14.
Overall, examination of the evidence related to potential interactions between reactive oxygen species (ROS) and dietary antioxidants and effects on human health indicates that consuming dietary antioxidant supplements has pros and cons for any population and raises numerous questions, issues, and challenges that make this topic a fertile field for future research overall, current knowledge makes it premature to generalize and make specific recommendation about antioxidant usage for those at high risk for cancer or undergoing treatment15.
SUMMARY
The world of antioxidants is a battlefield. It is not just a war going on inside our cells, but also a battle between the conventional scientific community, and the commercial pirates, who have hijacked the concept, to plug a myriad of ‘anti-oxidant remedies4.
The study of antioxidants use in cancer treatment is a rapidly evolving area. The importance of this concern is underlined by a recent study which estimates 23% of cancer patients take antioxidants. There has long been interest in the possibility that diets rich in antioxidants may reduce the incidence of cancer43.Epidemiological observations and cohort studies have suggested that persons with high dietary antioxidants intake are less likely to develop cancer particularly lung cancer17.
Potential antioxidant therapy includes natural antioxidant enzymes where antioxidant therapy may be beneficial includes diabetes mellitus and the prevention of chronic processes such as atherosclerosis and carcinogenesis. Further well-controlled prospective clinical trials of antioxidants are required to establish the efficacy and tolerability of antioxidant therapy in the treatment of human diseases18.
Hence various reports show a reduction in adverse effects of chemotherapy when given concurrently with antioxidants. Antioxidant vitamins and minerals should enhance the body’s natural defense mechanisms and improve the quality and length of life. Antioxidant have a beneficial effect on reducing extraneous oxidative damage; So, based on what is known to date an antioxidants-rich diet seems to be the most prudent advice when confronted with the advisability of supplementation during cancer therapy. In future, it is hoped that studies will further define the relationship between the many different cancer diseases, treatments and supplemented antioxidants.
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18. Goode, HF., Webster, NR. , Free radicals and antioxidants in sepsis, Crit Care Med. 1993, 21, 1770-6.
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