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Journal of the American College of Nutrition, Vol. 20, No. 90005, 464S-472S (2001)
Published by the American College of Nutrition

The Benefits and Hazards of Antioxidants: Controlling Apoptosis and Other Protective Mechanisms in Cancer Patients and the Human Population

Rudolf I. Salganik, MD, PhD

University of North Carolina, Chapel Hill, North Carolina

Address reprint requests to: Rudolf I. Salganik, MD, PhD, Research Professor, Department of Nutrition, 2217 B, McGavran-Greenberg Hall, School of Public Health, University of North Carolina Chapel Hill, NC 27599. E-mail: rsalganik{at}unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 
Cellular oxidants, called reactive oxygen species (ROS), are constantly produced in animal and human cells. Excessive ROS can induce oxidative damage in cell constituents and promote a number of degenerative diseases and aging. Cellular antioxidants protect against the damaging effects of ROS. However, in moderate concentrations, ROS are necessary for a number of protective reactions. Thus, ROS are essential mediators of antimicrobial phagocytosis, detoxification reactions carried out by the cytochrome P-450 complex, and apoptosis which eliminates cancerous and other life-threatening cells. Excessive antioxidants could dangerously interfere with these protective functions, while temporary depletion of antioxidants can enhance anti-cancer effects of apoptosis. Experimental data are presented supporting these notions. The human population is heterogeneous regarding ROS levels. Intake of exogenous antioxidants (vitamins E, C, beta-carotene and others) could protect against cancer and other degenerative diseases in people with innate or acquired high levels of ROS. However, abundant antioxidants might suppress these protective functions, particularly in people with a low innate baseline level of ROS. Screening human populations for ROS levels could help identify groups with a high level of ROS that are at a risk of developing cancer and other degenerative diseases. It also could identify groups with a low level of ROS that are at a risk of down-regulating ROS-dependent anti-cancer and other protective reactions. Screening populations could provide a scientifically grounded application of antioxidant supplements, which could significantly contribute to the nation’s health.

Key words: oxidants, antioxidants, apoptosis, cancer

Key teaching points:

• The human population is heterogeneous in relation to levels of ROS, as well as to almost all other features.

• People who over-generate ROS are at high risk for developing cancer, cardiovascular diseases, cataracts and other degenerative diseases because of the oxidative damage to cell constituents (DNA, proteins, lipids, etc) and cell structures.

• People with a low level of ROS might be in danger of harboring low activity of highly important protective reactions. These include apoptosis, which deletes precancerous, cancer, virus-infected and other cells threatening human health; phagocytosis, which fights infectious microorganisms; and detoxification reactions provided by cytochrome P-450 complexes. The ROS are essential triggers and mediators of all these protective reactions. Consequently, a low ROS level limits the activity of these protective reactions.

• Antioxidants protect people with a high level of ROS, whereas antioxidants might be detrimental in people with a low level of ROS by further decreasing the activity of ROS-dependent protective mechanisms.

• Screening the human population for ROS levels could provide a scientifically well-grounded, controlled application of antioxidants and might significantly contribute to improvement of human health.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 
Progress in understanding the deleterious effects of reactive oxygen species (ROS) on cell components and structures has led to the development of protective antioxidant supplements. The supplements are used to protect cell structures from oxidative damage and people from cancer and other ROS-dependent morbid conditions. However, accumulating data demonstrate that ROS, depending on dose, not only act as damaging entities, but also carry out some important beneficial functions. ROS are mediators, triggers or executioners of essential protective mechanisms such as apoptosis, phagocytosis and detoxification reactions. Among these mechanisms, apoptosis, which eliminates precancerous and cancerous, virus-infected and otherwise damaged cells, is particularly important. Increase of ROS concentration by depletion of antioxidants enhances apoptosis and thereby inhibits tumor growth. Excessive antioxidants decrease ROS level, inhibit apoptosis and suppress the elimination of cancer cells induced by anticancer drugs.

