The following article by Beldeu Singh develops the nutritional genesis of cancer cell formation based on free radical reactions causing lipid peroxidation of cell membranes. It explains the role of the free radical damaged cell membrane as a ROS (reactive oxygen species, also called free radicals) generating system that plays a key role in the increase of acidity of the cytoplasm that slowly inactivates the enzymes involved in aerobic respiration and the rerouting of glucose into anaerobic pathways to produce alcohol - the energy molecule in cancer cells instead of ATP - and how in the presence of excess ROS the cancer cell transforms into an alcohol-alkane bioreactor fuelled by ROS in which new toxic pathways are established that produce ROS-induced toxic chemicals such as alkanes and benzene. These, in turn cause tumour growth.
More importantly, it explains how fat soluble antioxidants stabilize oxidized biomembranes and restore their functional intergrity and how, in the presence of excess natural vitamin C, the ROS scavengers promote tumour regresssion by terminating toxic pathways and creating an equilibrium that favors ATP production.
One of our fat soluble antioxidants is the high density fraction of cholesterol - HDL or high-density lipids. Instead of decreasing cholesterol at any price, which we seem to be bent on doing with lipitor and other statin drugs, and which has serious side effects, we should welcome the fact that we have this vital substance. At the most we could intervene to increase the HDL part of cholesterol by dietary means. But then - there is apparently too much money in statins. They are one of the major sellers of the drug industry and arguably one of the worst influences on our health.
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THE FUTURE OF CANCER THERAPY: FAT-SOLUBLE ANTIOXIDANTS OR CHEMO-DRUGS
Recently, the media reported a "link" between high cholesterol and prostate cancer in a manner as if high cholesterol was the cause of prostate cancer. The headlines read as follows: "High cholesterol linked to cancer." A close scrutiny of the news report reveals that the Italian scientists were reporting "a possible relation between high cholesterol and prostate cancer" and "the scientists added that cholesterol-lowering drugs known as statins may help to lower a man's prostate cancer risk, though more studies are still needed (NST, April 13, 2006, p 16)."
"We found that, after allowing for any potential confounding factors, men with prostate cancer were 50% more likely to have had high cholesterol levels than our non-prostate cancer controls," said Dr Francesca Bravi, the study's lead author. "We also found that prostate cancer patients were 26% more likely to suffer from gallstones than our controls. Although not statistically significant, gallstones are often related to high cholesterol levels. To our knowledge, there have been no previous studies reporting any relationship between gallstones and prostate cancer. The researchers believe the "link" between high cholesterol and prostrate cancer can be explained since cholesterol is involved in the production of androgens - male sex hormones that have a role in the formation of prostate tissue and prostate cancer linked to high cholesterol" (cf; Sarah Hall, Health Correspondent; April 12, 2006, The Guardian).
That link is, in fact rather interesting. The higher incidence of gallstones may be due to metabolism of acetate. More acetate is formed in cells that are lower in oxygen or in cells that undergo oxygen stress. Acetates are mainly metabolized to alkoxyacetic acids but there is also a minor pathway through ethylene glycol to oxalic acid. The main pathway of ethylene glycol ethers is associated with significant clinical or experimental health effects, but the minor pathway is also interesting because of formation of urinary stones or gallstones.
The relationship between high cholesterol and prostrate cancer is understandable because the body makes steroids out of its own cholesterol. Low-density lipoprotein (LDL) cholesterol, commonly known as the "bad” cholesterol is the only form used for making all our steroids and it is converted to pregnenelone and then progesterone from which are produced cortisone, aldosterone, DHEA, estrogen and testosterone. The main cause for reduced hormonal output is a lack of enzymes, essential fatty acids and micronutrients but if LDL is too low these hormones may be low as well. The real problem is, however, primarily due to oxidized LDL entering cells in the prostate where the neutral LDL is used to produce hormones, whereas the oxidized LDL will cause lipid peroxidation in the cell membrane. Another reason, why oxidized LDL could cause problems in cells or many organs is that cholesterol is known to regulate the fluidity and the permeability of cell membrane (Dorota and Maciej, Reactive oxygen species and sperm cells, Reprod Biol Endocrinol. 2004; 2: 12). So, the real problem is oxidized LDL and keeping it within the normal margins is important and points to the need for maintaining high serum antioxidant levels as cofactors that lower health risk.
The observed association between gallstones and prostate cancer is also interesting because chronic acidosis promotes the formation of gall stones and we need to examine the possibility of acidosis in cancer cell formation. Lactic acid accumulation in cells results in acidosis. Mitochondria in our cells produce energy through a process that also produces lactate ions as by-products but not lactic acid. The acidic form of lactate (lactic acid) cannot be formed under normal circumstances in human tissues but it is formed when the oxygen in the cytoplasm is low. It is important to see how oxidized LDL can possibly produce oxygen stress in cells and cause cancers or other disease states.
Dr Francesca Bravi, of the Istituto di Ricerche Farmacologiche Mario Negri in Milan, explained that the research team is reporting a possible relation between high cholesterol and prostate cancer, they found in their study (Reuters, April 12, 12.04am). It is not a causative factor as reported by the media at large but merely an association that is in fact quite interesting and a common mechanism at the biochemical level may explain the statistically significant association between high cholesterol and prostate cancer.
The Italian scientists added that cholesterol-lowering drugs known as statins may help to lower a man's prostate cancer risk, but Bravi said further studies are needed to determine whether statins could reduce the risk of prostate cancer because current research is limited and inconclusive.
The news media did not say if it was an association between LDL and prostrate cancer and since HDL and LDL are so different in their role and function in the human body, it would seem like a design flaw in the study to report as association between "high cholesterol and prostrate cancer" and it would be scientifically meaningful to study associations between HDL/LDL ratios and prostrate cancers simultaneously with HDL and LDL levels and extent of lipid peroxidation.
We know as a general rule that a high total cholesterol reading may not be bad and it may be good if it’s the HDL (good cholesterol) component which is high because HDL is an antioxidant and it has the very useful role of bringing the circulating LDL (bad cholesterol) back to the liver where it is broken down to form bile salts that are then secreted as part of the bile juice to digest fats in the intestine. Bile acids are also needed for the absorption of the fat-soluble antioxidants.
Risk factors must be understood as factors that increase the incidence of disease in a particular group or increase the chances of the disease developing in people and may not always be the cause of the disease or condition.
Cigarette smoke is a risk factor because it contains up to 4000 toxic chemicals, of which at least 300 are very toxic and at least 40 are known carcinogens. These toxic chemicals generate free radicals in the body that cause oxidative damage to cell membranes, receptors on cells and biomolecules such as insulin, other hormones, proteins and lipid molecules and sufficient oxidative damage will disrupt cellular function and/or disrupt biochemical pathways, including signaling pathways. Smoking increases the circulating lipid peroxidation products compared to the basal level of lipid peroxidation products in normal human blood. Increased free radical production is by itself not evidence of oxidative damage. Transient increase in endogenous free radical production could be due to increased metabolic activity such as from a burst of physical activity or from excessive exercise. Continuous or prolonged high levels of free radicals, when in excess is a factor for elevating risk to disease states or conditions and could cause disease or disease states.
