By Omer Mercier Ph.D., LRG Science Team
*On June 16, 2010, Omer Mercier passed away. He is deeply missed by all who knew him. This article is a testament to his mind and the support he showed the LRG and GIST patients.
Under different forms, antioxidants are in wide use among health-conscious people and even more so among cancer patients. They take the form of such dietary supplements as Vitamin C, E and A, beta-carotene, lycopene, selenium, ginger (Zingiber officinale), cucurmin (turmeric), or pomegranate juice.
Occasional controversies have been raised concerning their use, on grounds of serious or sometimes questionable arguments. Another controversy was raised lately, whereby the authors warned that several antioxidants could block therapeutic actions of some anti-cancer drugs, among them Gleevec (imatinib), thus suggesting they should not be used.
Today, we are facing total confusion on this topic; should we refrain from taking antioxidants?
All of them or just some of them?
Our objective is to present a review of pertinent publications on biological actions of antioxidants, with particular emphasis on cancer patients. It does not focus on novel research results but rather attempts to sort out favorable and unfavorable arguments buried in existing publications, making it easier for GIST patients, and other cancer patients as well, to make decisions while understanding the issues at stake.
Note: This article was researched and prepared by LRG Science Team Member, Omer Mercier. Reasonable care was exercised in preparing this article. This article contains opinions based on an extensive, but not exhaustive review of the literature. Others may have different opinions. The information presented here is for information purposes only. Please discuss all supplement use with your doctor.</p class>
Antioxidants: many names and many sources
“An antioxidant is a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by being oxidized themselves. Although oxidation reactions are crucial for life [e.g. respiration], they can also be damaging; hence, plants and animal maintain complex systems of multiple types of antioxidants as well as enzymes. Low levels of antioxidants, or inhibition of the antioxidant enzymes, causes oxidative stress and may damage or kill cells.” [Wikipedia]
Antioxidants may be found in numerous natural foods (see box), including fruits and vegetables, nuts, grains, some meats, poultry and fish. [WCRF report, NCI 2004, Cancure 2009, Adhikari 2007, Ehrlich 2008, Rhode 2007, Riss 2007]
Some of them are naturally produced in our body. This is the case of SOD, glutathiones, coenzyme Q, and others. All have detoxifying actions (see below).
It is estimated that 50% of people in the USA are taking dietary supplements in some form and this is likely to be representative of what is observed in other developed countries [WCRF report 2007]. An even higher percentage is estimated for cancer patients [Hardy 2008].
Why are antioxidants needed?
Oxidative stress is a by-product of many natural processes; it is also caused by physical exercise, pollution, UV and sun exposition, excessive food intake, alcohol and tobacco use, activity-induced stress, etc. These external aggressions generate free radicals and other ROS, with damaging effect known as « oxidative stress ». This stress is normally controlled by natural antioxidants, on top of which are SOD and GPX (see box), which have protective effects, but any deficit may lead to DNA and RNA damage, unwanted amino acids oxidations, and cell apoptosis. It is also involved in the process of physiologic ageing.
Unless repaired by other mechanisms (e.g. tumor suppressor proteins), damage to DNA leads to changes in gene expression and chromosomal mutations (alterations in the amino acid sequences) which may change cell functioning and lead to cancer. [NCI factsheet 2004, WCRF report 2007]
Oxidative stress is known to be involved in a wide variety of diseases (e.g. Alzheimer’s disease, Parkinson’s disease, rheumatoid arthritis, or arteriosclerosis). It is also considered to be involved in the ageing process.
SOD (see box below) is one of the natural substances that contribute to conversion of harmful ROS; its positive action as an antioxidant has been recognized in joint diseases [Afonso 2007].