This review illustrates the notions outlined above with experimental data. To ensure effective defense against ROS-induced damage, while maintaining the ROS level which promotes apoptosis and other protective mechanisms, it is important to obtain answers to the following questions: a) How heterogeneous is the human population regarding the ROS level? b) Are people with very high and very low ROS levels at risk for developing cancer or other degenerative diseases? c) How high is the ROS level at which cells are damaged? d) How low is the ROS level unable to maintain apoptosis and other ROS-dependent protective functions? e) What is the optimal level of ROS, which induces minimal oxidative damage to cell structures but promotes cell protective mechanisms that eliminate precancerous, cancerous and other "bad" cells? It would also be necessary to establish optimal doses of antioxidants capable of coping with high and low levels of ROS. Answers to these questions could be provided through screening of the human population for ROS level and monitoring alteration of ROS under different doses of antioxidants. These studies might help to develop optimal regimens of antioxidants for different population groups that would be capable of preventing cancer, cardiovascular diseases, cataracts, and other ROS-dependent morbid conditions by maintaining optimal levels of protective reactions.


   BACKGROUND
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 
Cellular Oxidants and Antioxidants
Cellular oxidants, derivatives of oxygen, which are often called reactive oxygen species (ROS), are constantly produced in our cells (Fig. 1). Among cellular ROS, the most aggressive entities are superoxides and hydroxyl radicals [1]. There are a few main sources of ROS in our body. ROS are generated by mitochondria (Fig. 2) via the release of electrons from the electron transport chain and the reduction of oxygen molecules to superoxides (O2•). Superoxides, through the reaction catalyzed by superoxide dismutase (SOD), are transformed into the much less reactive hydrogen peroxide moiety (H2O2). However, when hydrogen peroxide interacts with ions of transition metals such as iron or copper, the most reactive ROS, hydroxyl radicals (OH•) are formed (Fenton reaction). Other sources of ROS, located in the endoplasmic reticulum, are cytochrome P450 complexes (Fig. 3), which generate superoxides to metabolize toxic hydrophobic compounds [2]. Important sources of ROS are phagocytes (Fig. 3), which produce superoxides, hydrogen peroxide and hydroxyl radicals to kill infectious microorganisms [3] and cancer cells [1,4].



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  		Fig. 1. The main reactive oxygen species (ROS) that are constantly generated in living cells.

 


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  		Fig. 2. The generation of ROS by mitochondria. Electrons released from mitochondria reduce oxygen molecules, thereby producing such ROS as superoxides (O2-). Superoxide dismutase (SOD) catalyzes H2O2 formation from superoxides. H2O2 might be deactivated by catalase (CAT). However, when H2O2 reacts with iron or copper ions, hydroxyl radicals (OH•), the most reactive form of ROS, are produced. Excessive antioxidants (AO) can inhibit production of O2- and other ROS.

 


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  		Fig. 3. (a) ROS generated by microsomal monooxygenases, which have cytochrome P450 as a central link. Oxidation is the way to transform hydrophobic toxic substances, drugs, steroids etc., and thereby remove them. Excessive antioxidants can inhibit this protective function.

(b) ROS generated by phagocytes kill infectious microorganisms and cancer cells. Excessive antioxidants can inhibit this protective mechanism.

 
Production of ROS is essential for a number of biochemical reactions involved in the synthesis of prostaglandins, hydroxylation of proline and lysine, oxidation of xanthine and other oxidative processes [1]. Numerous data demonstrate that ROS are capable of oxidizing cell constituents such as DNA, proteins, and lipids, thereby incurring oxidative damage to cell structures. Excessive oxidation leads to impairment of cell functions and development of morbid conditions [1,5]. Besides ROS, cells also generate reactive nitrogen species (RNS) such as nitric oxide (NO•), nitrogen dioxide (NO2•) and peroxynitrite (ONOO•) (Fig. 1) [6]. Nitric oxide and nitrogen dioxide carry out a number of physiological functions. Excessive NO•, NO2• and ONOO• damage cell constituents.

An array of powerful cellular antioxidants protects cells from excessive oxidation (Fig. 4). Among the endogenous antioxidants that scavenge ROS are glutathione, ubiquinol, bilirubin, uric acid, albumin and others. Potent antioxidant enzymes such as superoxide dismutase and catalase protect our cells from oxidative damage by inactivating ROS. Metallothioneins, ferritin, transferrin and ceruloplasmin eliminate ions of transition metals, which are capable of catalyzing the formation of hydroxyl radicals through the Fenton reaction [7,8] (Fig. 1).