High cholesterol, by itself is not the cause of disease conditions but it is associated with certain disease conditions. The good cholesterol (HDL) is produced in the liver and has functions that promote health. It is the oxidized "bad cholesterol" (LDL) that poses a health risk. Oxidized LDL is a lipid molecule that has suffered oxidative damage by losing an electron to free radicals. Oxidized LDL participates in plaque formation and contributes to artery clogging. Another problem with oxidized LDL in the body could perhaps be that the liver cannot break it down into bile salts and may cause damage to other lipid molecules and cellular membranes.
In general, a good HDL/LDL ratio is important from the health point of view as well in life insurance underwriting and if you are not a smoker and not obese or if the mid-body girth measurement does not indicate abdominal-visceral fat storage, it is a healthy sign. Low HDL levels when the LDL level is relatively high is a factor for concern and it is a risk factor in people with low blood antioxidant levels or declining blood antioxidant levels and low coenzyme Q10 or low glutathione levels increase the risk of disease or disease conditions.
Researchers at the Indiana University School of Medicine and pharmaceutical company GlaxoSmithKline, Inc. looked at the history of heart disease, age, sex, race, weight and other heart disease risk factors in almost 7,000 patients. They published the finding of their study - Having a high level of HDL cholesterol – the good cholesterol – is more important than having a low level of LDL – the bad cholesterol – in protecting individuals from heart attack - in the March issue of American Heart Journal. The researchers found the strongest predictor of future heart attack was previous heart disease; age was the second strongest predictor and the third strongest predictor was HDL level.
Prostate cancer is the most commonly diagnosed and second leading cause of cancer mortality in men living in the western world and its rapid increase is partly on account of the increase in the number of older people. Blood antioxidant levels decline with advancing age, dropping by 50% by the age of 40. Degenerative conditions, in general, tend to appear after decline beyond this level.
Diet has been identified as one risk factor associated with prostate cancer occurrence and in particular long chain fatty acids and oxidized lipids are implicated in cancer promotion. Many studies show that elevated blood lipid peroxidation is a factor in the development of cellular dysfunction (Jain et al, Diabetes Care 21:1511-1516, 1998: Jain, J. Bio Chem 264:21340-21345, 1989; Giugliano et al. Diabetes Care, 19:257-267, 1996). Experimental evidence confirms that lipid peroxidation products inhibit mitochodrial function. 4-Hydroxy-2-nonenal (HNE), a major product of lipid peroxidation, increases in concentration upon reperfusion of ischemic cardiac tissue and reacts with mitochondrial enzymes and inactivates them and inhibits mitochondrial respiration in vitro (David and Szweda, Biochemistry, Proc Natl Acad Sci USA, 1998 January 20; 95(2): 510–514).
In contrast, antioxidants can suppress tumor development and slow down the progress of prostate cancer and other cancers in most people. Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients. The specific roles of dietary agents in promoting or preventing prostrate cancer (PCA) and other cancers and development of disease states will remain controversial unless the biochemistry in which they play a role can be explained and understood, although the association of free radicals with disease states is widely accepted and supported by many studies and experimental evidence.
Epidemiological and laboratory studies also suggest that high selenium and vitamin E intake lowers risk of prostate cancer. Recent serendipitous findings of two randomized clinical trials support the hypothesis that selenium and vitamin administration will decrease prostate cancer risk. A study to assess these compounds is beginning. Other promising, but less developed, interventions in chemoprevention of prostate cancer include vitamin D supplementation and diet modification (The Future of Prostate Cancer Prevention; Otis et al, Annals of the New York Academy of Sciences 952:145-152 (2001). Vitamin E is a fat soluble antioxidant. Other factors in diet modification include a range of antioxidants, in particular conjugated linoleic acid (CLA).
"An interesting observation regarding the role of selenium on metastasis is that an inverse relationship between serum selenium level and the rate of distant metastases in cancer patients has been reported. These compounds exert chemopreventive effects through modification of cell proliferation and/or the activity of detoxifying enzymes, induction of detoxifying enzyme activity, and/or induction of apoptosis (cf:Takuji et al: Suppressing Effects of Dietary Supplementation of the Organoselenium 1,4-Phenylenebis (methylene) selenocyanate and the Citrus Antioxidant Auraptene on Lung Metastasis of Melanoma Cells in Mice, Cancer Research 60, 3713-3716, July 15, 2000). Other research also demonstrated that dietary supplementation of selenomethionine reduced experimental metastasis of melanoma cells in mice and inhibited the growth of metastatic tumors that formed in the lungs. It is concluded that selenomethionine is an active form of selenium that reduces experimental metastasis (Yan et al, Anticancer Res. 1999 Mar-Apr;19(2A):1337-42).
Julio et al, evaluated the effects of a commercial preparation of a CLA mixture of isomers (cis-9, trans-11 and trans-10, cis-12 isomers in approximately a 50:50 ratio) and the individual isomers on the proliferation of prostate cancer (PCA) cells in culture and concluded that their study shows an anti-proliferative and anti-viability effect of CLA on the androgen-independent human prostate cancer cell line PC-3, a human prostatic carcinoma cell line (Carcinogenesis; Vol. 25, No. 7, 1185-1191, July 2004).
Research shows that in early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. GSTP1 is the gene encoding the pi-class glutathione S-transferase (GST) (William et al, (The Johns Hopkins Comprehensive Cancer Center, Baltimore, USA); Annals of the New York Academy of Sciences 952:135-144 (2001). These findings have contributed to the model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. Oxidants inflict molecular, biomolecular and genomic (mDNA) damage with oxidative damage to membranes of the mitochondria. As more and more mitochodrial function is disrupted the cellular aerobic (ATP) energy output drops and as more and more mitochodria are disabled by inflammatory oxidants and lipid peroxidation, the cellular environment of low aerobic energy tends to promote transformation to anaerobic energy processes and precipitates neoplastic transformation to PIA and PCA cells.
Conjugated linoleic acid (CLA) is a dietary fatty acid. It has received considerable attention because of its anti-mutagenic and anticarcinogenic properties. CLA is the generic term of a group of positional and geometric isomers of the omega-6 essential fatty acid linoleic acid (LA). CLA has two critical roles in health. CLA has a significant effect in reducing body fat and equally important, it exerts an antioxidant activity and has anti-tumor properties. CLA is approximately two times more powerful an antioxidant than beta-carotene and yet another study concluded that CLA “may produce substances which protect cells from the detrimental effect of peroxides” (J Am Coll Nutr 2000 Apr;19(2 Suppl): 111S-118S). Peroxides cause lipid peroxidation. CLA lowers the rate of lipid peroxidation in the mitochondria and cell membranes. Hence, CLA has been studied for altering body composition and treating obesity and is useful in both cases as it lowers the number of lipid molecules that could suffer oxidative damage. It is a natural biomolecule and as a fat soluble antioxidant, it is also useful as a cardio-protective agent.
CLA is an anti-inflammatory agent and decreases the amount of inflammatory substances in cells, including arachidonic acid in the mitochondria while it scavenges free radicals in the lipid part of the cell membranes and protects the normal function of membranes that suffers through lipid peroxidation. It also provides electrons to free radical damaged lipid molecules and prevents lipid peroxidation and inhibits free radical chain reactions. That explains the anti-mutagenic and anticarcinogenic properties of CLA in PCA and other cancers.
