Published in medi.philica.com
Many chemotherapeutic agents, radiation therapy and photodynamic therapy kill cancer cells oxidatively, via the production of reactive oxygen species. These electronically modified oxygen derivatives (EMODs, formerly called oxygen free radicals) play a prominent, if not crucial, role in the induction of apoptotic killing of tumorous cells and pathogens. A long-standing concern with antioxidants is that they could theoretically interfere with the effectiveness of chemotherapy and radiation treatment of cancer. In spite of claims to the contrary, antioxidants can counter the effects of oxygen free radicals and as such, they may protect cells exhibiting metaplasia, dysplasia or neoplasia, allowing them to grow and metastasize. Significant in vitro data exists showing that antioxidants can block EMOD-induced apoptosis for a wide variety of cancerous cell types, such as leukemia, lymphoma, retinoblastoma, myeloma, pheochromocytoma and human cancers of the breast, lung, pancreas, liver, colon, rectum and endometrium. This data can not be ignored. Commonly used antioxidant vitamins, such as vitamins A, C and E, possess antioxidant qualities. It is concluded that extreme caution should be exercised before recommending antioxidant administration to patients with pre-malignant lesions or in patients with known cancerous growths until this issue is definitively scientifically clarified.
In their 1979 book, Cancer and Vitamin C, Linus Pauling and Ewan Cameron speculated that high-dose vitamin C might interfere with chemotherapy by drug detoxification and that cancer patients undergoing aggressive chemotherapy expected to cure cancer might refrain from taking high-dose vitamin C during their course of treatment. Discussions regarding the safe use of antioxidant vitamins in the general population can be lively and many cancer specialists now caution their cancer patients to avoid taking high doses of vitamin or antioxidant supplements. Concerns that antioxidant supplement use could pose a risk for adverse effects, especially in vulnerable cancer patients have previously been raised. 1
Accumulating data is creating a growing uneasiness over the safety of these antioxidants, in that they may be blocking the effectiveness of treatment methods which utilize the generation of tumoricidal oxidizing agents, such as oxygen free radicals (i.e., more correctly referred to as electronically modified oxygen derivatives, EMODs). Opinions vary widely but treatment decisions must be on the side of utmost patient safety when there is doubt or until definitive answers surface.
Antioxidants are taken in the hope and belief that they will improve health and guard against diseases like cancer and heart disease by eliminating so-called "harmful" oxgen free radicals that allegedly cause so-called damaging "oxidative stress." They are also marketed as "anti-aging products" but none of these claims have been scientifically conclusively tested, proven or confirmed.
Profiteers and marketers of antioxidant supplements claim that, "Well-publicized vitamin scares feed the pharmaceutical industry. Successful reports of safe, inexpensive vitamin therapy do not." However, it has been difficult to determine benefits, if any, and the safety of many of these supplements, especially the antioxidant vitamins and more particularly for their use in cancer patients. Even though the word "vitamin" generally connotes health and well being, accumulating scientific data indicates that the antioxidant vitamins can pose significant dangers and potential for harm.
Reactive Oxygen Species (EMOD) Induced Apoptosis
The development of a beneficial or a detrimental cellular response by a nutrient will depend, in part, on the nutrient's antioxidant or prooxidant properties and the cellular oxygen environment. Antioxidant nutrients, such as carotenoids, tocopherols or
ascorbate derivatives, will exhibit an antioxidant or prooxidant characteristic depending on their respective redox potential and the congruent chemistry of the cell. Antioxidants acting as chemopreventives inhibit the continual growth of transformed clones of cells through their prooxidant activity. In contrast, when antioxidant activity occurs in transformed cells an enhanced or prolific growth may result. Therefore, the redox character of each antioxidant must be considered in terms of the extracellular and intracellular EMOD environment. 2
Twice Nobel laureate, Dr. Otto Warburg was the first to implicate ground state oxygen's role in cancer origination and the role of hypoxia in protecting neoplastic cells. 3 Reactive oxygen species appear to be essential as activators of apoptosis to remove or kill cells that have accumulated mutations. 4-6
In short, apoptosis (cellular suicide) is one of the most important means of eliminating precancerous and cancerous cells from the body. 7
Tumoricidal EMODs and Apoptosis
A major goal in cancer therapy and in the management of cancer patients is to reestablish the sensitivity of transformed cells towards apoptotic signals and to allow the execution of apoptotic cell death. 8, 9 In short, treatment aims to selectively kill the cancer cells and protect normal cells. The regulation of EMOD levels appears to be a means to this lofty goal.
Increasingly, EMODs have been found to play a crucial role in intracellular apoptotic execution (suicide). 10-14 Many chemotherapeutic drugs, radiotherapy and photodynamic therapy generate EMODs within treated carcinoma cells and EMODs appear essential for induction of apoptosis of the neoplastic cells. In fact, the chemotherapeutic agents tamoxifen, doxorubicin, mitomycin C, etoposide and cisplatin are superoxide (EMOD) generating agents and induce oxidative stress and apoptosis. 15, 16
Adequate levels of oxygen are needed to effectively generate adequate tumoricidal EMOD levels and to kill a wide range of cancer cell types, while utilizing varying tumoricidal techniques. Tumor hypoxia is another therapeutic limiting factor since it can reduce the effectiveness of radiotherapy, some O2-dependent cytotoxic agents, and photodynamic therapy. 17
The synthetic retinoid fenretinide [N-(4 hydroxyphenyl) retinamide] induces apoptosis of cancer cells and acts synergistically with chemotherapeutic drugs, thus leading to oxidative stress and apoptosis. 18 The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving signaling pathways mediated by free radicals or reactive oxygen species (EMODs). 19
Free radical theory
Harman's free radical theory erroneously speculated that diseases, such as cancer, and aging resulted from the "stochastic" accumulation of oxidative damage purportedly caused by EMODs, from environmental sources and from normal by-products of cellular energy metabolism. 20-24 Subsequently, these alleged damaging derivatives of oxygen, which were termed either oxygen free radicals or "reactive oxygen species (ROS)", were defined as being inherently deleterious and harmful. However, this notion has been discounted. 25
It is overly simplistic and categorically wrong to group EMODs into a unitary oxidative process that affects all cell types and metabolic pathways in a harmful way. Considerable research has shown that guidelines for diet and supplement usage should adhere closely to what has been clinically proved, and by this standard there is no basis to recommend antioxidant use, in the absence of vitamin deficiencies. 26
Antioxidants enter the fray
It was believed that the alleged harmful aspects of EMODs could be prevented or reversed by the use of antioxidants, such as vitamins A, C and E. However, the promises antioxidant vitamins held for the control or even elimination of diseases have come up empty due to the fact that their anticipated benefits were based on the erroneous free radical theory. 27-32
In fact, meta-analyses of randomized controlled trials have not shown that antioxidant supplements reduce cancer incidence. Antioxidant supplements that millions of North Americans take to stave off disease and slow the aging process do not boost longevity and appear to actually increase the risk of dying. Recent randomized, double blind, clinical studies and meta-analyses have shown that the use of antioxidants can increase the risk of cancer, atherosclerosis, strokes and overall mortality. 33-38
Widespread vitamin use
Dietary supplement use has been increasing in the U.S. over the past two decades, with about 50% of the general population reporting regular dietary supplement use in 2001. 39
Despite inconclusive evidence that such use is beneficial, surveys have shown that dietary supplement use is higher among individuals with health concerns, especially those diagnosed with cancer. 40
According to a review of 32 studies conducted between 1999 and 2006 by researchers at Fred Hutchinson Cancer Research Center and published Feb. 1, 2008 in the Journal of Clinical Oncology, investigators found that survivors of breast cancer reported the highest use (75 percent to 87 percent), whereas prostate-cancer survivors reported the least (26 percent to 35 percent). Reportedly, 31 percent to 68 percent of cancer patients and survivors who use supplements do not disclose this information to their doctors or they fail to record it in their charts. Cornelia (Neli) Ulrich, Ph.D., an associate member of the Hutchinson Center's Public Health Sciences Division said, "While supplement use may be beneficial for some patients, such as those who cannot eat a balanced diet, research suggests that certain supplements may actually interfere with treatment or even accelerate cancer growth."