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  		Fig. 4. Principal cellular antioxidants that scavenge or inactivate excessive ROS and thereby protect cells from oxidative damage.

 
There is good evidence that endogenous antioxidants do not completely remove ROS in animal and human cells. This raises the question of why, despite the existence of a powerful cellular system of antioxidants, the short-living ROS are not removed entirely and are permanently present in cells. The reasonable explanation for this phenomenon is that continuously produced ROS are needed to perform some important biological functions [1]. Seemingly, the cells are tuned to remove excessive ROS and to leave the required level of oxidants.

The Beneficial Functions of ROS
Indeed, ROS play a crucial role in a few lifesaving biological mechanisms. Phagocytic cells protect us from deadly microorganisms, killing them by producing an avalanche of ROS. When neutrophils and other phagocytic cells engulf bacteria, they greatly increase consumption of oxygen ("respiratory burst"), which is rapidly transformed to ROS that kill the dangerous intruders. NADPH supplies electrons, required for the reduction of oxygen and the formation of ROS (Fig. 3). In turn, NADP+ receives electrons from the pentose cycle pathway by NADPH oxidase through cytochrome b245 [9]. Importantly, by a burst of ROS, phagocytes kill not only invading bacteria [3,9], but also cancer cells [1,4]. Excessive antioxidants scavenge these beneficial ROS and can thereby interfere with the protective functions of phagocytes [10].

Detoxification reactions, ensured by the cytochrome P450 family, are dependent on the integrity of the microsomal ROS-generating system. NADPH and NADH supply reducing equivalents for the reduction of cytochrome b5 and cytochrome P450 (Fig. 3). The latter oxidizes hydrophobic toxic substances, steroids and drugs, transforming them into hydrophilic ones, which are removed from the body. In view of the pivotal role of ROS in the functioning of the cytochrome P450 complex, it is reasonable to suggest that excessive antioxidants could interfere with this important cell function. Data support this suggestion [11].

ROS are essential mediators of apoptosis (Fig. 5), which eliminates cancer and other cells that threaten our health [12–17]. Excessive antioxidants interfere with this highly important protective mechanism [18–21], as also described in this paper.



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  		Fig. 5. Schematic representation of apoptosis. ROS generated by mitochondria are essential mediators of apoptosis. Together with cytochrome C, Apaf-1, and ATP, released from mitochondria, ROS activate proteolytic enzymes, termed caspases, which promote deoxyribonuclease, and thereby destroy targeted "bad" cells.

 
It seems plausible that ROS generation is prevented from being entirely suppressed by endogenous antioxidants because of their important beneficial functions. Seemingly, endogenous antioxidants might be regulated to scavenge ROS to a certain level, but not more. The remaining oxidants are required for carrying out apoptosis, phagocytosis, detoxification and certain other biochemical reactions. Oxidative modification of DNA is also not entirely repaired in healthy animals, despite the existence of potent enzymatic machinery for the repair of DNA [22].

Are moderate oxidative modifications of DNA required for our well being? It seems reasonable to suggest that oxidatively modified DNA might be required to induce mutations necessary for the selection of the fittest to survive in the changing environment, thereby preventing extinction of the population. Industrial pollution as a source of mutations has existed for no more than 150–200 years. Perhaps all living beings should have independent mechanisms for inducing a certain level of mutations. It is also possible that this is the reason why the enzymatic machinery of DNA-repair is adjusted to remove most, but not all, oxidatively modified promutagenic nucleotides from DNA. A mechanism for maintaining a certain level of endogenous antioxidants might exist. This would prevent their excessive accumulation, which in turn might abundantly scavenge ROS and interfere with beneficial ROS-dependent mechanisms.


   APOPTOSIS AND CANCER
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 
Apoptosis, sometimes called "a guardian angel" or "cell policeman," is a cell suicidal altruistic mechanism targeted to selectively eliminate cancerous and other cells that threaten our health and life. The sacrifice of the "bad" cells occurs to save the integrity and life of the whole organism [12,13]. Apoptosis is carried out by a multistage chain of reactions in which ROS act as triggers and essential mediators [12–15]. Recently, it became evident that mitochondria play a critical role in apoptosis [16]. Schematically, apoptotic signals, which arise in cancer cells, promote accumulation of the p53 protein that triggers the release of ROS, cytochrome C and a few other regulators from mitochondria. The latter activate a cascade of proteolytic enzymes, called caspases, that digest a number of pivotal cell proteins and promote a caspase-activated deoxyribonuclease (Fig. 5). Cleavage of the critical proteins and DNA results in apoptotic cell death. Importantly, most anticancer drugs and radiation kill cancer cells by inducing apoptosis [17–21]. Mutations in the p53 gene make cancer cells resistant to apoptosis and, accordingly, to anticancer drugs [13].