However, ROS also have beneficial effects. For instance, in wound repair and blood homeostasis, they help recruiting platelets to the site of injury. They also participate in the adaptive immune system through recruitment of leukocytes, and in elimination of bacteria and pathogens. So, total elimination of free radicals and other ROS cannot be contemplated
Regarding ageing, note that another theory has been proposed, whereby oxidative stress and molecular damage from ROS would be the consequence (rather than the cause) [McGill 2009]. Yet, the authors do not challenge the fact that ROS are harmful. The link between oxidative stress and cancer has not been challenged either. There is a growing consensus though, that consumption of antioxidant supplements does not increase lifespan.
The HIF-1 issue
If hypoxia causes oxidative stress and cell death (by apoptosis or by slowing of proliferation), it is also part of a process leading to malignant tumor progression and to build-up of resistance to chemotherapy and radiotherapy treatments. [Vaupel-Harrison 2005, Vaupel-Mayer 2005]. This adaptation process is regulated by transcription factor HIF-1. This protein (as the gene with the same name which governs it) has a central action in the growth and proliferation of cancer cells, as well as in chemoresistance, once hypoxia is sensed [Ke-Costa 2006, Rohwer 2009, and others]. HIF-1 is expressed in varying extent in GIST (see [Takahashi 2003, Chen 2005]) and especially so in gastric GISTs. In fact, the activity of HIF-1 is strongly correlated with the degree of aggressiveness and risk of GIST (tumor size, mitotic count, etc.). The above process is quite different from the direct effects of oxidative stress, as presented earlier.
Therapies addressing downregulation of HIF-1 or inhibition of its transcriptional activity are still under study. Two exogenous antioxidants, namely Vitamin C and N-acetycysteine (NAC), have been studied (on mice) for their potential efficiency in blocking HIF-1 signaling: [Gao 2007]. However, doses are still unknown.
It was pointed out that the same antioxidants could have an antitumor effect 1) due to their action on HIF-1 and 2) by inhibition of ROS, a cause for genomic instability.
Some natural foods, having reductive activity have also been studied to that end [Losso 2005]. They belong to the families of isoflavones (soybean and soy products), quinones (e.g. Vitamin K2 from dairy products, fish oil, natto), semiquinones like coenzyme Q10 (heart, kidney and other organ meats, fish, nuts, soy, spinach, yeast), polyphenols (e.g. green tea, cucurmin), vitamins (e.g. vitamin C or sodium ascorbate, vitamin B3, vitamin K), sulforophanes (e.g. broccoli), beta-carotene, amino-acids (e.g. taurine), etc. However, we are warned that dosing, metabolism paths and side effects have not been mastered so far. A book from the same author is in print [Losso 2007].
To compound the issue further, HIF-1 is not the only protein involved in cell proliferation [Rohwer 2009].
Would vitamin C overcome resistance to Gleevec?
It is claimed in [Tarumoto 2004] that vitamin C, and probably other antioxidants as well, have an inhibitive action on the movement of Nrf2 transcription factor to the cell nucleus under oxidative stress, thus inhibiting synthesis of GSH, a substance known to be involved in resistance to several anti-cancer drugs, including imatinib. Based upon this in-vivo study, vitamin C could be beneficial in case of tumor resistance to Gleevec.
The mitochondria issue: Would vitamin C prevent tumor cell apoptosis?
Mitochondria may be seen as the energy plant of cells, transforming “fuel” into ATP. The main process involved is mostly aerobic respiration, i.e. using the oxygen in air. When oxygen is insufficient, an anaerobic process is involved, called glycolysis.This is the case for tumor cells located far from existing blood vessel, but it has been proven that cancer cells exhibit a dysfunction of their mitochondrial metabolism, favoring glycolysis even in presence of oxygen.
Much like batteries, mitochondria take hydrogen out of nutrients (glucose, fats, amino-acids) and burn it to form water, the produced energy being stored in the form of ATP. In a much-quoted paper published in October 2008, Dr. Heaney and colleagues, from Sloan-Kettering Cancer Research Center and from Columbia University in New York, stated that, at any dose, even as low as 100 mg, Vitamin C antagonizes the effects of antineoplastic drugs, among them Gleevec (imatinib). [M.L. Heaney 2008]
In fact, it is not the antioxidant action of vitamin C which is culprit. The mechanism of action is described as follows: imatinib (and such other anti-cancer drugs as doxorubicin, cisplatin, vincristine, and methotrexate) has a destructive effect on the tumor cells mitochondria, depolarizing their membrane, and that causes apoptosis of the tumor cells. On the other hand, vitamin C offers a protective effect on the mitochondrial membrane, helping the tumor cells to escape death.