Apoptosis (cellular suicide)
Apoptosis is crucial in the control of the neoplastic process as genetically damaged or mutated cells can be eliminated by apoptosis. 41 Apoptosis, necrosis, and growth arrest can all be regulated by EMOD levels. 42, 43 Apoptosis is largely based on oxygen free radicals released from mitochondria and serves as a precise mechanism used in apoptotic signaling pathways. Thus, EMODs function as significant anti-tumorigenic species. 44, 45
Agents that generate free radicals have repeatedly been shown to kill cancer cells selectively, while frequently sparing normal cells and antioxidants can block this cancer-killing effect and accelerate cancer growth both in vitro and in vivo. 46-49
Arguably, antioxidants have been claimed to prevent cancer in those with no sub-clinical cancer but they may accelerate the growth of hitherto undetected cancers. 50
Therefore, even modest quenching of oxygen radicals by dietary antioxidants could block initiation or completion of apoptosis. Administration of antioxidants subsequent to a mutagenic event may effectively intercept free radicals that are critical in promoting apoptosis. Antioxidants, such as vitamins C and E, act as reducing agents to neutralize free radicals. If a therapeutic agent (radiation, chemotherapy or PDT) works by releasing free radicals (EMODs), it is logical that antioxidants will interfere with its action. Some antioxidants are also strong nucleophiles (e.g., GSH, N-acetyl cysteine, and -lipoic acid), and they may interfere with the anticancer effects of platinum coordination complexes (e.g., cisplatin and carboplatin) and alkylating agents.
Antioxidants blocked cancer cell apoptosis
Many chemotherapy drugs produce free radicals in order to kill cancer cells, and large doses of antioxidant supplements may block cancer cell death via apoptosis. Taking antioxidants may increase tumor resistance to chemotherapy or affect the rate of recurrence or metastasis over time.
Certain cancer cells should be more sensitive to generated reactive oxygen species, and this can serve as a useful tool that can be exploited when trying to kill cancer cells but spare normal cells. Even a moderate increase in the accumulation of oxygen radicals in malignant cells of animals fed an antioxidant-poor diet appears to increase reactive oxygen species to the critical killing level required for progression of apoptosis, as has been shown in animal experiments. 51
Conversely, even modest quenching of oxygen radicals by dietary antioxidants could block initiation or completion of apoptosis as was seen with CT26 (colon) and Hepa 1-6 (liver) tumor cells. The antioxidant, N-acetylcysteine, which decreases H2O2 levels, inhibits mitogen-activated protein kinase and normal cell proliferation but increases tumor cell proliferation as H2O2 concentration drops from the apoptotic toxicity threshold. 52
Hydrogen peroxide has two distinct effects. It initially inhibits the caspases and delays apoptosis. Then, depending on the degree of the initial oxidative stress, the caspases are activated and the cells die by apoptosis, or they remain inactive and necrosis occurs. 53, 54
Hydrogen peroxide has been accused of acting as a "genotoxicant or epigenetic" agent but although H2O2 can cause DNA damage, it is, at best, a very weak mutagen in mammalian cells. 55
Hydrogen peroxide (H2O2) is a moderately strong oxidant that induces apoptosis of tumor cells in vitro. 56 Additionally, N-ß-Alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD) exhibits selective cytotoxicity toward certain human tumor cell lines. 5-S-GAD has been shown to release hydrogen peroxide autonomously. 57
Using human leukemia cells with genetic alterations in mitochondrial DNA and biochemical approaches, it was demonstrated that arsenic-trioxide (As2O3), a clinically active anti-leukemia agent, inhibits mitochondrial respiratory function, increases free radical generation, and enhances the activity of another superoxide (O2.-) generating agent against cultured leukemia cells and primary leukemia cell isolates. 58
Photodynamic therapy (PDT) is a therapeutic approach for the treatment of malignant tumors, which utilizes EMOD generation, especially singlet oxygen. When PDT is combined with hyperoxygenation, the hypoxic condition is improved and the cell killing rate at various time points after PDT is significantly enhanced. 59, 60
The use of hyperbaric oxygen increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, and appears to enhance the efficiency of PDT. 61, 62 Hyperoxygenation may provide effective ways to improve PDT efficiency by oxygenating both preexisting and treatment-induced cell hypoxia. 63
Antioxidants suppress or block EMOD-induced apoptosis
The eight most common malignancies are cancers of lung, breast, colon and rectum, stomach, prostate, liver, cervix, and esophagus, but all cell types are susceptible to neoplastic changes. The complex biochemical process of apoptosis involves caspases (cysteine proteases cleaving after particular aspartate residues), mitochondrial pathways and/or reactive oxygen species (EMODs), which are usually, but not always, key components. 64
Various cancer chemopreventive agents can induce apoptosis in premalignant and malignant cells in vivo and/or in vitro, which serve as an anticancer mechanism. Many of these apoptogenic-inducing agents function as prooxidants in vitro. EMODs and cellular redox tone appear to be uniquely exploitable targets in cancer chemoprevention via the stimulation or induction of cytoprotection in normal cells and/or the induction of apoptosis in transformed neoplastic cells.