Because of the pivotal role of ROS in triggering apoptosis, antioxidants can inhibit this protective mechanism by depleting ROS [18–21]. This is why antioxidants could interfere with the therapeutic activity of anticancer drugs that kill cancer cells by apoptosis. Our data demonstrate that, indeed, apoptosis induced in human breast cancer cells by cisplatin, a widely applied anticancer drug, is accompanied by an increase in ROS generation (Fig. 6). We have further demonstrated that the powerful antioxidant alpha-tocopherol inhibits ROS generation (Fig. 6) and apoptotic death of breast cancer cells induced by cisplatin (Fig. 7) [21]. It appears that antioxidants might inhibit the therapeutic activity of anticancer drugs in patients [20].



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  		Fig. 6. The anticancer drug, cisplatin, kills breast cancer cells by the induction of apoptosis. The antioxidant vitamin E inhibits the cisplatin-induced apoptotic death of cancer cells by scavenging ROS that are essential for carrying out apoptosis (see Fig. 7). MCF-7 breast cancer cells were grown in Eagle’s MEM in 6-well plates (4 x 104 cells per well) and incubated for 24 hours with 15 µM cisplatin. Vitamin E (15 µM) was added to the medium simultaneously with cisplatin or separately. Apoptosis was determined by TUNEL assay and morphological cell patterns [31].

 


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  		Fig. 7. The antioxidant vitamin E inhibits cisplatin-induced ROS generation in cancer cells. The conditions of the experiment were as in Fig. 6. ROS generation was determined using the avidin-FITC which reacts specifically in apoptotic cells with 8-oxo-deoxyguanine, the biomarker of ROS generation, as described in reference [23].

 
We reasoned that if depletion of ROS by antioxidants suppresses apoptosis, then a rise in ROS concentration could enhance the apoptotic death of cancer cells. The concentration of ROS can be increased by enhancing ROS generation or by depleting antioxidants. We tried to increase ROS accumulation by depleting antioxidants. Experiments to verify this reasoning were performed at the University of North Carolina at Chapel Hill [23]. Transgenic mice developing brain tumors were fed a diet depleted of antioxidants, while control mice were fed a standard diet. The antioxidant-depleted diet significantly increased ROS concentration in brain tumors that, in turn, led to a dramatic increase in apoptotic death of brain tumor cells (Fig. 8). Because of intensive apoptosis, a sharp decrease in tumor volume resulted (Fig. 9). Quantitative evaluation of the changes in brain tumor size is presented in Table 1. Importantly, an enhancement of apoptosis was not observed in normal tissues of animals fed the antioxidant-depleted diet. Neither weight loss nor changes in behavior or pathology of normal tissues were found in mice fed the antioxidant-depleted diet for four months [23]. Similar results were obtained in transgenic mice developing mammary tumors. The data indicate that antioxidants scavenging ROS can interfere with cancer cell-killing apoptosis and vice versa: an increase of ROS concentration could enhance apoptosis, thereby selectively removing cancer cells. Currently, clinical studies are in preparation to verify this presumption.



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  		Fig. 8. Increased oxidative stress results in enhanced apoptosis in the brain tumors of mice fed an antioxidant-devoid diet. The distribution of TUNEL-positive (black label, arrow) apoptotic cells in brain tumor for control (A) and in mice on the antioxidant-devoid diet (B) is shown. Oxidized guanine residues (8-oxo-Gua), biomarkers of ROS generation, were detected in brain tumors, using specific monoclonal antibodies (C and D) or an avidin-FITC conjugate (E and F). By both methods, cells in tumors of antioxidant-depleted mice (D and F) exhibit higher levels of 8-oxo-Gua residues than do cells in the tumors of control brains (C and E).