Therefore, vitamin C is declared to be good for normal cells, protecting them in different ways, but not for cancer cells. Interestingly, the authors noted that the antioxidant properties of vitamin C were not involved in their observations but only the protective action on mitochondria.
In fact, this was proven in-vitro, i.e. on lab cultured cells, and on mice, and for hematopoietic cancers (lymphomas and leukemias). It remains to be confirmed for other cancers (e.g. GIST and other sarcomas) and more importantly through human testing. Heaney’s claim has been widely commented and relayed in various media. It was also severely criticized, on several grounds: the study used the wrong metabolite of vitamin C, thus biasing the results, and, being based on in-vivo tests, should not supersede other reports having opposite conclusions and based upon human trials [Fluhrer 2008].
Last, Heaney’s thesis was severely criticized [Saul /orthomolecular editorial 2008] on the grounds that mice fabricate their own vitamin C, in very large quantities; also, vitamin C has a dual nature, being both an antioxidant and a pro-oxidant, killing malignant cells. Besides, chemotherapy drugs have also been found to be inactive for many cancer patients and have their own limitations.
What has been proven?
For decades, it has been known that people who eat fruits and vegetables, which are good sources of antioxidants, have less risk of developing heart disease. Some types of fruits and vegetables probably protect against some cancers [WCRF/AICR report, Hardy 2008]. However, even if their action against oxidative stress has been ascertained, direct links between specific antioxidant molecules and lower cancer risk have been mostly identified on the basis of laboratory studies. As will be further stated below, various studies indicate that a mix of substances with antioxidant properties, such as found naturally in food products, have more favorable properties than chemically isolated molecules.
Several wide-scale studies have been launched to find unbiased proof of specific food products benefits. The major randomized trials on antioxidants and cancer risk are listed below [NCI factsheet 2004, WCRF report, Hardy 2008, Albanes 2009].
- The Chinese Cancer Prevention Study, published in 1993, showed that a combination of beta-carotene, vitamin E and selenium significantly reduced both gastric cancer and cancer overall.
- The Alpha-Tocopherol /Beta-Carotene Cancer Prevention Study (ATBC), published in 1994, showed that lung cancer rates of Finnish male smokers increased significantly with beta-carotene and were not affected by vitamin E.
- The Beta-Carotene and Retinol Efficacy Trial (CARET), also published in 1994, established an increased lung cancer risk for the high-risk population taking these antioxidants.
- The Physicians’ Health Study I (PHS), in 1996, found no change in lung cancer rates among U.S. male physicians taking beta-carotene and aspirin.
- The Women’ Health Study (WHS), in 1999, found there was no benefit or harm from beta-carotene supplements among healthy U.S. female health professionals age 45 and older with respect to prevention of cancer and cardiovascular disease [Lee 1999]. In 2005, the extended study reported that there was no overall benefit from vitamin E supplements with respect to incidence of cancer, overall mortality and cardiovascular disease [Lee 2005]. In fact, this was contested [Patterson 1997], on the grounds that vitamin E had a favorable impact on colon cancer and that several supplements had protective effects against several cancers.
- In the context of the Cancer Prevention Study (CPS)-II Nutrition Cohort, sponsored by the American Cancer Society, and based on study of 39,376 women between 1998 and 2001, it was proven [Li 2009] that antioxidants from exogenous sources interact with those from endogenous sources (positive action when the latter are defective) but patient genotype remained the most important risk factor toward breast cancer. Indeed, the patient’s genotype (gene polymorphisms) does modify the individual’s capacity to neutralize ROS by endogenous antioxidants.