The following is a summation of the wide variety of neoplastic cell types which have been protected by various antioxidants, wherein apoptosis was blocked:
-The antioxidant, N-acetylcysteine (NAC), blocked cancer cell kill with human metastatic melanoma with prooxidant Elesclomol (formerly STA-4783). 65
- Salganik's studies showed that depletion of antioxidants decreased tumor size and metastasis with murine retinoblastoma. 51
- The antioxidant, vitamin E, blocked breast cancer cell kill and blocked the killing effect of prooxidant radiation in vitro. The antioxidant, NAC, blocked lymphoma cancer cell kill. 66 Zeisel stated that, "If oxidants produced are being quenched by antioxidants, over-supplementation may actually produce an environment that is beneficial to the tumor and allow it to survive."
- Antioxidants, including vitamin E, C, beta-carotene and catalase, blocked breast cancer cell kill initiated by prooxidant acting tamoxifen. 67, 68
-The antioxidant, NAC, blocked multiple myeloma cancer cell kill with prooxidant acting Arsenic trioxide (As2O3). 69
-The antioxidant, NAC, blocked melanoma cancer cell kill with the prooxidant fumagillin analog, TNP-470. 70, 71
-ROS scavengers (antioxidants) blocked human leukemia cancer cell kill with prooxidant 2-methoxyestradiol (2-ME). 72
- Antioxidants (NAC, catalase, SOD mimetics, and vitamin E) blocked prostate cancer cell kill with prooxidant phenylethyl isothiocyanate (PEITC). 73, 74
- The antioxidants NAC and catalase blocked prostate cancer cell kill with prooxidant acting sulforaphane (SFN). 75, 76
- The antioxidants catalase and SOD mimetics blocked human breast cancer cell kill with prooxidant benzyl isothiocyanate (BITC). 77
- The antioxidants, ROS scavengers or the NAD(P)H oxidase inhibitors, blocked human leukemia cancer cell kill with prooxidant acting cannabidiol. 78
- The antioxidant, metallothionein, blocked human hepatocellular liver carcinoma cell kill with prooxidant acting etoposide. 79
- The antioxidant benzoquinone blocked human colon adenocarcinoma cell kill with prooxidant acting ALA. 80
-Green tea EGCG, acting as a prooxidant apoptotic agent, blocked Burkitt lymphoma, human prostate carcinoma and multiple myeloma cell kill by antioxidants, catalase and superoxide dismutase (Mn SOD). 81-84
- The antioxidants NAC and Trolox (water-soluble vitamin E) blocked chronic lymphocytic leukemia (CLL) lymphocytes and acute myeloid leukemia (AML) blasts killing with prooxidant adaphostin. 85-88
- The antioxidant Tiron blocks human non-small cell lung cancer cell kill with prooxidant acting bortezomib. 89
- The antioxidant NAC blocked human hepatoma cell kill with the prooxidant acting cinnamaldehyde. 90, 91
- The antioxidant resveratrol (which also has prooxidant activity) blocked murine pheochromocytoma cell kill with prooxidant hydrogen peroxide (H2O2). 92
- The antioxidant selenoprotein P blocked human pancreatic cancer cell kill with prooxidant gemcitabine. 93
- The antioxidants vitamin C and tiron blocked human endometrial cancer cell kill with prooxidant bortezomib. 94
- The antioxidant vitamin C (Ascorbic acid) blocked human colon cancer cell kill with prooxidant acting camptothecin and flavone. 95
-The antioxidants, tiron, catalase, SOD and the sulfhydryl antioxidant pyrrolidine dithiocarbamate (PDTC), blocked human colorectal carcinoma cell kill with prooxidant acting flavone. 96
-The antioxidants NAC and catalase blocked human leukemia cells with prooxidant acting Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin. 97, 98
Published data has shown that antioxidants blocked the killing of the following cancer cell types:
- - human metastatic melanoma 65
- - murine retinoblastoma 51
- - human breast cancer 66, 67, 68
- - human lymphoma 66
- - human melanoma 70, 71
- - human leukemia 72, 78, 97, 98
- - human prostate 73, 74, 75, 76
- - human hepatocellular liver carcinoma 79
- - human colon adenocarcinoma 80
- - human multiple myeloma 69, 81-84
- - Burkitt's lymphoma 81-84
- - human chronic lymphocytic leukemia 85-88
- - human acute myeloid leukemia 85-88
- - human non-small cell lung cancer 89
- - human hepatoma 90, 91
- - murine pheochromocytoma 92
- - human pancreatic cancer 93
- - human colon cancer 95
- - human endometrial cancer 94
- - human colorectal carcinoma 96
And finally, as reported on 2-04-09 in the journal Nature, Stanford researcher, Robert Cho, found that breast cancer stem cells make much higher levels of protective antioxidants than other cancer cells. Use of a drug to block the antioxidant, glutathione, caused the cancer stem cells to become far more vulnerable to radiation. Using cells from mice and human breast cancer, the antioxidant glutathione protected the cancer cells from being killed by radiation EMOD-induced apoptosis.
Other important reactions inhibited by antioxidants
Vanden Hoek et al. demonstrated the loss of cardiomyocytes preconditioning protection with antioxidants in cardiomyocytes. 99
Anti-parasitic prooxidant activity can be blocked by antioxidants. Leishmania parasites over expressing peroxiredoxin are protected from hydrogen peroxide-induced programmed cell death (PCD). The physiological role of this peroxiredoxin is stabilization of the mitochondrial membrane potential and, as a consequence, inhibition of PCD through removal of peroxides. 100
Schistosoma mansoni are able to defend themselves against oxygen-mediated killing mechanisms of host because the parasites have developed antioxidant enzyme systems to protect themselves. S. mansoni superoxide dismutase, SOD, glutathione peroxidase (GPX), glutathione reductase (GR), and glutathione-s-transferase (GST), are major antioxidant enzymes that are involved in detoxification and protective processes. 101-108
Onchocerca cervicalis microfilariae (mf) viability was monitored by uptake of the radiolabel, [3H]2-deoxy-D-glucose. Hydrogen peroxide and singlet oxygen, but not superoxide radical or hydroxyl radical, are toxic for mf. Hydrogen peroxide was toxic for mf within 2 h at concentrations as low as 5 microM. Antioxidants can block some of the EMOD species involved in mf killing. 109
The murine malaria parasite Plasmodium yoelii was killed in vitro when incubated with glucose and glucose oxidase, a system generating hydrogen peroxide, or with xanthine and xanthine oxidase, a system which produces the superoxide anion and subsequently other products of the oxidative burst. Catalase blocked the killing in both cases. Hydrogen peroxide appears to be the main reactive oxygen species killing P. yoelii and can be blocked by antioxidants, such as catalase. 110 Thus, anti-malarial therapy can rely on EMODs and deadly malarial parasite can be protected by antioxidants.