The Italian scientists stated that statins have also been shown to help prevent diabetics and people at high risk of heart disease from suffering a heart attack or stroke. There is a grave doubt about statins because coenzyme Q10 (CoQ10) and cholesterol are both synthesized from the same substance - mevalonate. Statin drugs (Lipitor, Zocor, etc) also inhibit the body's synthesis of coenzyme Q10. Statins interfere and inhibit the synthesis of coQ10 as an inherent role of the drugs in the body. The use of statins can decrease the body's synthesis of coenzyme Q10 by as much as 40%. CoQ10 is involved in the production of an important molecule in the energy cycle - ATP. ATP serves as the normal cell's major energy source and drives a number of biological processes including membrane integrity, muscle contraction and the production of antioxidant enzymes, protein and antibodies, and normal cell functions, including phagocytosis.
CoQ10 is a fat soluble antioxidant found naturally in the energy-producing center of the cell known as the mitochondria. CoQ10 is present in as much as ten times in heart cells compared to other cells. Co-Q10 can be manufactured in the body and the process involves many steps and requires at least eight vitamins - ie a cellular environment rich in antioxidants.
CoQ10 protects the lipid part of the cell membranes from oxidative damage (lipid peroxidation). Naturally, the depletion of CoQ10 in heart cells will increase the risk of heart attacks as damage to the cell membranes of heart cells and low cellular energy levels will result in fatal arrythmias. So, it is not surprising that CoQ10 levels are low in people with congestive heart failure (CHF), a debilitating disease characterized by a heart that is not able to pump blood effectively. Interestingly CoQ10 levels also tend to be lower in people with high cholesterol compared to healthy individuals of the same age.
Its role in the energy cycle means that it not only improves glucose metabolism but also improves cellular function. Additionally it is an antioxidant that scavenges (neutralizes) free radicals in the lipid medium and prevents or minimize oxidative damage to lipid molecules. It helps alleviate a host of health conditions associated with free radical damage in people and the results will be better if there is no mineral deficiency especially selenium deficiency.
Low blood levels of coenzyme Q10 have been detected in patients with some types of cancers (National Cancer Instutute, www.cancer.gov, 01/11/2005: Austin S. Alt Med Review 1997;2:4-11), a relationship that shows that it is depleted by free radicals generated by the by-products of cancer cell metabolism which may include toxic chemicals such as alkanes and benzene and its production in the cancer cells declines and eventually terminates and that coincides with lactate increase in the cancer cell and coincides with the cancer cell becoming a fast growing malignancy. Tumour formation takes place after that as the increasing ROS fuels lipid peroxidation and formation of toxic metabolites more rapidly.
Coenzyme Q10 has shown an ability to stimulate the immune system and to protect the heart from damage caused by certain chemotherapy drugs (National Cancer Instutute, www.cancer.gov, 01/11/2005) which shows that it neutralizes free radicals generated by chemo-drugs. There is research that showed partial remission of breast cancer in "high risk" patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10 (Lockwood et al, Mol. Aspects Med., 15: s231-s240, 1994). The role of coQ10 in tumour regression is well documented. In a clinical protocol, 32 patients having -"high-risk"- breast cancer were treated with antioxidants, fatty acids, and 90 mg. of CoQ10. Six of the 32 patients showed partial tumor regression. In one of these 6 cases, the dosage of CoQ10 was increased to 390 mg. In one month, the tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After 3 months, the patient was in excellent clinical condition and there was no residual tumor tissue (Lockwood et al, Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10; Pubmed, Biochem Biophys Res Commun. 1994 Mar 30;199(3):1504-8).
If lipid molecules lose an electron to free radicals, CoQ10 and other fat soluble antioxidants readily give up an electron to that lipid molecule or lipid part of the molecule and reverses oxidative damage and it can then be metabolized or used by the body and helps prevent harmful free radical chain reactions in cells that promote disease conditions in tissues. That explains why CoQ10 is depleted in people with high cholesterol especially high LDL. Oxidized LDL poses a health problem as it tends to participate in plaque formation in arteries. Oxidized circulating LDL, which are lipid molecules could exert oxidative stress in cell membranes in the prostrate gland especially in older people because CoQ10 levels are lower in older people. That may explain the higher incidence of prostrate cancers in older people or older people with high LDL. Hence, a combination of CLA and CoQ10 is a better alternative to statins in improving liver function and consequently increasing HDL out of the liver and decreasing the risk of lipid peroxidation damage to cell membranes in the prostrate in order to lower the risk of prostrate cancer and tumour development, especially in older people.
Obesity is also linked to higher incidence of diabetes and cancers, while there is a higher incidence of cancers in diabetics. One of the primary factors is that obese people tend to have more free radicals in their bodies and eating long chain fatty acids will increase the amount of circulating lipoproteins. That means more lipid molecules are presented for lipid peroxidation and that, in turn, increases the risk of development disease states and accelerates the progression of diseases.
There are numerous studies that show that the blood of diabetic patients has elevated levels of lipid peroxidation products (see; Sushil et al, Effect of hyperketonemia on Plasma Lipid Peroxidation Levels in Diabetic Patients; Diabetics Care 22:1171-1175, 1999). Lipoproteins have a greater susceptibility to lipid peroxidation and there is experimental evidence of increased lipid peroxidation levels in diabetics (Sushil et al, Effect of hyperketonemia on Plasma Lipid Peroxidation Levels in Diabetic Patients; Diabetics Care 22:1171-1175, 1999) and that exercerbate the risk of cardiovascular disease, heart attacks and cancers. Again, in such cases, CLA and CoQ10, and consuming medium chain fatty acids are better long term alternatives to improve body composition, improve cellular function and reduce the risk of oxidative damage to cell membranes as a way to reduce risk of initiation of disease states in the body. These are natural biomolecules in contrast to drugs.
In diabetic patients, alpha-lipoic acid (ALA) improves skeletal muscle glucose transport, resulting in increased glucose disposal Betty et al, Diabetes 50:404-410, 2001). Alpha-Lipoic Acid is a powerful fat and water-soluble antioxidant. It directly recycles vitamin C and indirectly recycles vitamin E by giving electrons to the spent vitamin molecules.
The accumulating information from research points to free radical damage to lipid molecules such as high LDL and circulating lipoproteins and oxidative damage within cells as a cause of disease states, including cancers and leaky gut syndrome. It is anticipated that in the future, scientists will find more evidence of a causal link between the amount of fat carried in the blood and cancers, especially lipoproteins produced from ingesting hydrogenated vegetable oils and oils with long chain fatty acids. Such lipoproteins circulate in the bloodstream and can be damaged by excess free radicals and the free radical damaged lipoproteins will easily participate in plaque formation and as artery-clogging agents. The reactive oxygen radical also causes lipid peroxidation in circulating lipid molecules (eg LDL) and in the lipid part of cell membranes and inactivate the cell membrane. Cell membranes contain various types of lipids, the specific composition of which is important for maintaining membrane fluidity. Peroxidation of polyunsaturated fatty acids (PUFAs) in cell membranes can produce cell dysfunction associated with loss of membrane function and integrity (see:Dorota and Maciej, Reactive oxygen species and sperm cells, Reprod Biol Endocrinol. 2004; 2: 12). The data point to the nutritional genesis of disease states starting with lipid peroxidation and lipid peroxidation of the lipid part of cell membranes.