 


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  		Fig. 9. The tumors of mice fed an antioxidant-depleted diet are reduced in size. Compared with tumors in mice fed a standard diet (A and B), the tumors in mice fed an antioxidant-depleted diet (C) were significantly smaller. Magnification: A= 60x; B and C= 120x.

 

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  		Table 1. Alterations in Apoptosis Rate and Brain Tumor Size Induced in TgT121 Transgenic Mice by Antioxidant-Depleted Diet

 

   DAMAGING EFFECTS OF ROS AND PROTECTION BY ANTIOXIDANTS
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 
Numerous in vitro experiments demonstrate that ROS damages DNA, inducing premutagenic modifications of nucleotides and promoting oxidation of proteins and lipid peroxidation [1,24–26]. Data support the notion that increased formation of ROS may play an important role in carcinogenesis, atherosclerosis, diabetes, emphysema, cataracts and neurodegenerative diseases [1,5,7,24–29]. Manifestations of an increased level of ROS are detected in most of these morbid conditions. However, in many cases it is not easy to discriminate whether an increase in ROS is the cause or a consequence of the disease. Our experiments clearly demonstrate the detrimental effect of excessive ROS in animals. Using Wistar rats, an OXYS rat strain with an inherited over-generation of hydroxyl radicals was developed [26]. An increase in oxidative impairment of DNA proteins and lipids is characteristic of OXYS rats compared with control rats. Development of cataracts, emphysema, scoliosis, cardiomyopathy and manifestations of carcinogenesis in the form of a sharp increase of liver preneoplastic foci were observed in OXYS rats [26–28]. Low life span and poor breeding are innate features of OXYS rats. These data support the view that over-generation of ROS can be a cause of many degenerative diseases and premature aging [1,5,7,24].

If the high level of ROS is the cause of degenerative diseases in OXYS rats, then application of antioxidants could presumably protect the impaired functions from oxidative damage. We have shown that an impairment of long-term memory is characteristic of OXYS rats. Memory and some cognitive functions are impaired in people with ROS-promoted neurodegenerative diseases. The integrity of N-methyl-D-aspartate (NMDA) receptors, Na/K-ATPase, and brain protein SH-groups is required for carrying out cognitive functions. We determined the level of these neurochemical processes in OXYS rats and the protection of these functions by a few selected antioxidants such as butylated hydroxytoluene (BHT), emoxipine and carnosine [29]. Studies found that BHT protects rat brains from the oxidative alteration of NMDA receptors and Na/K-ATPase, but does not protect SH-groups. Emoxipine protects rat brains from oxidative impairment of SH-groups, but not NMDA receptors and Na/K-ATPase. Carnosine protects all these neurochemical functions from oxidative damage [29]. Importantly, the data demonstrate that various antioxidants are targeted to protect different neurochemical functions. It seems plausible that combinations of such targeted antioxidants might provide more efficient protection of different functions against oxidative damage than randomly combined antioxidants.


   SHOULD WE TAKE OR AVOID ANTIOXIDANTS TO PREVENT THE DEVELOPMENT OF CANCER?
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
CONCLUSION
 REFERENCES
 
If excessive ROS cause degenerative diseases of aging, particularly cancer and atherosclerosis, can we protect people from these diseases and aging by giving them antioxidants? Alternatively, if antioxidants interfere with highly important protective mechanisms, particularly apoptosis, is it safe to take antioxidants? It seems that there is no simple unequivocal answer. First, we should attempt to answer the question: how efficient are antioxidants in humans for cancer prevention? The answer to this question appears controversial. No reduction in the incidence of lung cancer among male smokers was found in a large randomized, double-blind trial of daily supplementation with alpha-tocopherol or beta-carotene alone, both alpha-tocopherol and beta-carotene, compared with placebo. An even more discouraging and unexpected finding from this Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) trial was the higher incidence of lung cancer and mortality among the male smokers who received beta-carotene [30,31]. This trial was followed by the Carotene and Retinol Efficacy Trial (CARET) that examined the effect of a combination of beta-carotene and vitamin A (retinol) on the incidence of lung cancer among smokers and workers exposed to asbestos [32]. An increase in lung cancer observed in the antioxidant-supplied group resulted in the premature stopping of the study.

