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Apoptosis or cellular suicide is one of the most important means of eliminating precancerous and cancerous cells from the body. Cellular apoptotic execution is usually modulated by levels of electronically modified oxygen derivatives serving as the effector stimulus initiating subsequent cellular death. Studies have shown that antioxidants can block apoptosis in many tumorous or neoplastic cell types. Caution should be exercised to prevent creating insufficient electronically modified oxygen derivative (EMOD) levels and to avoid the injudicious use of antioxidants, especially in subjects with compromised immunity or with cancerous or precancerous conditions. Allowance of cellular proliferation may represent an EMOD insufficiency state and an EMOD insufficiency syndrome may explain clustering of common diseases, such as cancer, atherosclerosis, diabetes and obesity. In short, sufficient prooxidant levels can induce cancer cell apoptosis, which can be blocked or nullified by certain antioxidants.
An accumulating body of evidence favors the involvement of intracellular reactive oxygen species at some point during apoptotic execution. 1-5
The critical role of cellular redox status in the regulation of death signaling has been demonstrated. 6-9 Investigators have shown that intracellular increase in H2O2 was a critical effector mechanism during drug-induced apoptosis of human tumor cells. 4 This increase in H2O2 was responsible for early cytosolic acidification, thus creating an environment conducive for caspase activation.
Most of the past studies seem to imply that the mitochondrial burst of H2O2 is likely to be a downstream effector mechanism for the execution signal. Hydrogen peroxide (H2O2) is considered to be a mediator of most forms of apoptotic cell death. 5
Many investigators have demonstrated the critical role of intracellular H2O2 in rendering the cytosolic milieu permissive for efficient apoptotic execution. 4, 5, 10 I believe that this strongly indicates that H2O2 is one of the essential agents for cellular killing.
Tumor cell hypoxia
Otto Warburg was the first scientist to implicate ground state oxygen in cancer, 11 although he was later derided for it. It appears that EMODs, not ground state oxygen, are primary effectors for modulation of cellular apoptosis.
A pro-oxidant intracellular milieu is an invariable finding in cancer cells and has been shown to endow cancer cells with a survival advantage over their normal counterparts. 12, 13 However, I believe that it is this very feature which allows us to have selectivity for cancer cell killing.
Most human tumors develop regions of chronically or transiently hypoxic cells during growth. 14 Clinical studies have shown that metastatic spread is associated with hypoxia in the primary tumor. 15, 16
Hypoxia (oxygen tension [pO2] value 10 mmHg) is associated with lower overall and disease-free survival, greater recurrence, and less locoregional control in head and neck carcinoma, cervical carcinoma and soft-tissue sarcoma. Tumor hypoxia is associated with adverse clinical outcomes and reduced patient survival. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of radiotherapy, some O2-dependent cytotoxic agents, and photodynamic therapy. 17
Both radiotherapy and photodynamic therapy generate electronically modified oxygen derivatives (EMODs) within treated carcinoma cells and they are felt to be essential for induction of apoptosis of the neoplastic cells. At least 127 genes and signal transducing proteins have been reported to be sensitive to reductive and oxidative (redox) states in the cell. 18
Evidence from both animal and human studies indicates that exercise may reduce the risk of breast cancer. Among eleven human studies that took into account many of the established risk factors for breast cancer, eight reported a decrease in the risk of breast cancer in pre-menopausal, post-menopausal or all women with high levels of physical activity compared to women with low levels of activity. 19 With exercise, there is a consequent increase in oxygen consumption of up to 10 to 15 fold and a concomitant increase in EMOD production.
The chemotherapeutic agents doxorubicin, mitomycin C, etoposide and cisplatin are superoxide generating agents 20. The anti-estrogen tamoxifen, increasingly used alongside other breast cancer therapies, has also been shown to induce oxidative stress and increased apoptotic-inducing EMOD levels within carcinoma cells in vitro. 21
Testosterone deficiency, through castration, increases EMODs and this is the best treatment for prostate cancer, which has resulted in cases of long term total remission of the cancer. Administration of testosterone to the castrated group resulted in decreases in EMODs, which would "allow" for continued growth of prostate cancer. Additionally, antioxidant enzymes are restored by testosterone administration, which would result in a further deficiency state of EMODs and a more favorable environment for cancer survival and growth. 22
When normal androgenic status is disrupted, such as under the condition of castration-induced deprivation, EMODs are increased in the prostate via up-regulation of Nox-dependent EMOD anabolism and down-regulation of a number of key antioxidant enzyme EMOD scavengers. All of these factors help to increase EMODs, which will aid in controlling neoplastic growth, and thus, it has been found that castration is the best treatment for prostatic cancer. This data strongly supports my Unified theory, which states that EMODs are normally of low toxicity and are essential secondary cellular messengers.