Active oxygen radicals (O2-) are known to be involved in the development of various chronic diseases, including cancer. One study demonstrated that auraptene, which is a coumarin-related compound widely occurring in citrus juices (e.g., grapefruit), exhibited a marked inhibition of 12-O-tetradecanoylphorbol-13-acetate induced (TPA3-induced) O2- and hydroperoxide production and inhibited skin tumor promotion in mice by topical application (Akira et, Inhibitory Effect of Citrus Nobiletin on Phorbol Ester-induced Skin Inflammation, Oxidative Stress, and Tumor Promotion in Mice; Cancer Research 60, 5059-5066, September 15, 2000). There are numerous similar experimental studies. Therefore, antioxidants such as auraptene have been effective as antitumor agents. Saintot et al, (Tumor progression and oxidant-antioxidant status. Carcinogenesis (Lond.), 17: 1267-1271, 1996), reported that the presence of nodes and/or metastases is directly associated with low plasma concentrations of cholesterol and malondialdehyde. Auraptene also reduces the production of lipid peroxidation products, including malondialdehyde, in rat carcinogenesis (Tanaka et al, Citrus auraptene exerts dose-dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug-metabolizing enzymes. Cancer Res, 58: 2550-2556, 1998). Thus, we would expect that the antioxidative property of auraptene contributes to the antimetastatic activity found in the present study (Takuji et al: Suppressing Effects of Dietary Supplementation of the Organoselenium 1,4-Phenylenebis(methylene)selenocyanate and the Citrus Antioxidant Auraptene on Lung Metastasis of Melanoma Cells in Mice, Cancer Research 60, 3713-3716, July 15, 2000).
Other than ROS, excess nitric oxide (NO) is also related to disease states and cancers. Excess (NO) may be generated by free radical induced endothelial dysfunction. Excess NO generation has attracted attention because of its relevance to epithelial carcinogenesis (Ohshima et al, Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat. Res., 305: 253-264, 1994;Medline: Xie et al, Destruction of bystander cells by tumor cells transfected with inducible nitric oxide (NO) synthase gene. J. Natl. Cancer Inst., 89: 421-427, 1997: Tsuji et al, Helicobactor pylori extract stimulates inflammatory nitric oxide production, Cancer Lett., 108: 195–200, 1996). NO has also been reported to cause mutagenesis (Arroyo et al, Cooney R. V. Mutagenecity of nitric oxide and its inhibition by antioxidants. Mutat Res., 281: 193-202, 1992).
Nobiletin, a polymethoxyflavonoid in citrus fruits, was identified as an inhibitor of both NO and O2- generation. Nobiletin does not significantly scavenge O2- generated from the xanthine/xanthine oxidase system nor inhibit xanthine oxidase activity and it may have the complimentary role to inhibit the assembly or activity of a multicomponent NADPH oxidase system in differentiated HL-60 cells (see;Akira et, Inhibitory Effect of Citrus Nobiletin on Phorbol Ester-induced Skin Inflammation, Oxidative Stress, and Tumor Promotion in Mice; Cancer Research 60, 5059-5066, September 15, 2000) and that inhibitory role related to NADPH may be critical in inhibiting toxic pathways in cancer cells.
Nobiletin has been reported to induce differentiation of mouse myeloid leukemia cells (Sugiyama et al, Studies on the differentiation inducers of myeloid leukemic cells from Citrus species. Chem. Pharm, Bull., 41:714–719, 1993), to exhibit antiproliferative activity toward a human squamous cell carcinoma cell line (Kandawaswami et al, Antiproliferative effects of citrus flavonoids on a human squamous cell carcinoma in vitro. Cancer Lett., 56:147–152, 1991), to exert antimutagenic activity (Wall et al, Plant antimutagenic agents, 2 Flavonoids. J. Nat. Prod. (Lloydia), 51:1084-1091, 1998), and to suppress the induction of matrix metalloproteinase-9 (Ishiwa et al, A citrus flavonoid, nobiletin, suppresses production and gene expression of matrix metalloproteinase 9/gelatinase B in rabbit synovial fibroblasts. J. Rheumatol., 27: 20-25, 2000). Its role in inhibiting the formation of toxic metabolites by ROS and metalloproteins synthesized in cancer cells for electron transport is by disrupting the metalloprotein pathways in cancer cells.
Relationships of nutrition and vitamins to the genesis and prevention of cancer are increasingly evident. Nutritional antioxidants support prostacyclin synthesis by preventing lipid hydroperoxide-mediated inhibition of prostacyclin synthetase. By exerting anticarcinogenic, immunostimulant and anti-metastatic effects, nutritional antioxidants should act to inhibit neoplasia at each stage of its development (McCarty MF, An antithrombotic role for nutritional antioxidants: implications for tumor metastasis and other pathologies, Med Hypotheses. 1986 Apr;19(4):345-57). How do natural or nutritional antioxidants function in cell biochemistry to lower the risk of cancer cell formation or shrink tumours?
Ordinarily, a healthy human cell with sufficient minerals, high in natural antioxidant enzymes and other natural antioxidants that promote strong and efficient free radical scavenging activity tends to promote aerobic energy production through the Kreb's cycle to produce ATP molecules. The human cell is not genetically programmed to drive biochemical pathways to ferment alcohol for use as cellular fuel to produce energy. However, when the biochemical concentrations in the cell change or their relative amounts change, alternative biochemical pathways may be initiated that proceed to produce alcohol instead of ATP as the energy molecule.
A good example to understand this process is the industrial hydrogenation of oils. If hydrogen is added to oils nothing happens but when a catalyst, say nickel is added and the temperature is elevated while the pressure of the hydrogen gas is raised, it promotes hydrogenation of the oil through a chemical reaction in which unsaturated bonds between carbon atoms are reduced by attachment of a hydrogen atom to each carbon. Hydrogenation is widely applied to the processing of cooking oils and fats in order to convert unsaturated fatty acids to saturated ones so that they have a longer shelf life.
Most hydrogenation reactions are reversible and proceed to favorable equilibria depending on catalysts, pressure and temperature. Similarly, biochemical reactions also proceed on different pathways depending on the biomolecules and chemicals in cells. Along one pathway, glucose may be converted step-wise into alcohol, while alcohol may be broken down biochemically in the healthy cell by another pathway. In the cell, maintaining the equilibrium between the oxidative and antioxidative capacities and the PH (acidic-alkaline value) determines whether glucose will be routed to produce ATP or alcohol. The reaction catalyzed by lactate dehydrogenase is reversible. This allows a cell to synthesize glucose from lactate. In the reverse process, lactate is converted to glucose through gluconeogenesis, an anabolic pathway that synthesizes glucose from smaller precursors such as lactate.