Antioxidants mimic the ability of chorionic gonadotropin to suppress apoptosis
Dharmarahan et al. have recently reported that members of the bcl-2 gene family are expressed and estradiol regulated in rabbit luteal cells during corpus luteum (CL) regression, and that estradiol and chorionic gonadotropin (hCG) are effective inhibitors of apoptosis in the rabbit CL in vivo and in vitro. Bcl-2 and related proteins are known to regulate levels of reactive oxygen species or their intermediates in cells as one possible mechanism to control apoptosis. This onset of apoptosis was blocked in a dose-dependent fashion by treatment with SOD, ascorbic acid, N-acetyl-L-cysteine, or catalase. 111
Antioxidant blocked methotrexate-induced apoptosis
The mechanism by which low dose methotrexate (MTX) exerts its anti-inflammatory and immunosuppressive effect in rheumatoid arthritis (RA) patients is still debated. Recently, it has been related to the induction of apoptosis. MTX may most likely induce apoptosis through oxidative stress. The high susceptibility of T cell lines to MTX induced apoptosis may account for the beneficial effect of MTX treatment in rheumatoid arthritis, which is characterized by hyperproliferation of T cells. 112
On the other hand: others support antioxidant use with chemotherapy
Frequently, marketers of dietary supplements and some alternative physicians have made claims that antioxidants can actually kill cancer cells. Some arguments have been presented that antioxidants are beneficial during chemotherapy. It has been theorized that, during chemotherapy, the use of antioxidants may actually help to protect tumor cells as well as healthy cells. A review on the use of antioxidants during chemotherapy, published in Cancer Treatment Reviews, was a collaborative effort led by Dr. Keith Block and researchers from the University of Illinois at Chicago and M.D. Anderson Cancer Center in Houston.
The researchers reviewed articles in the medical literature. Only 33 of 965 articles considered, including 2,446 subjects, met the inclusion criteria. Antioxidants evaluated were: glutathione, melatonin, vitamin A, an antioxidant mixture, N-acetylcysteine, vitamin E, selenium, L-carnitine, Co-Q10 and ellagic acid. Nine studies reported no difference in toxicities between the 2 groups. Only 1 study (vitamin A) reported a significant increase in toxicity in the antioxidant group. This review provides some evidence that antioxidant supplementation during chemotherapy might reduce dose-limiting toxicities but it must be kept in mind that many of these so-called antioxidants have considerable prooxidant activity to which their salutary effects could also be attributed. Larger, well-designed studies of antioxidants impact on PDT, chemotherapy and tumoricidal radiation therapy are warranted. 113 However, until such data is available, considerations for utmost patient safety must prevail.
It is of interest to note the controversial history of vitamin C (ascorbate, ascorbic acid) in the prevention of cancer. One clinical case report showed that vitamin C together with other oxidants, when added adjunctively to first-line chemotherapy, prevented recurrence in two ovarian cancer patients. 114 This high dose, intravenous vitamin C therapy was believed to operate through the generation of hydrogen peroxide. Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation (EMOD generation).
There is the possibility that cell membranes and their associated proteins could contain transition metals accessible to extracellular fluid and could react to generate EMODs. In either case, ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation. It was concluded that ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues. 115, 116
Vitamin C acts as a cosubstrate for hydroxylase and oxygenase enzymes involved in the biosynthesis of procollagen, carnitine, and neurotransmitters. 117 These enzymes produce EMODs and ascorbate acts as a cosubstrate for them and thus, serves as a prooxidant. 118
Nonetheless, a number of authors hold the position that antioxidants do not interfere with chemotherapy or radiation and that at commonly used dosages they actually appear to enhance the success of these treatments. 119-124
However, there appears to be agreement that the antioxidant N-acetylcysteine (NAC), a derivative of the naturally occurring amino acid cysteine, should be avoided by cancer patients because of studies showing interference with chemotherapeutic agents, such as cisplatin and doxorubicin. 125, 126
A 2005 report concluded that cancer patients should avoid antioxidant supplements while receiving chemotherapy or radiation treatment 127 and a Wall Street Journal article argued that antioxidants could block the beneficial effects of standard cancer therapy. 128
Yet, those who defend the use of antioxidants often point to older or prior studies which claim that antioxidants such as vitamin C, vitamin E, coenzyme Q10, glutathione, and selenium can reduce the toxicity of free radicals. 129-133 A 2007 article not only defends the use of antioxidants in cancer patients, it states that, "In 15 human studies, 3,738 patients who took non-prescription antioxidants and other nutrients actually had increased survival." 134 Thus, the debate continues and the opposite position was upheld in a 2008 article in which the Journal of the National Cancer Institute recently published a review of randomized trial data, which suggested that cancer patients should avoid the routine use of antioxidant supplements because they may potentially decrease the efficacy of cancer therapy by protecting the tumor and reducing patient survival. The researchers looked at clinical trials investigating the impact of antioxidants on radiation therapy and found evidence suggesting that antioxidant supplementation reduced overall survival. 135
There is widespread antioxidant availability, extensive antioxidant food advertising, and pervasive promotion of antioxidants in the media. There are valid theoretical reasons to question the use of antioxidants in cancer patients, which emphasizes the need for scientific clarification of this issue. In the interim, patient safety must remain the number one concern.