This data may relate to the results from the Finasteride Prostate Cancer Prevention Trial, which demonstrated that androgen-blockade at the cellular level lowers prostate cancer risk but increases the prevalence of high-grade cancers. 23
Many human cancer cells overproduce hydrogen peroxide. High levels (up to 0.5 nmol/hr/104 cells) of hydrogen peroxide are constitutively released from a wide range of human tumor cells. I believe that this makes the tumor cell more vulnerable to increases in EMODs and creates selectivity for PDT and cancer therapy. In other words, adding a specified amount of EMODs to neoplastic and normal cells can induce apoptosis in a cancer cell and not do so in a normal cell. This establishes a unique therapeutic site for selectivity in the killing of tumorous cells, without doing harm to normal cells.
On September 12, 2005, Mark Levine's group published online for PNAS results showing that, "Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues." 24
Dehydroascorbic acid (DHA) may be the key to vitamin C therapy. Dr. Benade et al. at the National Cancer Institute found that in cultures vitamin C selectively destroyed cancer cells by generating excess intracellular H2O2. 25 Ascorbic acid and ascorbic acid salts are preferentially toxic to tumor cells, which are thought to be related to intracellular generation of hydrogen peroxide. 26, 27
I believe that the cancer cells have higher levels of EMODs, due to low levels of antioxidants and antioxidant enzymes, and it therefore takes a smaller amount of additional EMODs to reach apoptotic levels than for normal cells to reach apoptotic levels. This may be the trigger point of selectivity for toxicity to cancer cells without harming normal cells.
Myeloperoxidase (MPO) deficiency
EMOD insufficiency levels appear to be related to increased risk of neoplasia.
Myeloperoxidase is a heme-containing enzyme that catalyzes the reaction between hydrogen peroxide and chloride ions, producing hypochlorite or hypochlorous acid (HOCl), a potent oxidation agent. 28 Evidence from a number of investigators indicates that individuals with total MPO deficiency show a high incidence of malignant tumors. 29
There appears to be a high incidence of malignancy in patients with complete MPO deficiency, suggesting a relationship between a defective MPO system and neutrophil-mediated tumor cell cytotoxicity. 30 Patients with cancer of the larynx show a deficiency of neutrophil myeloperoxidase. Activity of myeloperoxidase in neutrophils from patients with gastric carcinoma is slightly elevated. 31
Decreased MPO activity in PMN from acute myeloid leukemia (AML) patients may contribute to the increased susceptibility to infections and that in the pre-remission phase of the disease it may account for approximately 15% of the infections. 32
A complete lack of myeloperoxidase (MPO) was demonstrated in a boy suffering from acute myeloid leukemia during the acute phase of the disease and after a remission was achieved. This indicates a possible connection between MPO deficiency and leukemia. 33 Also, mice deficient in myeloperoxidase have somewhat increased atherosclerosis. 34 I believe that this follows the pattern of disease clustering in the EMOD insufficiency syndrome.
EMOD insufficiency levels, secondary to antioxidants, also appear to be related to increased risk of neoplasia.
A study on human gliomas cells demonstrated that overexpression of CuZnSOD can inhibit tumor cell growth. 35 Again, H2O2 may be generated to sufficiently high levels such that it demonstrates antineoplastic properties, in accordance with my Unified theory. To the contrary, in tumor cells, the activity of CuZnSOD is usually low. 36
Catalase deficiency in humans was first documented by Dr. Takahara in 1946. 37 Japanese acatalasemic patients are phenotypically normal with the exception of an increased tendency in development of progressive oral gangrene, presumably as a result of tissue damage from H2O2 produced by peroxide-generating bacteria such as streptococci and pneumococci as well as by the phagocytic cells at the sites of bacterial infection. 38
Mice null for the Gpx1 and Gpx2 genes appear normal under normal housing conditions, although they tend to be more sensitive to oxidative stress. More recently, knockout mice for catalase were generated, and these mice null for catalase appear normal as well. 39 Animals null for CAT and Gpx1 and Gpx2 develop normally. 40 This argues strongly for the low toxicity of EMODs, which is an integral part of my Unified Theory (available at www.thepundit.com). 43, 44
I believe that it is of utmost importance to consider the fact that animals null for CAT and Gpx1 and Gpx2 appear to develop normally and live normal lives. This must weaken the argument that EMODs are extremely toxic and causative of up to 100 pathophysiologies.
The results show that (1) the increased liver antioxidant capacity of CAT and Gpx in male mice might be a sign of oxidative stress; (2) the increase in CAT and Gpx activities in male mice is strongly correlated with incidence of hepatic tumors; (3) the significantly increased SOD activity in tumor-bearing mice might have induced damage with accumulated hydrogen peroxide. 41
The free radical theory
Denham Harman 42 proposed in 1956 the "free radical theory," speculating that damage to aerobic organisms occurs due to harmful free radical production of oxidative products. Subsequently, these alleged damaging derivatives of oxygen, which were termed either oxygen free radicals or "reactive oxygen species (ROS)", were defined as being deleterious and harmful. For greater accuracy, I will use the term "electronically modified oxygen derivatives (EMODs)" to replace the less accurate term of reactive oxygen species.