When oxygen and natural antioxidants are present in large amounts in cells (aerobic conditions), the Kreb's cycle and electron transport system moves biochemically in the direction to produce ATP, the aerobic energy molecule in healthy cells. Under conditions of extremely low cellular oxygen or the absence of oxygen, pyruvic acid can be routed by the cell into the biochemical pathway for lactic acid fermentation. Prolonged lactic acid fermentation in the cell drives to make anaerobic respiration as the dominant process to produce alcohol for cellular respiration, which, if it cannot be reversed, at that point a cancer cell is formed. But how does oxygen deprivation occur in only certain cells?
There may not be a genetic switch that switches the energy process from one system to another but may be due to biochemical equilibria dependent on the available oxygen molecules in the cytoplasm.
Cell membrane lipid integrity is a key factor in its permeability and in its function as a medium through which transport of molecules takes place and that maintains the equilibria for healthy and optimal cell function. That functional integrity is maintained by both water and fat soluble antioxidants and a minimum threshold supply of energy from ATP.
The polyunsaturated fatty acids in cell membranes are easily oxidized by hydroxyl radicals and other oxidants. A single hydroxyl radical can result in the peroxidation of many polyunsaturated fatty acid molecules as the reactions involved in this process are part of a cyclic chain reaction. As the oxygen molecule passes through oxidized cell membranes, it converts the oxygen molecule into ROS. An oxidized cell membrane acts as a ROS generator. Inside the cell ROS can produce complete degradation (i.e., peroxidation) of essential complex molecules in the cells, including lipid molecules, proteins and DNA and excess ROS will initiate toxic pathways.
When the lipid part of the cell membrane is extensively damaged by free radicals and other oxidants like oxidized LDL, the oxygen molecule that moves across the cell membrane that has suffered oxidative injury, it is robbed of electrons and it cannot be utilized as the oxygen molecule for aerobic respiration but moves into the cell cytoplasm as a harmful reactive specie that causes more free radical damage inside the cell. As free radicals and oxidized LDL take electrons from the lipid part of cell membranes, the process, over time leads to an accumulation of excess in positive charge in the cell membrane, a situation found in cancer cells.
Several studies have demonstrated that hypoxia alone, without subsequent reoxygenation or reperfusion, can result in the production of the superoxide [superoxide anion radical (O2·)] oxidants in some tissues (Park et al, Oxidative changes in hypoxic rat heart tissue. Am. J. Physiol. 260 (Heart Circ. Physiol. 29): H1395-H1405, 1991: Park et al, Oxidative changes in hypoxic-reoxygenated rabbit heart: a consequence of hypoxia rather than reoxygenation. Free Radic. Res. Commun. 14: 179-185, 1991: Tribble, D. L., and D. P. Jones. Oxygen dependence of oxidative stress. Rate of NADPH supply for maintaining the GSH pool during hypoxia. Biochem. Pharmacol. 39: 729-736, 1990).
These reactive oxygen species (ROS) produced in oxidized cell membranes, cause cellular damage through covalent modifications of lipids, proteins, and nucleic acids. These oxygen radicals cause peroxidation of membrane phospholipids and the resulting accumulation of peroxidation products such as malondialdehyde (MDA) (see:Jain, The accumulation of malonyldialdehyde, a product of fatty acid peroxidation, can disturb aminophospholipid organization in the membrane bilayer of human erythrocytes. J Biol Chem 1984;259:3391-3394). Oxidation of cell membrane unsaturated fatty acids generates lipid hydroperoxides, which can either be reduced by glutathione peroxidases or, after reacting with metals, can become reactive compounds such as malondialdehyde, 4-hydroxynonenal, and peroxyl radicals (Vaca et al, Interaction of lipid peroxidation products with DNA. A review. Mutat Res 1988;195:137–49: Marnett LJ, Oxyradicals and DNA damage, Carcinogenesis 2000;21:361–70).
Lipid peroxidation can result in the formation of reactive products that will react with other molecules and degrade them. These products have been known to cross-link membrane components and result in altered membrane permeability and lipid organization and cellular dysfunction (ref:Sushil Jain, The Mechanism(s) Of Complications And Benefits Of Vitamin E Supplementation In Diabetic Patients, Department of Pediatrics, Louisiana State University Health Sciences Center, July 24, 2000).
N-Dimethylglycine (DMG) is produced in the human body to transport oxygen across the cell to the mitochondria, small organelles within the cell, where energy reactions take place. The reactive oxygen specie cannot be transported by the oxygen transport system in the cell but may cause oxidative damage to it and that in turn prevents the efficient transport of the oxygen molecule to areas in the cell where it can be utilized in the normal aerobic respiratory process. Excess ROS will damage DMG oxygen transport system in the cell and oxidative stress will eventually halt the production of DMG, a process that effectively maintains oxygen stress in the cell.
Cancer cells have altered membrane composition and membrane permeability, which results in the movement of potassium, magnesium and calcium out of the cell and the accumulation of sodium and water in the cell (Seeger and Wolz, 1990; cf; Steve Haltiwanger M.D., C.C.N., The Electrical Properties of Cancer Cells Steve Haltiwanger M.D., C.C.N., The Electrical Properties of Cancer Cells). The site of an injury is characterized by excess free radicals and the cell membranes of proliferating cells at the site of injury also have lower than the cell membrane potential of healthy adult cells, a characteristic feature common to cancer cells. However, when the wound heals and the repair is completed, proliferation stops and the membrane potential returns to normal whereas, in cancerous tissue the electrical potential of cell membranes continues to be maintained at a lower level than that of healthy cells and continue to proliferate abnormally fast (see; Cone, 1975: cf; Steve Haltiwanger M.D., C.C.N., The Electrical Properties of Cancer Cells Steve Haltiwanger M.D., C.C.N., The Electrical Properties of Cancer Cells). A continuous production of ROS and hydroxyl radicals for lipid peroxidation is necessary to take away sufficient amount of electrons from molecules in the cell membrane and maintain its altered electrical potential and as more oxygen molecules pass through such a membrane they are converted into ROS.
The prevailing low oxygen in the cytoplasm and the poor transport of available oxygen molecules within the cell creates an acidic medium in which glucose is rerouted in a different pathway that produces lactate, MDA and other products instead of ATP. The drop in ATP production in such as process also affects cell membrane integrity.
In glycolysis, glucose is broken down to phosphoglyceraldehyde which is converted to pyruvate. Puruvate enters the mitochondria where it is fed into the Kreb's cycle to form ATP, the aerobic respiration energy. However, when the mitochondrial membrane has suffered lipid peroxidation, it loses its functional integrity and the pyruvate cannot enter the mitochondria. In ROS-induced respiration in an acidic cytoplasm, the electron transport system switches to another system using inorganic metal ions and metalloproteins and this new biochemical uses pyruvate to produce alcohol, acetic acid, acetates and MDA. Alcohol alters the levels of certain metals in the body, thereby facilitating ROS production.