The above data led to a tendency to deny protective effects of antioxidant supplements against cancer [33–35], despite findings from numerous studies supporting their protective effects [36–41]. The Chinese Cancer Prevention Study found lower gastric and esophageal cancer rates and a reduction in mortality among people whose daily diets were supplemented with beta-carotene, vitamin E and selenium for more than 5 years [36]. A strong correlation was found between a higher intake of antioxidants and a lower incidence of lung cancer in nonsmokers [37]. Vitamin E and beta-carotene lowered the rates of occurrence of gastric cancer [38]. A high intake of vitamin E reduced the risk of colon cancer [39]. Data from the ATBC trial that demonstrated a high incidence of lung cancer among male smokers found that vitamin E decreased the incidence of prostate cancer [31]. Diets rich in vegetables and fruits that contain a variety of antioxidants clearly have cancer-preventive effects [41–45]. However, the possibility that some non-identified natural compounds in these foods could also contribute to their cancer-protective activity cannot be ignored. Patients with low baseline beta-carotene levels were at increased risk of prostate carcinoma compared to those with high beta-carotene levels. Further, people with low plasma concentrations of beta-carotene benefited from supplementation with beta-carotene, in contrast to people with a high level of this compound in the plasma [40].

Possible explanations for these contradictory findings are outlined below:

  1. Antioxidants can protect healthy people, but they also can harm people who, being smokers, are constantly exposed to chemical carcinogens in tobacco. Lung tissues of heavy smokers unavoidably harbor numerous mutagenized precancerous cells. ROS-dependent apoptosis targets these precancerous and cancerous cells for deletion. Antioxidants, which scavenge ROS, suppress apoptosis and prevent the apoptotic death of precancerous and cancer cells, thereby potentially promoting the development of lung cancer. In addition, antioxidants scavenge excessive ROS, but do not remove numerous chemical carcinogens, which appear in lungs as a result of cigarette smoking. This is seemingly why antioxidants can prevent lung cancer in non-smokers [37]. In non-smokers, lung cancer is induced predominantly by constantly generated ROS, whereas in smokers, chemical carcinogens induce this disease. At the same time, smokers were protected by alpha-tocopherol and beta-carotene against prostate cancer. The prostate, unlike the lungs, does not experience the heavy pro-mutagenic effect of tobacco smoke. Therefore, the prostate obviously does not harbor the multitude of mutagenized precancerous cells as in lung tissues. Prostate DNA most probably is modified by ROS and, to a much lesser extent, by cigarette carcinogens. Antioxidants in the prostate, by scavenging constantly generated ROS, could prevent their carcinogenic effect, thereby reducing the incidence of prostate cancer.
  2. The effect of antioxidants could depend on their initial levels in the body. Only in rare cases have baseline levels of antioxidants been measured, despite the importance of this information [40]. Data demonstrate that baseline antioxidant levels could influence decisions regarding the intake of antioxidants.
  3. The cancer-preventive effect of antioxidants depends on the baseline level of ROS in cells, which is largely determined by the rate of ROS generation and antioxidant defense. Antioxidants could be efficient in individuals with a high level of ROS and non-efficient or even cancer promoting in people with a low level of ROS. The reason for the negative effect of antioxidants could be inhibition of ROS-dependent cancer-protective apoptosis and phagocytosis. However, ROS levels, and therefore the expected activity of antioxidants, have yet to be measured in people before intake of antioxidant supplements is recommended.
  4. The human population is heterogeneous in all inherited features [46,47] and the diversity of the population regarding the levels of constantly generated ROS is hardly exceptional. Obviously, there are people with an innate high level of ROS who are at a high risk of developing cancer, degenerative diseases and premature aging. At the same time, there are groups of people in the population with a low level of ROS, who also are in danger because of poor functioning of apoptosis and other ROS-dependent protective mechanisms. The heterogeneity of the human population regarding ROS levels depends on the rate of ROS production and on the activity of endogenous antioxidants. The heterogeneity of the human population can probably be described by the normal distribution curve where the extremes are "ROS hyper-producers" from one side and "ROS hypo-producers" from the other side of the curve. Therefore, requirements for protective antioxidants may differ among individuals. Antioxidants are reasonable to apply under a control of ROS levels, in accordance with the rate of ROS accumulation data. An excessive intake of antioxidants can be as harmful as a lack of these protective entities. Unfortunately, widely advertised, poorly controlled application of antioxidants can lead to unwanted consequences to our health. Only recently have non-invasive methods for the control of ROS level or for studying the protective effects of antioxidants and pro-oxidants became available [43]. Screening human populations for innate levels of ROS could identify low and high "ROS-producers" and help determine true requirements for antioxidants. Screening could help justify decisions regarding intake of antioxidant supplements as well as food sources of antioxidants.
  5. Currently, antioxidants are applied in mostly empirically determined combinations and concentrations. It is assumed that combinations of water-soluble and lipid-soluble antioxidants in these supplements are sufficient to meet all body requirements. However, in reality, the situation is far more complex. We have determined that different antioxidants protect various memory-related neurochemical functions oxidatively impaired in OXYS rats that over-generate ROS [25]. Seemingly, some antioxidants have a targeted protective effect, which provides the opportunity for optimal scientifically grounded combinations of these compounds.