Significant data exists that electronically modified oxygen derivatives are key agents for the induction of apoptosis or cellular suicide. Apoptosis is widely believed to be essential for controlling and curtailing growth and metastasis of neoplastic cells. Prooxidants are believed to be major contributors in the complex apoptotic process. Thus, antioxidants would logically be expected to block or interfere with EMOD-induced apoptosis in the killing of cancerous cells. In short, antioxidants could be expected to protect tumorous cells from oxidative death. Additionally, antioxidants could interfere with normal cellular metabolic processes and with the killing of pathogens, including parasites. These concerns have been supported by in vitro studies and in the literature, in that antioxidants block the apoptotic killing of a wide variety of human cancer cell types, including leukemia, lymphoma, retinoblastoma, myeloma, pheochromocytoma and human cancers of the breast, lung, pancreas, liver, colon, rectum and endometrium. It is concluded that careful consideration must be given for the use of antioxidants in patients with pre-malignant lesions or in those with established tumorous growths, due to the likelihood that these mutated cells may be protected and perpetuated by antioxidants blocking or attenuating oxygen free radical induced apoptosis. Until scientifically tested, treatment modalities should always place patient safety first. Thus, based on current data and theoretical considerations, the use of antioxidants in cancer patients appear to pose unnecessary dangers and could harbor considerable potential for harm.
Because of the overall weak evidence of benefit and the strong possibility of detrimental effects of antioxidants, caution is recommended with their use in cancer patients undergoing oxidation-related treatments, such as chemotherapy, photodynamic therapy or radiation therapy.
1. Gottlieb N. (1999) Cancer treatment and vitamin C: the debate lingers. J. Natl. Cancer Inst. 24:2073-2075.
2. Schwartz JL. The dual roles of nutrients as antioxidants and prooxidants: Their effect on tumor cell growth. J. Nutr. 126: 1221S-1227S, 1996.
3. Warburg, O. On the origin of cancer cells. Science 1956; 123: 309-314.
4. Tsang WP., Chau SP., Kong SK., Fung KP. and Kwok TT. (2003) Reactive oxygen species mediate doxorubicin induced p53-independent apoptosis. Life Sci., 73, 2047-2058.
5. Liu L, Trimarchi JR., Navarro P, Blasco MA. and Keefe DL. (2003) Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability and apoptosis. J. Biol. Chem., 278, 31998-32004.
6 Djavaheri-Mergny M., Wietzerbin J. and Besancon F. (2003) 2-Methoxyestradiol induces apoptosis in Ewing sarcoma cells through mitochondrial hydrogen peroxide production. Oncogene, 22, 2558-2567.
7. Howes M.D., PhD., R. (2007). Cancer, Apoptosis and Reactive Oxygen Species: A New Paradigm. PHILICA.COM Article number 86.
8. Nicholson DW. (1996) ICE/CED3-like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotechnol., 14, 297-301.
9. Nicholson DW. (1996) From bench to clinic with apoptosis-based therapeutic agents. Nature, 407, 810-816.
10. Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84:131-41.
11. Clement MV, Ponton A, Pervaiz S. Apoptosis induced by hydrogen peroxide is mediated by decreased superoxide anion concentration and reduction of intracellular milieu. FEBS Lett 1998; 440:13-18.
12. Hirpara JL, Clement MV, Pervaiz S. Intracellular acidification triggered by mitochondrial-derived hydrogen peroxide is an effector mechanism for drug-induced apoptosis in tumor cells. J Biol Chem 2001;276:514-521.
13. Simizu S, Umezawa K, Takada M, Arber N, Imoto M. Induction of hydrogen peroxide production and Bax expression by caspase-3(-like) proteases in tyrosine kinase inhibitor-induced apoptosis in human small cell lung carcinoma cells. Exp Cell Res 1998;238:197-203.
14. Mansat-de Mas V, Bezombes C, Quilletary A, et al. Implication of radical oxygen species in ceramide generation, c-Jun N-terminal kinase activation and apoptosis induced by daunorubicin. Mol Pharmacol 1999;56:867-74.
15. Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, Fattorossi A, Isola G, Benedetti Panici P, Mancuso S. Tamoxifen induces oxidative stress and apoptosis in estrogen receptor-negative human cancer cell lines. Br J Cancer 1999;79:257-263.
16. Yokomizo A, Ono M, Nanri H, Makino Y, Ohga T, Wada M, Okamoto T, Yodoi J, Kuwano M, Kohno K. Cellular levels of thioredoxin associated with drug sensitivity to cisplatin, mitomycin C, doxorubicin, and etoposide. Cancer Res 1995;55:4293-4296.
17. Vaupel P and Harrison L. Tumor Hypoxia: Causative Factors, Compensatory Mechanisms, and Cellular Response. Oncologist, November 1, 2004; 9(suppl_5): 4 - 9.
18. Marco Corazzari et al. Fenretinide: A p53-independent way to kill cancer cells. Biochem Biophys Research Comm. Vol. 331 Issue 3. 10 June 2005, Pages 810-815.
19. Penny E. Lovat et al. Mechanisms of free-radical induction in relation to fenretinide-induced apoptosis of neuroblastoma. J. Cell. Biochem. 89: 698-708, 2003.
20. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298-300, 1956.
21. Harman D., 1981. The aging process. Proc. Natl Acad. Sci. USA 78, 7124-7128.
22. Beckman K.B., Ames, B.N., 1998. The free radical theory of aging matures. Physiol. Rev. 78, 547-581.
23. Finkel T, Holbrook N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239-247.
24. Harman D. 1961. Mutation, cancer and aging. Lancet 1: 200-201,
25. Howes R.M. The Free Radical Fantasy: A Panoply of Paradoxes. Ann. N. Y. Acad. Sci. 2006;1067:22-26.
26. Williams KJ. and Fisher EA. Oxidation, lipoproteins, and atherosclerosis: which is wrong, the antioxidants or the theory? Current Opinion in Clinical Nutrition & Metabolic Care. 8(2):139-146, March 2005.
27. Howes M.D., PhD., R. (2007). The Consequent Downfall of the Free Radical Theory. PHILICA.COM Article number 75. (accessed 28 November, 2008).
28. Howes, RM. © 2004. U.T.O.P.I.A. - Unified Theory of Oxygen Participation in Aerobiosis. Free Radical Publishing Co. Kentwood, LA. www.thepundit.com. (accessed 28 November, 2008).
29 Howes RM. © 2005. The Medical and Scientific Significance of Oxygen Free Radical Metabolism. Free Radical Publishing Co. Kentwood, LA. www.thepundit.com. (accessed 28 November, 2008).
30. Howes RM. Hydrogen Peroxide Monograph 1: Scientific, Medical and Biochemical Overview & Monograph 2: Antioxidant Vitamins A, C, & E: Equivocal Scientific Studies, © 2006. Free Radical Publishing Co. Kentwood, LA. www.thepundit.com. (accessed 28 November, 2008).