The major alcohol-metabolizing enzymes are alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1). Alcohol dehydrogenase converts alcohol to acetaldehyde, which can react with other proteins in the cell to generate hybrid molecules known as adducts. CYP2E1 also generates acetaldehyde, as well as highly reactive oxygen-containing molecules called oxygen radicals, including the hydroxyethyl radical (HER) molecule. The increasing population of ROS causes more lipid peroxidation, resulting in reactive molecules such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) that rapidly react with proteins to form MDA-protein and HNE-protein adducts. MDA also can combine with acetaldehyde and protein to form mixed MDA-acetaldehyde-protein adducts (MAA). That establishes the new toxic pathways that continue in the rapidly dividing cancer cells and ATP production is shut down in due course. In turn, the production of coQ10 is halted and tumours begin to form.
A study on the reduced energy supply brought about by fermentation on membrane lipids as well as in the ATP level and synthesis rate in cultivated potato (Solanum tuberosum) cells submitted to anoxia stress, showed that during the first phase of about 12 h, cells coped with the reduced energy supply brought about by fermentation and their membrane lipids remained intact, but in the second phase (12–24 h), during which the energy supply dropped down to 1% to 2% of its maximal theoretical normoxic value, was characterized by an extensive hydrolysis of membrane lipids to free fatty acids and the membrane integrity could not be preserved (André et al, Membrane Lipid Integrity Relies on a Threshold of ATP Production Rate in Potato Cell Cultures Submitted to Anoxia, Plant Physiol. 1999 May 1; 120(1): 293–300).
With lactic acid accumulation, there is a corresponding increase of hydrogen ion concentration that inhibits the activity of enzymes that promote the aerobic energy process. Prolonged oxygen stress in the cell prevents the lactic acid to be converted back into pyruvic acid to be used in the aerobic process and lactic acid acccumulates in the cell. Through ROS-induced reactions and under continuing oxygen stress, the pyruvic acid is converted into acetaldehyde that converts into alcohol- the energy for cancer cells.
The presence of the first molecules of alcohol in the cell initiates to use more oxygen to break down the alcohol and the increased oxygen use causes further oxygen stress in that cell and it breaks down the alcohol into the reactive acetaldehyde, which is a toxic molecule that generates more oxygen radicals in the cell. The new cycle of free radical generation interferes with both of pathways of ATP production and suppresses ATP production. "Oxygen free radicals cause lipid peroxidation of cell membranes (Kavanagh and Kam. Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection; British Journal of Anaesthesia, 2001, Vol. 86, No. 1 110-119) and damage various cellular components (David and Szweda, Biochemistry: Cardiac reperfusion injury: Aging, lipid peroxidation, and mitochondrial dysfunction, Vol. 95, Issue 2, 510-514, January 20, 1998). Lipid peroxidation of cell membranes enhances further generation of oxygen free radicals" (Kavanagh and Kam. Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection; British Journal of Anaesthesia, 2001, Vol. 86, No. 1 110-119). This process only serves to alter the biochemical equilibria that favour pathways found in cancer cells formation.
Numerous reports state that formaldehyde and acetaldehyde were found to produce an increase in total malignant tumors in the treated groups and showed specific carcinogenic effects on various organs and tissues.
The breakdown of carbohydrates through glycolysis results in the formation of pyruvic acid and hydrogen ions (H+). A build up of H+ increases acidity in cells and interfere with ATP production. In order to maintain the equilibrium that promotes ATP production, nicotinamide adenine dinucleotide (NAD+), removes the H+. In this reaction, the NAD+ is reduced to NADH which yields the H+ to the electron transport gate in the mitrochondria for the H+ to be combined with oxygen to form water (H2O). However, when oxygen is in low amounts in the cytoplasm, the NADH cannot release the H+ to the electron transport system and consequently hydrogen ions accumulate in the cell. Conditions of hypoxia, show evidence of reductive stress by demonstrating an increase in the cellular NADH/NAD+ ratio (Priya et al, Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions, J Appl Physiol 84: 1960-1966, 1998).
It has been experimentally shown that lactate productivity is increased by growing the cells first under aerobic conditions and shifting them to anaerobic conditions, which are favorable for the production of lactate (Dong-Eun Chang et al, Homofermentative Production of d- or l-Lactate in Metabolically Engineered Escherichia coli RR1, Appl Environ Microbiol, 1999 April; 65(4): 1384–1389).
An acidic environment due to increasing amounts of H+ will slow down aerobic enzyme activity. To prevent the rise in acidity within the cell, pyruvic acid accepts H+ to form lactic acid which then dissociates into lactate and H+. Some of the lactate diffuses into the blood stream and takes some H+ with it as a way of reducing the H+ concentration in the muscle cell. As the concentration of lactate in the cell decreases, more of the lactic acid dissociates into lactate and H+.
Ordinarily, lactate in cells is transported across the cell membrane by specific proteins and passes into the bloodstream and later enters liver cells where it is resynthesized by the liver through the Cori Cycle to form glucose to provide more energy.
This pattern of metabolism implies some sort of transport system for the removal of lactate from sites of production and uptake at sites of metabolism. Studies in various mammalian tissues have shown that lactate can be transported across the cell membrane by three mechanisms: by free diffusion or  by a monocarboxylate transporter (MCT), which works as a lactate/H+ symporter or  by anionic antiports such as lactate/Cl–-HCO3– exchangers (Deutick et al., 1982; Poole and Halestrap, 1993). The latter pathway does not seem to play a significant role in mammalian skeletal muscle (Juel and Wibrand, 1989; Roth and Brooks, 1990a; McDermott and Bonen, 1994). The undissociated lactic acid can easily diffuse across the membrane (Poole and Halestrap, 1993) but, at physiological pH, more than 95 % of the lactic acid is dissociated as a lactate anion and a proton (pKa=3.86).
It appears that the majority of lactate transport in mammalllian cells is due to the MCT-protein-mediated transport (Juel and Wibrand, 1989) (Roth and Brooks, 1990a,b) (Bonen and McCullagh, 1994; McDermott and Bonen, 1994)(cf:Donovan and Gleeson, Evidence for facilitated lactate uptake in lizard skeletal muscle; The Journal of Experimental Biology 204, 4099-4106 (2001). Monocarboxylates are transported across membranes via a family of proton-coupled carrier proteins known as monocarboxylate transporters (MCTs) and these proteins fail to transport lactate out of cancer cells when they suffer free radical damage. Also, in the increasingly acidic environment due to the accumulation of H+ ions, all the enzymes that would promote aerobic respiration and any enzyme involved in the process to export lactate out of the cell are inactivated. That, in turn, prevents the transport of lactate out of the cell and prevents the conversion of lactic acid into lactate and there is a lactic acid build-up in the cell. This contributes to increasing acidity in the cell and helps to establish the anaerobic energy pathways found in cancer cells
While the rate of oxygen consumption of cancer cells is somewhat below the values given by normal cells, malignant cells utilize anywhere from 5 to 10 times as much glucose as normal tissues and convert most of it into lactate. Lactate is found in tumors at levels much higher than in the corresponding normal tissues and quantitative studies of biopsies from human cancers have indicated a positive correlation between tumor lactate concentration and incidence of metastasis (Dalia Rivenzon-Segal et al, Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo 13C MRS, Translational Physiology, Vol. 283, Issue 4, E623-E630, October 2002). Also, lactate concentrations were significantly higher (P = 0.001) in tumors with metastatic spread (mean ± SD, 10.0 ± 2.9 µmol/g; n = 20) compared with malignancies in patients without metastases (6.3 ± 2.8 µmol/g; n = 14) (Stefan et al, High Lactate Levels Predict Likelihood of Metastases, Tumor Recurrence, and Restricted Patient Survival in Human Cervical Cancers, Cancer Research 60, 916-921, February 15, 2000}.