- Studies under sponsorship of the Women’s Health Initiative (WHI) on postmenopausal women showed that use of multivitamins had little or no influence on the risk of common cancers (colorectal, gynecological, kidney, bladder, stomach and lung cancers (as well as on cardiovascular disease and on total mortality) [Neuhouser 2009]. From another cohort, it was shown that daily supplementation of calcium plus vitamin D had no influence on occurrence of colorectal cancer [Wactawski 2009].
- The Selenium and Vitamin E Cancer Prevention Trial (SELECT), performed in the U.S., Puerto Rico and Canada, found that healthy men age 50 or older, with a follow-up ranging from 4.2 to 7.3 years, did not benefit from selenium and/or vitamin E supplements with respect to prostate cancer [Lippman 2009].
- The Physicians’ Health Study II (PHS), in their 2009 final report concluding an 8-year observation period, stated that neither vitamin E nor C supplementation reduced the risk of prostate or total cancer; also, no significant effect was found on colorectal, lung, or other site-specific cancers [Gaziano 2009].
Why such contradiction? As expressed in [Laika’sMedLibLog 2009], earlier tests on vitamin E were conducted on smokers and, in more recent trials, people had intense surveillance with early PSA detection and no one, in the placebo group, was under food or vitamins deprivation.
Another set of publications have addressed the benefit of antioxidants for cancer patients. For some time, on the basis of in-vitro and animal studies, antioxidants were thought to decrease the effectiveness of radiotherapy and chemotherapy treatments, on the grounds that, by inhibiting apoptosis, they would protect cancer cells with damaged DNA and neutralize ROS generated by treatments [Zeisel 2004, D’Andrea 2005]. That was contradicted later, on the grounds that human studies proved that antioxidants and other nutrients taken as supplements did not interfere with anti-cancer therapies but rather decreased toxic side effects and increased patients’ survival [Moss 2006, Block 2007, Simone 2007].
As of 2007, an extensive review of published reports was performed [Bjelakovic 2007]. Its main conclusions were that beta carotene, vitamin A and vitamin E supplements were without significant effects on gastrointestinal cancers and were either neutral or increased mortality; vitamin C and selenium had no significant effect on mortality.
It is obvious from the above partial survey that conclusions are generally controversial, yet with time, a shift from favorable to more or less unfavorable influence, the latter applying to synthetic dietary supplements. Unfortunately, for obvious practical reasons, large-scale cohort studies cannot be based on natural foods but on supplements in order to obtain results with statistically meaningful value. And, as already mentioned, statistical analysis always compares people under supplementation with people under healthy western-style diet, all being under close medical scrutiny and therefore diagnosed at an early stage in the event of any cancer occurrence.
The following table summarizes currents recommendations, on basis of most recently published data:
|Foods containing folate|
|Foods containing carotenoids|
|Foods containing beta-carotene|
|Foods containing lycopene|
|Foods containing vitamin C|
|Foods containing selenium|
|Foods containing vitamin E|
|Foods containing vitamin D|
|Retinol (Vit. A)|
|Alpha-tocopherol (Vit E)||Cancer Pts||Nse||Nse||Nse||Nse||Nse||Nse||Nse|
|Ascorbic acid (Vit C)||Nse||Nse||Nse||Nse||Nse||Nse||Nse||Nse|
|Convincing decreased risk||Probable decreased risk||Limited suggestive decreased risk||Limited suggestive increased risk||Probable increased risk||Convincing increased risk||Unlikely Effect||No significant effect|
(*) supplemented with recommendations from [Hardy 2008, Kufe 2003, Gaziano 2009] (**)Other cancers: gallbladder, gynecological, kidney, bladder, & skin.