31. Howes RM. Cardiovascular Disease and Oxygen Free Radical Mythology. © 2006. Free Radical Publishing Co. Kentwood, LA. www.thepundit.com. (accessed 28 November, 2008).
32. Howes RM. Diabetes and Oxygen Free Radical Sophistry. © 2006. Free Radical Publishing Co. Kentwood, LA. www.thepundit.com. (accessed 28 November, 2008).
33. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev (2004) (4):CD004183.
34. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet (2004) 364:1219-28.
35. Caraballoso M, Sacristan M, Serra C, Bonfill X. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev (2003) (2):CD002141.
36. Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Aliment Pharmacol Ther (2006) 24:281-91.
37. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, and Gluud C. "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention; Systematic Review and Meta-analysis." JAMA 2007;297:842-857. Vol. 297 No. 8, February 28, 2007.
38. Miller ER III, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46.
39. Blendon RJ, DesRoches CM, Benson JM., Brodie M. & Altman DE. (2001) Americans' views on the use and regulation of dietary supplements. Arch. Intern. Med. 161:805-810.
40. Rock CL. Supplement: Free Radicals: The Pros and Cons of Antioxidants. Antioxidant Supplement Use in Cancer Survivors and the General Population. The American Society for Nutritional Sciences J. Nutr. 134:3194S-3195S, November 2004.
41. White MK. and McCubrey JA. (2001) Suppression of apoptosis: role in cell growth and neoplasia. Leukemia, 15, 1011-10121.
42. Aw TY., 1999. Molecular and cellular responses to oxidative stress and changes in oxidation-reduction imbalance in the intestine. Am. J. Clin. Nutr. 70, 557-565.
43. Kwon YW, Masutani H., Nakamura H, Ishii Y, Yodoi J, 2003. Redox regulation of cell growth and cell death. Biol. Chem. 384, 991-996.
44. Duranteau J, Chandel NS, Kulisz A, Shao Z, Schumacker PT\, 1998. Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J. Biol. Chem. 273, 11619-11624.
45. Valko M, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. Epub 2006 Aug 4.
46. Begin ME, Ells G, Horrobin DF. Polyunsaturated fatty acid induced cytotoxicity against tumor cells and its relationship to lipid peroxidation. J Natl Cancer Inst 1988;80:188-94.
47. Begin ME. Effects of polyunsaturated fatty acids and of their oxidation products on cell survival. Chem Phys Lipids 1987;45:269-313.
48. Das UN, Begin ME, Ells G, Huang YS, Horrobin DF. Polyunsaturated fatty acids augment free radical generation in tumor cells in vitro. Biochem Biophys Res Commun 1987;145:15-24.
49. Lhuillery C, Cognault S, Germain E, Jourdan ML, Bougnoux P. Suppression of the promoter effect of polyunsaturated fatty acids by the absence of dietary vitamin E in experimental mammary carcinoma. Cancer Lett 1997;114:233-4.
50. Horrobin DF. The paradox of antioxidants and cancer. American Journal of Clinical Nutrition, Vol. 74, No. 4, 555, October 2001.
51. Salganik RI., Albright CD, Rodgers J, Kim J, Zeisel SH., Sivashinskiy MS. & Van Dyke TA. (2000) Dietary antioxidant depletion: enhancement of tumor apoptosis and inhibition of brain tumor growth in transgenic mice. Carcinogenesis 21: 909-914.
52. Laurent A, et al. Controlling Tumor Growth by Modulating Endogenous Production of Reactive Oxygen Species. Cancer Research 65, 948-956, February 1, 2005.
53. Hampton MB and Orrenius S. Dual regulation of caspase activity by hydrogen peroxide: implications for apoptosis. FEBS Lett (1997) 414: 552-6.
54. Davies KJ. The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. IUBMB Life. 1999 Jul; 48(1):41-7.
55. Takeuchi T, Matsugo S and Morimoto K. (1997) Mutagenicity of oxidative DNA damage in Chinese hamster V79 cells. Carcinogenesis, 18, 2051-2055.
56. Fang J, Sawa T, Akaike T and Maeda H. Tumor-targeted Delivery of Polyethylene Glycol-conjugated D-Amino Acid Oxidase for Antitumor Therapy via Enzymatic Generation of Hydrogen Peroxide. Cancer Research 62, 3138-3143, June 1, 2002.
57. Nishikawa T, Nishikawa S, Akiyama N and Natori S. Correlation between the Catalase Level in Tumor Cells and Their Sensitivity to N-ß-Alanyl-5-S-Glutathionyl-3,4-Dihydroxyphenylalanine (5-S-GAD). J. Biochem, 2004, Vol. 135, No. 4 465-469.
58. Pelicano H, et al. Inhibition of Mitochondrial Respiration. A Novel Strategy to Enhance Drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem., Vol. 278, Issue 39, 37832-37839.
59. Al-Waili, NS and Butler, GJ. Phototherapy and malignancy: Possible enhancement by iron administration and hyperbaric oxygen. Med Hypotheses. 2006;67(5):1148-58.
60. Tomaselli F, et al. Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis. Eur J Cardiothorac Surg. 2001 May;19(5):549-54.
61. Tomaselli F, et al. Acute effects of combined photodynamic therapy and hyperbaric oxygenation in lung cancer. Lasers Surg Med. 2001;28(5):399-403.
62. Maier A et al. Combined photodynamic therapy and hyperbaric oxygenation in carcinoma of the esophagus and the esophago-gastric junction. Eur J Cardiothorac Surg. 2000 Dec;18(6):649-54,
63. Chen Q, et al. Improvement of tumor response by manipulation of tumor oxygenation during photodynamic therapy. Photochem Photobiol. 2002 Aug;76(2):197-203.
64. Fiers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene (1999) 18: 7719-30.
65. Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang C-Y, Zhang M, Du Z, Barsoum J and Bertin J. Elesclomol [STA-4783] induces cancer cell apoptosis through oxidative stress. Molecular Cancer Therapeutics 7, 2319-2327, August 1, 2008.
66. FREE RADICALS: THE PROS AND CONS OF ANTIOXIDANTS. Division of Cancer Prevention National Cancer Institute. Division of Cancer Treatment and Diagnosis, National Cancer Institute. National Cancer Institute. National Center for Complementary and Alternative Medicine National Institutes of Health. Office of Dietary Supplements National Institutes of Health. (at http://www.nutrition.org/, References to the published, final version of this manuscript should include the following citation: J. Nutr. 134:3143S-3163S, 2004.