There are data showing that some antioxidants might have pro-apoptotic anticancer effects. This property was discovered in alpha-tocopherol succinate, an analog of alpha-tocopherol, but not in alpha-tocopherol and alpha-tocopheryl acetate applied in comparable doses [48–50]. Moreover, alpha-tocopherol inhibited pro-apoptotic activity of alpha-tocopheryl succinate. The succinate moiety of alpha-tocopheryl succinate played an indispensable role in promoting apoptosis by the alpha-tocopherol analog [48]. However, alpha-tocopherol at very high doses is capable of promoting apoptosis in cancer cells, most probably due to the damaging effect of an excess of this compound [51]. Individual antioxidants at defined doses might prevent tumor growth by inducing cell differentiation, promoting transforming growth factor-beta, inhibiting protein kinase C activity, suppressing transcription factors, and by other mechanisms not related to ROS inhibition [52,53].

Some trials have failed to demonstrate protective or anticancer properties of combinations of antioxidants, vitamins E, C, A and beta-carotene, commonly found in supplements [25]. However, diets rich in a multitude of certain vegetables and fruits have been found to be protective against cancer and cardiovascular diseases [39–41]. A few well-controlled studies demonstrate that consumption of diets enriched in a variety of fruits and vegetables from diverse botanical families significantly reduces oxidative damage to DNA and other cellular constituents, thereby preventing the development of cancer and cardiovascular diseases [42–45].


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
REFERENCES
 
The data discussed in this review show that the biological effects of antioxidants in humans are controversial. Depending on the oxidative status of cells, antioxidants can be protective against cancer or cancer promoting. Since ROS induce oxidative carcinogenic damage in DNA, antioxidants can prevent cancer in healthy people harboring increased levels of ROS. However, since ROS in moderate concentrations act as indispensable mediators of cancer-protective apoptosis and phagocytosis, in people with a low ROS level, an excess of antioxidants can block these cancer-preventive mechanisms and promote cancer. An excess of antioxidants, which interferes with apoptosis, also can be cancer-promoting in people who are constantly exposed to the effect of environmental carcinogenic factors (tobacco smoke, industrial pollutants), which result in a high accumulation of pre-cancerous and cancerous cells. In cancer patients, an excess of antioxidants can interfere with the therapeutic activity of anticancer drugs, which kill cancer cells by ROS-dependent apoptosis. It is becoming increasingly clear that the beneficial effect of antioxidants can be achieved if these factors are taken into account.

The human population is heterogeneous regarding the ROS level. Screening the human population regarding innate or acquired ROS levels can provide the necessary information about individual oxidative status. High doses of antioxidants can reduce the ROS level in people who over produce ROS and protect them against cancer, cardiovascular diseases, cataracts and other ROS-dependent morbid conditions. For people with a low ROS level, high doses of antioxidants can be deleterious, suppressing the already low rate of ROS generation and the ROS-dependent cancer preventive apoptosis. Screening and monitoring the human population regarding the ROS level can transform antioxidants into safe and powerful disease-preventive tools that could significantly contribute to the nation’s health.


   ACKNOWLEDGMENTS
 
This work was supported by a grant from the Institute of Nutrition of the University of North Carolina.

Received April 26, 2001.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 BACKGROUND
 APOPTOSIS AND CANCER
 DAMAGING EFFECTS OF ROS...
 SHOULD WE TAKE OR...
 CONCLUSION
 REFERENCES
 

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