Scientific reasons for avoiding some dietary supplements
For some time, it had been assumed that all antioxidants had a protective effect on cells, by their scavenging action on free radicals, which cause oxidative stress and may lead to DNA damage [G. D’Andrea 2005]. On the other hand, some chemotherapy drugs do produce free radicals, leading to cancer cell DNA damage. Because they have a clearing action on free radicals, antioxidants would protect cancer cells from dying. Out of precaution, and until clear-cut advantage is proven, it is therefore recommended to avoid taking antioxidant supplements while on cytotoxic chemotherapy or radiotherapy.
As it was pointed out, some supplements may have both advantages and disadvantages, due to their quite complex or multiple modalities of action (for instance being anti-angiogenic, anti-inflammatory, or linked to the immune system).
Few foods products or dietary supplements have been proven to contradict chemotherapy treatments ; yet, there are some, e.g. Saint-John’s Wort reduces plasma levels of drugs metabolized by CYP3A4 enzyme including Gleevec, green tea products are blocking anticancer effects of Velcade (bortezomib), etc. [Hardy 2008, Golden 2009, Kufe 2003].
This survey on antioxidants reminds us that the human body requires exogenous antioxidants, being unable to synthesize all needed substances. Antioxidants absorbed with natural food products are considered as relatively safe but converging clinical trials have shown that dietary supplements brings little or no advantage, some having possible deleterious action (see summary table). This gives significant weight to the old recommendation to refrain from synthetic antioxidants.
Why contradictions? Because natural foods contains high levels of antioxidants, most of which are already supplied in a normal diet. Besides, some like polyphenols have dual actions, namely antioxidant and pro-oxidant activities. Last, it is presumed that many substances have mutual interactions. (See NCI review [Seifried 2003]).
It was also shown earlier in this survey that a given compound may have multiple, and sometimes conflicting, modes of action, one of another being privileged depending on the individual’s cell signaling modes. An illustration of such individuality is that men having certain SNP on their VDR (Vitamin D Receptor) gene have a higher risk of prostate cancer if they are vitamin D depleted [Ahn 2009].
Research remains active in this field, because it crosses understanding of protein signaling in the cell and of processes of tumor genesis and control. The identification of natural products that would be effective for cancer prevention will therefore remain as important as the development of new drugs [Bode 2009].
As treatment options progress, many cancer survivors may live long enough to develop new primary cancer or other chronic disease. Hence, they should be attentive at reducing general risks.
Many oncologists and physicians are rightfully concerned about their cancer patients’ consumption of dietary supplements,
- Because they are not confident of their inocuity
- Because most dietary supplements have not been FDA approved and are obtained by mail order or through diet stores
- Because most patients do not report their use
Frequently repeated recommendations are [Kufe Ch 4 §29, Schwartzberg 2008]:
- For physicians, to keep themselves informed about antioxidants (and other dietary supplements as well) and to refrain from having a blanket negative position about them
- For patients, to maintain careful observance of their anti-cancer medications, to prefer natural food as their main source of antioxidants (especially because of their higher bioavailability and inocuity, being naturally bound to other substances), to discuss the issue with a qualified dietician so as to avoid unfortunate drug interactions and to refrain from taking doses grossly exceeding physiological values. “Let thy food be thy medicine”, as said Hippocrates.
- It is stressed that other dietary or herbal supplements are not addressed in the present review.
- Apoptosis is the process whereby cells are programming their death, for regulation of cell number and elimination of unneeded or aging cells. It involves no inflammation. Defective apoptosis is an important factor in cancer biology.
- A common drug, which is also a precursor in the formation of glutathione in the body.
- Mitochondria are membrane-enclosed objects in cells. They have their own DNA genome and participate in many processes in the cell cycle, cell life, energy generation, etc. They are particularly sensitive to ROS.
- Pro-oxidant would generate ROS and contribute to oxidative system. A substance may have both antioxidant and pro-oxidant actions, depending on physiological conditions.
- Single Nucleotid Polymorphism : a non-pathological gene abnormality, limited to one amino-acid discrepancy.
- e.g. ginger may interfere with blood-thinning medications or aggravate a bleeding disorder.
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