67. Gundimeda U, Chen Z-H and Gopalakrishna R. Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells. J. Biol. Chem. Volume 271, Number 23, Issue of June 7, 1996 pp. 13504-13514.
68. Peralta EA, Viegas ML, Louis S, Engle DL and Dunnington GL. Effect of vitamin E on tamoxifen-treated breast cancer cells. Surgery. Volume 140, Issue 4, October 2006, Pages 607-615.
69. Grad JM, Bahlis NJ, Reis I, Oshiro MM, Dalton WS, Boise LH. Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. Blood (2001) 98: 805-13.
70. Marcin O, Wojciech W, Ewa S, Andrzej M, Jacek B. A novel mechanism of action of the fumagillin analog, TNP-470, in the B16F10 murine melanoma cell line. Anti-Cancer Drugs. 16(8):817-823, September 2005.
71. Okrój M, Stawikowska D, S?omi?ska EM, Mysliwski A, Bigda J. The atypical pattern of cell death in B16F10 melanoma cells treated with TNP-470. Cell Mol Biol Lett. 2006;11(3):384-95.
72. Hileman EO, Liu J, Albitar M, Keating MJ, Huang P. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol. 2004 Mar;53(3):209-19.
73. Xiao D, et al. Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential. Carcinogenesis 2006 27(11):2223-2234.
74. Wu SJ, et al. Effects of antioxidants and caspase-3 inhibitor on the phenylethyl isothiocyanate-induced apoptotic signaling pathways in human PLC/PRF/5 cells. Eur J Pharmacol. 2005 Aug 22;518(2-3):96-106.
75. Singh SV, et al. Sulforaphane-induced Cell Death in Human Prostate Cancer Cells Is Initiated by Reactive Oxygen Species. J. Biol. Chem., Vol. 280, Issue 20, 19911-19924, May 20, 2005.
76. Cho SD, et al. Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. Nutr Cancer. 2005;52(2):213-24.
77. Xiao D, et al. Benzyl isothiocyanate-induced apoptosis in human breast cancer cells is initiated by reactive oxygen species and regulated by Bax and Bak. Mol Cancer Ther. 2006;5:2931-2945.
78. McKallip RJ, et al. Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22phox and Nox4 Expression. Mol Pharmacol 70:897-908, 2006.
79. Shimoda R, et al. Human hepatocellular liver carcinoma), 24 h pretreatment with cadmium resulted in concentration-dependent increases in MT levels and marked decreases in etoposide-induced apoptosis. (Metallothionein Is a Potential Negative Regulator of Apoptosis. Toxicological Sciences 73, 294-300 (2003).
80. Wenzel U, Nickel A and Daniel H. α-lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-.-generation. Apoptosis. Volume 10, Number 2 / March, 2005. pp. 359-368.
81. Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881-6.
82. Gupta S, Ahmad N, Nieminen AL, Mulhtar H. Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells. Toxicol Appl Pharmacol 2000;164:82-90.
83. Nakazato T, Ito K, Kizaki YI and M. Green Tea Component, Catechin, Induces Apoptosis of Human Malignant B Cells via Production of Reactive Oxygen Species. Clinical Cancer Research Vol. 11, 6040-6049, August 15, 2005.
84. Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881-6.
85. Kay NE. ROS: double-edged sword for leukemic cells. Blood, 15 March 2006, Vol. 107, No. 6, pp. 2212-2213.
86. Chandra J, Hackbarth J, Le S, et al. Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells. Blood. 2003;102: 4512-4519.
87. Shanafelt TD, Lee YK, Bone ND, et al. Adaphostin-induced apoptosis in CLL B cells is associated with induction of oxidative stress and exhibits synergy with fludarabine. Blood. 2005;105: 2099-2106.
88. Mow BM, Chandra J, Svingen PA, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro. Blood. 2002;99: 664-671.
89. Ling Y-H, Liebes L, Zou Y and Perez-Soler R. Reactive Oxygen Species Generation and Mitochondrial Dysfunction in the Apoptotic Response to Bortezomib, a Novel Proteasome Inhibitor, in Human H460 Non-small Cell Lung Cancer Cells. J. Biol. Chem., Vol. 278, Issue 36, 33714-33723, September 5, 2003.
90. Wu SJ, et al. Effects of vitamin E on the cinnamaldehyde-induced apoptotic mechanism in human PLC/PRF/5 cells. Clin Exp Pharmacol Physiol. 2004 Nov;31(11):770-6.
91. Wu. S-J, Ng L-T and Lin C-C. Effects of vitamin E on the cinnamaldehyde-induced apoptotic mechanism in human PLC/PRF/5 cells. Clinical and Experimental Pharmacology and Physiology, Volume 31, Number 11, November 2004 , pp. 770-776(7).
92. Jang JH, Surh YJ. Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutat Res (2001) 496: 181-90.
93. Maehara S, et al. Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells. Int J Cancer. 2004 Nov 1;112(2):184-9.
94. Llobet D, et al. Antioxidants block proteasome inhibitor function in endometrial carcinoma cells. Anti-Cancer Drugs. 19(2):115-124, February 2008.
95. Wenzel U, Nickel A, Kuntz S and Daniel H. Ascorbic acid suppresses drug-induced apoptosis in human colon cancer cells by scavenging mitochondrial superoxide anions. Carcinogenesis, Vol. 25, No. 5, 703-712, May 2004.
96. Chen YC, et al. Flavone inhibition of tumor growth via apoptosis in vitro and in vivo. Int J Oncol. 2004 Sep;25(3):661-70.
97. Hou D-X, Tong X, Terahara N, Luo D, Fujii M. Delphinidin 3-sambubioside (Dp3-Sam), a Hibiscus anthocyanin, induces apoptosis in human leukemia cells through reactive oxygen species-mediated mitochondrial pathway. Arch-Biochem-Biophys. 2005 Aug 1; 440(1): 101-9.
98. Feng R., Ni H., Wang S. Y., Tourkova I. L., Shurin M. R., Harada H. and Yin X. Cyanidin-3-rutinoside, a Natural Polyphenol Antioxidant, Selectively Kills Leukemic Cells by Induction of Oxidative Stress. The Journal of Biological Chemistry. 2007; 282(18): 13468-13476.
99. Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 2000;86:534-40.