Ordinarily, excess lactic acid that is formed in the cell is transported into the bloodstream and carried into the liver. However, when the lipid part of cell membranes is damaged and has suffered oxidative injury, it becomes inactivated and as the lactate transport system is inhibited, it becomes impossible for lactic acid to be transported across the damaged cell membrane and as it accumulates within the cell and the equilibria can only drive anaerobic pathways as the dominant energy process in an acidic cytoplasmic environment of oxygen stress. A cancer cell is formed.
As the cancer cell is formed and it divides, there are no early signs or symptoms of cancer or prostate cancer. As the tumour is formed, it may grow and spread to surrounding areas. As the tumor grows, lactate levels in the cancer cells increase. The tumour begins to produce an increasing number of toxic chemicals that generate hydroxyl radicals that cause pain and the patient will start to notice symptoms. Lactate enhances hydroxyl (OH+) radical generation (Aktar et al, Biochem. Mol. Biol. Int, 46, 137, 1998).
Hence, it can be concluded that in hypoxia, with the initial oxygen stress and rise in acidity in the cytoplasm, mitochondrial respiration decreases, antioxidants would protect biochemical pathways in the cell that promote the conversion of glucose into ATP and help maintain the equilibria that favors this pathway. Experimental evidence shows that strong influence of antioxidants during hypoxic exposure can be as effective in protecting cell function in a reducing environment as they have been in oxidizing environments (Priya et al, Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions, J Appl Physiol 84: 1960-1966, 1998).
The change in the cell membrane followed by a rise in ROS and free radicals, oxygen stress, increasing acidity of cytoplasm, rerouting of glucose in the anaerobic pathway to produce lactate, inhibition of the lactate transport system and enzyme inactivation, and loss of coenzume Q10 production the cell and consequent mitochondrial dysfunction are factors that contribute to the reliance of cells on anaerobic energy production and transforms normal cells into cancer cells. Later on, they begin to produce toxic organic compounds that fuel their growth and tumour formation through the establishment of toxic pathways to produce toxic chemicals that generate more ROS and (OH+) to fuel free radical reactions.
Cancer cell have long been known to release different amounts of certain chemicals than healthy cells. Normal cells in the body constantly react with oxygen to produce energy and carry out their normal functions. A natural by-product of this energy acquisition is the production of harmful small molecules called free radicals. These molecules not only can damage lipids, proteins, cell membranes, and genes, they alter the role of the cell membrane, turning it into an ROS generator and initiate new toxic pathways in anaerobic respiration. The later process is a secondary development and results in the release of tiny chemicals called alkanes and benzenes (see:M. McCulloch et. al, Diagnostic Accuracy of Canine Scent Detection in Early- and Late-Stage Lung and Breast Cancers”:Integrative Cancer Therapies. March 2006, Vol 5, No 1). Organic compounds, such as alkanes, methylated alkanes, aromatic compounds and benzene derivatives have been identified by gas chromatography/mass spectroscopy in the exhaled breath of patients with lung and breast cancers (Philips et al, Volatile organic compounds in breath as markers of lung cancer:a cross-sectional study, Lancet, 1999;353:1930-1933: O'Neill et al, A computerized classification technique for scanning for the presence of breath biomarkers in lung cancer, Clin Chem, 1988;34:1613-1618).
Anaerobic microrganisms use insoluble electron acceptors such as iron oxide and oxy-anions like selenate for use in pathways to derive energy for survial and growth. Through a sequence of complex organic reactions glucose, proteins and lipids can be degraded by a fermentation process to form organic compounds such as lactate, alcohol, propionate and butyrate that can used in proton-reducing reactions to produce acetate, hydrogen and carbon dioxide. Lactate can be easily converted to other organic compounds under anaerobic conditions.
Cancer cells have much higher iron concentrations than normal cells are and studies also reveal enhanced glutathione (GSH) levels in tumors and carcinomas (Schnelldorfer et al, Cancer, 2000 Oct 1;89(7):1440-7) which are probably required to support their relatively higher rate of division and high rates of bioreactions in the production of toxic metabolites.
Apart from protecting itself from NO-mediated iron depletion, the large concentrations of iron in cancer cells may be to its use to synthesize iron-sulfur proteins to transfer electrons NADH to the iron-requiring oxygenase and suggests another energy pathway in mature cancer cells that form tumours. It is possible that the role of phenol hydroxylase is to transfer electrons from NADH via the iron-sulfur proteins to an oxygenase component that requires iron for metabolic activity or other enzymes, such as napthalene dioxygenase for use in napthalene degradation. Glutathione conjugation of naphthalene is a major metabolic pathway for rats (Rozman et al., 1982, Elimination of thioethers following administration of naphthalene and diethylmaleate to the rhesus monkey. Drug Chem. Toxicol. 5: 265-275. (Cited in ATSDR, 1990); Summer et al., 1979, Urinary excretion of mercapturic acids in chimpanzees and rats. Toxicol. Appl. Pharmacol. 50: 207-212. (Cited in U.S. EPA, 1986) and in the eyes of rodents, the 1,2-naphthoquinone metabolite has been shown to bind irreversibly to lens protein and amino acids or to undergo conjugation with glutathione (U.S. EPA, 1986).
Alkanes are products of ROS-induced lipid peroxidation of polyunsaturated fatty acids (Kneepkens et al, The hydro-carbon breath test in the study of lipid peroxidation: principles and practice, Clin Invest Med 1992;15:163 – 86: Kneepkens et al, The potential of the hydrocarbon breath test as a measure of lipid peroxidation, Free Radic Biol Med 1994;17:127 – 60: Phillips et al, Effect of age on the breath methylated alkane contour, a display of apparent new markers of oxida-tive stress. J Lab Clin Med 2000;136:243 – 9). In cancer cells ROS oxidize polyunsaturated fatty acids in membranes to alkanes that continue to produce hydroxyl radicals for lipid peroxidation.
Aldehydes and isoprene also can be formed endogenously by lipid peroxidation. Formaldehyde, is also formed by oxidative stress (e.g., from polyamine oxidation by ROS) and is increased in tumors just as benzene derivatives.
Phenol, catechol, and quinol (hydroquinone) had long been recognized as metabolites of benzene, but the oxidation of benzene to resorcinol, hydroxyquinol (1,2,4-trihydroxybenzene) and other trihydric phenols was uncertain (Dennis Parke, Personal Reflections on 50 Years of Study of Benzene Toxicology;Environmental Health Perspectives, Volume 104, Supplement 6, December 1996).
Glutathione is also possibly used for the halogenation of alkenes. Hydrogenation of alkenes produce saturated hydrocarbons - alkanes. Alkanes can also be used in anaerobic respiration as in some bacteria as a source for carbon and energy and the oxidation of alkanes probably takes place in the cell membrane of cancer cells from where they can easily escape and their smell can be picked up by trained dogs or their presence in exhaled breath of patients with tomours in the lungs can tested by gas chromatography/mass spectroscopy.