Unfortunately, the overly optimistic predictions based on the free radical theory have repeatedly failed to scientifically support the free radical theory. 43-47 The Harvard School of Public Health web site summed it up this way, "The evidence accumulated thus far on antioxidant vitamins isn't promising. Randomized trials of vitamin C, vitamin E, and beta-carotene haven't revealed much in the way of protection from heart disease, cancer, or aging-related eye diseases (website accessed 2/09/06). I present in great detail the essential task of EMODs for the normal functioning of aerobic cells and their crucial role as secondary cellular messengers in my e-books, 43-47 which are available in "The Howes Selective World Library of Oxygen Metabolism at www.thepundit.com.
The free radical theory erroneously stated that diseases and the aging process resulted from the "stochastic" accumulation of oxidative damage purportedly caused by EMODs, from sources such as the environment and from normal by-products of cellular metabolism. 48-50 Contrary to the free radical theory of aging, which argues that EMODs are uncontrolled, EMODs are under strict metabolic control. There is a compartmentalization of oxidative events, which strongly suggests EMODs' crucial role influencing and modulating physiological stimuli, signaling mechanisms, and functional homeostasis. 51, 52
Tests of effect of vitamin E and other antioxidant vitamins or their combinations on clinical manifestations of cardiovascular disease, cancer and diabetes, have consistently shown that commonly used antioxidant vitamin regimens (vitamins E, C, beta carotene, or a combination thereof) do not significantly reduce overall cardiovascular events, diabetes or cancer in studies such as HOPE, 53 GISSI, 54 ATBC, 55 Hennekens study, 56 Omenn's study, 57 Brown's study, 58 MRC/BHF, 59 Vivekananthan's meta-study, 60 Miller's meta-study. 61 Antioxidants actually appear to cause harm and in some studies they may increase overall mortality, which is discussed in a 2005 nutrition and supplement review in JAMA. 62 Yet, one should keep in mind the fact that certain vitamin supplements may be beneficial for some people, such as those with a deficiency state, pregnant women, women of childbearing age, and people with restricted dietary intakes.
Apoptosis is a form of cell death necessary to make way for new cells and to remove cells in which the DNA has been damaged to the point of cancerous change. Thus, it is believed that one of the most important functions of apoptosis is the elimination of preneoplastic and neoplastic cells. 63 In most forms of cellular suicide, the signaling cascade requires EMODs as essential intermediate messenger molecules. 64
Inhibition of apoptosis by antioxidants may explain why, in several studies in heavy smokers, vitamin E and β-carotene enhanced carcinogenesis in the lung. 65 Increased formation of EMODs also accompanies apoptosis induced by most, if not all, other stimuli, 66 and free radical scavengers often nearly always delay such apoptosis. 67-76
Davies 77 has shown that cellular division or cell death is EMOD concentration dependent, when utilizing the EMOD, H2O2. Cellular responses go from proliferation, to arrest, to apoptosis.
The primary means that the human body has to rid itself of precancerous and cancerous cells is by electronically modified oxygen derivative-induced apoptosis. This crucial process can be blocked or negated by either small molecule antioxidants or by antioxidant enzymes. Cellular proliferation, cellular arrest and cellular suicide appear to be modulated by relative concentrations of electronically modified oxygen derivatives. Cautious use of antioxidants may be appropriate for individuals with tumorous or preneoplastic growths. EMODs appear to be gaining an increasingly important role in the modulation of cellular proliferation and cellular death. EMODs offer a therapeutic site in the selective killing of neoplastic cells, without causing harm to normal cells. Indeed, the potential of therapeutically increasing EMOD levels in combating disease offers the possibility of a promising opportunity.
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Prof. Hon. Randolph M. Howes, M.D., Ph.D.
Adjunct Assistant Professor of Plastic Surgery, The Johns Hopkins Hospital, Baltimore, Md., U.S.A. and Espaldon Professor of Plastic and Reconstructive Surgery, University of Santo Tomas, Manila, Philippines.
Address for communication: 27439 Highway 441, Kentwood, Louisiana 70444-8152, USA. Email: firstname.lastname@example.org
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Howes M.D., PhD., R. (2007). Cancer, Apoptosis and Reactive Oxygen Species: A New Paradigm. PHILICA.COM Article number 86.
1 Peer review [reviewer #47336] added 20th August, 2011 at 19:55:19
Although the main proposal made in the preprint appears reasonable, an adequate treatment of the problem requires a more precise approach that also includes Integrative Cancer Biology and Complex Systems biology modeling approaches that are currently available.
Recent preprints posted on Nature Proceeds address much more precisely the problem through adequate mathematical modeling of apoptosis in cancer and radical dose effects, etc., as well as other, relevant advanced technology/methodology aspects of this important problem of understanding Cancer, Apoptosis and Reactive Oxygen Species. However, this is not a *new* paradigm as claimed, because it has been around for at least ten years. What is a trully new paradigm —but not in this preprint— is an approach that allows personalized cancer therapy based on novel technologies linked with precise/ adequate mathematical modeling of apoptosis in cancer which is discussed only summarily and incompletely in this preprint. The cited list of references also falls far short from providing a strong, or sufficient basis for the conclusions drawn in the preprint. In spite of its flaws, this preprint is an improvement over the other 3 or 4 articles posted recently at Nature Proceeds on similar subjects.
Originality: 2, Importance: 4, Overall quality: 5