100. Harder S, Bente M, Isermann K, and Bruchhaus I. Expression of a Mitochondrial Peroxiredoxin Prevents Programmed Cell Death in Leishmania donovani. Eukaryotic Cell, May 2006, p. 861-870, Vol. 5, No. 5.
101. Callahan HL, Crouch RK, James ER 1988. Helminth antioxidant enzymes: A protective mechanism against host oxidants? Parasitol Today 4: 218-225.
102. Mkoji GM, Smith JM, Prichard RK 1988a. Antioxidant systems in Schistosoma mansoni. Correlation between susceptibility to oxidant killing and the levels of scavengers of hydrogen peroxide and oxygen free radicals. Int J Parasitol. 18: 661-666.
103. Mkoji GM, Smith JM, Prichard RK 1988b. Antioxidant systems in Schistosoma mansoni: Evidence for their role in protection of the adult worms against oxidant killing. Int J Parasitol 18: 667-673.
104. Nare B, Smith JM, Prichard RK 1990. Schistosoma mansoni: levels of antioxidants and resistance to oxidants increase during development. Exp Parasitol 70: 389-397.
105. O'Leary KA, Tracy JW 1991. Schistosoma mansoni: glutathione S-transferase-catalyzed detoxication of dichlorvos. Exp Parasitol 72: 355-361.
106. O'Leary KA, Hathaway KM, Tracy JW 1992. Schistosoma mansoni: Single-step purification and characterization of gutathione 5-transferase isoenzyme 4. Exp Parasitol 75:47-55.
107. James ER 1994. Superoxide dismutase. Parasitol Today 10:481-484.
108. Mei H, LoVerde PT 1995. Schistosoma mansoni: cloning the gene encoding glutathione peroxidase. Exp Parasitol 80:319-322.
109. Callahan HL, et al. Hydrogen peroxide is the most toxic oxygen species for Onchocerca cervicalis microfilariae. Parasitology. 1990 Jun;100 Pt 3:407-15.
110. Dockrek HM. and Playfair JH. Killing of Plasmodium yoelii by enzyme-induced products of the oxidative burst. Infect Immun. 1984 Feb;43(2):451-6.
111. Dharmarahan AM, et al. Antioxidants mimic the ability of chorionic gonadotropin to suppress apoptosis in the rabbit corpus luteum in vitro: a novel role for superoxide dismutase in regulating bax expression. Endocrinology. 1999 Jun;140(6):2555-61.
112. Herman S, Zurgil N and Deutsch M. Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflammation Research. Volume 54, Number 7 / July, 2005. pages 273-280.
113. Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials. International journal of cancer. Journal international du cancer 2008;123(6):1227-39.
114. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr 2003;22:118-23.
115. Buettner GR. & Jurkiewicz BA. (1996) Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat. Res. 145, 532-541.
116. Halliwell B. (1990) "How to characterize a biological antioxidant", Free Radical Res. Commun. 9, 1-32.
117. Levine M. (1986) New concepts in the biology and biochemistry of ascorbic acid. New Engl. J. Med. 314,892-902.
118. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, and Levine L. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. PNAS. September 20, 2005. Vol. 102. No. 38. pp. 13604-13609.
119. Kagreud A, Peterson HI. Tocopherol in irradiation of experimental neoplasms. Acta Radiol Oncol 1981;20:97-100.
120. Perez Ripoll EA, Rama BN, Webber MM. Vitamin E enhances the chemotherapeutic effects of adriamycin on human prostatic carcinoma cells in vitro. J Urol 1986;136:529-531.
121. Jaakkola K, Lahteenmaki P, Laakso J, et al. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 1992;12:599-606.
122. Prasad KN, Kumar A, Kochupillai V, Cole WC. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr 1999;18(1):13-25.
123. Lamson DW, Brignall MS. Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev 1999;4(5):304-29.
124. Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther. 2006 Mar;5(1):63-82.
125. Olson RD, Stroo WE, Boerth RC. Influence of N-acetylcysteine on the antitumor activity of doxorubicin. Semin Oncol 1983;10:S29-S34.
126. Roller A, Weller M. Antioxidants specifically inhibit cisplatin cytotoxicity of human malignant glioma cells. Anticancer Res 1998;18:4493-4497.
127. D'Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA 2005;55:319-21.
128. Parker-Pope T. Cancer and Vitamins: Patients Urged to Avoid Supplements During Treatment; The Wall Street Journal 2005 Sep 20 Sect. D:1.
129. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 1997;23:209-40.
130. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 1997;23:209-40.
131. Judy WV, Hall JH, Dugan W, et al. Coenzyme Q10 reduction of adriamycin cardiotoxicity. In: Folkers K, Yamamura Y, eds. Biomedical and Clinical Aspects of Coenzyme Q, Vol. 4, Elsevier, 1984:231-41.
132. Sieja K, Talerczyk M. Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy. Gynecol Oncol 2004;93:320-27.
133. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol 1995;13:26-32.
134. Simone CB 2nd, Simone NL, Simone V, Simone CB. Antioxidants and other nutrients do not interfere with radiation or chemotherapy. Altern Ther Health Med. 2007 Mar-Apr;13(2):40-7.
135. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg J. 2008. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy?. Journal of the National Cancer Institute. May 27, 2008. 100(11)773-783.
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Originality = 50.00, importance = 25.00, overall quality = 100.00
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The full citation for this Article is:|
Howes M.D., PhD., R. (2009). Dangers of Antioxidants in Cancer Patients: A Review. PHILICA.COM Article number 153.
1 Peer review [reviewer #47336] added 20th August, 2011 at 19:10:22
Although the main proposal or working hypothesis of this review seems warranted, one really needs to take into account the key/important question of dose dependence effects of antioxidants in cancer patients at various stages. This otherwise well-documented review has not however adequately addressed this most important, anti-oxidant dose aspect of the problem reported here, thus failing to provide a useful practical guide for either further research in cancer, or for the clinical physician who treats patients at various stages of cancer.
Moreover, technical aspects related to the deployment of novel techniques and methodology for cancer detection and cancer treatment monitoring are also inadequately addressed in this preprint. The effects of antioxidants on cancer treatments with signaling medicines for stage III cancer patients is another major topic inadequately addressed in this review. Last-but-not-least, several refs. cited, such as Nos. 118, 122, 131, 134, etc. , do not appear to support either the abstract presented or the conclusions drawn by the reviewer.
Originality: 2, Importance: 1, Overall quality: 4