Many halogenated alkanes and benzene and their related compounds are carcinogenic as they produce hydroxyl radicals and drive the ROS-induced toxic pathways and lipid peroxidation increases.. At this stage there is more pain in the cancer patient.
Excessive reactive oxygen species and hydroxyl radicals in cells rapidly oxidize virtually all important biomolecules. It can be seen that the normal cell transforms into a cancer cell through changes in cellular chemistry that alters its energy pathway and finally, the cancer cell becomes a complex alcohol-alkane bioreactor fueled by ROS and (OH+) using alternative pathways and lipid peroxidation increases.
There is increased lipid peroxidation in cancer patients and elevation of the concentration of malondialdehyde (MDA) (see;Ray et al, Lipid peroxidation, free radical production and antioxidant status in breast cancer. Breast Cancer Res Treat 59:163-70, 2000). Malondialdehyde can react with DNA bases to form the mutagenic adduct malondialdehyde-deoxyguanosine (M1-dG) (Simon et al, Levels of Malondialdehyde-Deoxyguanosine in the Gastric Mucosa Relationship with Lipid Peroxidation, Ascorbic Acid, and Helicobacter pylori, Cancer Epidemiology Biomarkers & Prevention Vol. 10, 369-376, April 2001).
In this complex ROS bioreactor, there appears to be species-dependent alternatives in the initiation of toxic pathways depending on biochemicals present in the cytoplasm. With the initial formation of alcohol and lactate, benzene is eventually formed either through lactones as intermediates that possibly require glutathione or metabolic breakdown of alcohol to aldehydes and acetaldehydes to produce phenylacetaldehyde and benzaldehyde or acetyldehyde-thiamine pyrophosphate which is very unstable and diacetyl is formed directyl that can be converted into acetoin and 2,3-butaedial and 2-butanone. That may explain thiamine deficiency in some (perhaps 30%) of patients with solid tumours and fast growing malignancies (see; Boros et al, Thiamine supplementation to cancer patients: a double edged sword; Anticancer Res 1998;18(1B):595-602).
Benzene increases lipid peroxidation through the generation of hydroxyl radicals. It is carcinogenic and promotes tumour growth. It is also produced in tumour cells in sufficient amounts to maintain lipid peroxidation in the cell membranes of cancer cells and together with alkanes, maintain the oxidized state of the lipid part of the cell membrane so that it maintains the cell membrane as a generator of ROS and maintains the acidity in the cytoplasm and that, in turn, maintains the production of alcohol and lactate.
Napthalene is formed from two molecules of benzene and perhaps napthalene is also formed in tumour cells in trace amounts as it also generates hydroxyl radicals. The first step in the metabolism of naphthalene is formation of naphthalene-1,2-oxide through the action of cytochrome P-450 enzymes in the presence of the coenzyme NADPH. These oxides are metabolized further by three pathways, one of which involves conjugation by glutathione transferases. (Napthalene, CAS 91-20-3, First Listed in the Eleventh Report on Carcinogens (2004).
ROS redox of benzene and phenol to quinol and other myelotoxic metabolites also uses up glutathione and produces more ROS to support cancer cell biochemistry. Benzene is also oxidized by ROS to yield a metastable radical that rearranges to form phenol as the major metabolite, with only traces of catechol (3%) and henylmercapturic acid (1%), a pathway that uses up glutathione. Hence it is not a simple case of ROS or free radical oxidation of cellular glutathione. Glutathione conjugation is associated with the free radical scavengining (detoxification) mechanism in healthy cells but it can also be used by cancer cells in toxic pathways to generate toxic compounds and may also explain the high concentration of glutathione in cancer cells.
Why do fat soluble antioxidants such as CLA or coQ10 show antitumeric or anticancer activity and promote regression of tumours? The answer obviously lie in their ability to provide electrons to oxidized LDL and other oxidized lipid molecules and they also scavenge free radicals in the cell membranes and stabilize biomembranes, restore their original functional integrity and prevent lipid peroxidation in cancer cells so that such lipids do not form toxic metabolites that generate more ROS to fuel cancer cell biochemistry. And so, they must be used together with ROS scavenging antioxidants for combined effect.
It is clear that the first step in cancer therapy is to stop consuming long chain fatty acids and to switch to medium chain fatty acids, stop consumption of toxic substances or those substances that will produce toxic metabolites and that includes cigarettes, alcohol, artificial agents suspected of producing toxic metabolites such as formaldehyde etc and products that deplete minerals in the body or produce metalloproteins in the body and any other substance that generates free radicals in large numbers and cause lipid peroxidation. It follows that it is advisable to stop the consumption of diary milk as it contains a factor that accelerates cell proliferation and since diary products contain lactones and other lipid molecules produced under anaerobic respiration that could undergo lipid peroxidation to produce toxic metabolites.
The second step is the administration of fat soluble antioxidants to stabilize the cell membrane and restore its integrity so as to reduce ROS generation in the cell membrane and prevent lipid peroxidation, together with antioxidants that effectively scavenge ROS. That could lower the acidity in the cytoplasm and promote the rerouting of glucose in the normal pathway to form ATP and as more ATP is formed within the cell, it will promote greater stability in the cell membrane. Reducing the ROS could also interrupt the toxic pathways and reduce the production of toxic chemicals in tumor cells..
A key tool in this strategy for cancer therapy is the use of an intervention that initiates Fenton Reactions to convert the ROS and Hydroxyl radicals into water and oxygen. That would aid to rapidly alter the acidity of the cytoplasm and promote ATP production and quickly shut down the alcohol-alkane bioreactor.
Finally, any natural biomolecule that indirectly induces hydrogen peroxide formation in cancer cells while it promotes free radical scavenging activity in normal cells and promotes aerobic respiration must be considered. There are studies that point to the use of natural vitamin C and a recent study indicates the indirect production of hydrogen peroxide formation in cancer cells that kills them. That needs further research and remains an interesting option as vitamin C also boosts immune function and white blood cell function.
Fat soluble antioxidants, such as CLA that help to reduce circulating lipids and promote weight loss by reducing the fat composition in the body would find a very useful role when used together with other fat soluble antioxidants to neutralize oxidized LDL. Consumption of medium chain fatty acids also promote weight loss and provide a higher proportion of non-glucose energy to cells in the body. The growth of symbiotic bacteria in the gut must be promoted as they produce short chain fatty acids which are very useful to the body and promote health. Antibiotics minimize this potential.
The fourth step entails the further disruption of cancer cell biochemistry, namely its enzymes and free metal ions and iron-sulfur proteins (metalloproteins) through metalloprotein inhibitors. Spices are known for their anti-cancer properties and science is rediscovering the role of spices such as black pepper, ginger, turmeric, cinnamon, clove etc that can be used and there are other ubiquitous natural biomolecules in the body, such as taurine that can be administered.
The beneficial effects of taurine as an antioxidant in biological systems have been attributed to its ability to stabilise biomembranes, to scavenge reactive oxygen species, and to reducethe peroxidation of unsaturated membrane lipids. Taurine (2-amino ethane sulphonic acid) is asulphur-containing amino acid that is the most abundant free amino acid in excitable tissues