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Prostate Cancer, Inflammation and Antioxidants

Written By

Marika Crohns, Tuomas Westermarck and Faik Atroshi

Published: January 16th, 2013

DOI: 10.5772/53296

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1. Introduction

Prostate cancer (PCa) is a long latency type of tumour that usually develops in men older than 50 years of age. Prostate epithelial neoplasia (PIN), the initial malignant lesion, progresses to invasive carcinoma over the course of years. Because of the particular features of prostate carcinogenesis, this type of tumour may represent a paradigm for cancer prevention. The lack of a comprehensive aetiology for prostate cancer and the need for an effective and inexpensive biological treatment modality, devoid of side effects, has resulted in a multitude of therapeutic trials. Present evidence suggests that chemo preventive agents may be used in cancer treatment (Tallberg et al. 2008; Crohns et al. 2009). Because they are considered pharmacologically safe and derived from natural sources, most chemo preventive agents can be used in combination with chemotherapeutic agents to enhance the effect at lower doses and thus minimize chemotherapy-induced toxicity. There are various therapies that can successfully reduce the size of tumours, however, often patients suffer a relapse and the tumour re-grows. Some researchers believe that this happens because the therapies fail to eradicate a small proportion of cells that drive tumour growth known as cancer stem cells. They believe that these are the cells that should be targeted to eliminate the tumour forever.

Today, cancer is considered to be a complex multistep disorder, the result of a combination of factors including exposure to radiation and/or carcinogens (damage to DNA), infection, genetics, aging, immune function disorders, and lifestyle factors such as smoking (Nelson et al. 2003; Mahan et al. 2004). Several clinical trials have evaluated the effect of dietary nutrients on prostate tumour development. These dietary agents may help to suppress the transformative, hyper proliferative and inflammatory processes that initiate carcinogenesis. The curative effect does not seem to involve apoptosis (Tallberg and Atroshi, 2011).

Most human diseases are due to chronic inflammation resulting in loss of function of a joint, a blood vessel or an entire organ. In some organs, such as the heart and brain, acute inflammation can be fatal. Oxidative stress is a major by-product of cellular metabolism and its regulation is critical for preventing disease and aging. Levels of reactive oxygen species (ROS) are generally higher in proliferating tumour cells than in normal cells, and this may explain why ROS is a key component in the efficacy of chemotherapeutic drugs (Crohns et al. 2009).

This review focuses on the mechanisms of free radical formation and ROS signalling in prostate cancer on the basis of current literature. We also highlight the mechanisms by which inflammatory processes contribute to prostatic carcinogenesis and how antioxidants react to neutralize free radicals.


2. Prostate cancer as an age-related disease

Prostate cancer is the common among men in the developed world. The risk increases after the age of 50 (Sakr et al., 1994; Abate-Shen and Shen, 2000; Schaeffer, 2003; Yancik 2005). Aggressive treatment for older men is not advisable because of an increased risk of short-term and long-term treatment-related adverse effects (Lu-Yao et al. 1999). The development of cancer lesions can be in two different regions of the prostate gland, in the peripheral zone, which is most common, and the remaining lesions are found in the transition zone located in the periurethral region (McNeal, 1988). Prostatic cancer multifocality makes accurate clinical staging difficult, and repeated revisions have been undertaken in an effort to optimize prognostic accuracy (McNeal, 1988; Andreoiu and Cheng, 2010).

Normal aging is associated with changes in body composition. While treatments for the disease continue to improve with each passing decade, the disease itself has likely been around since ancient times. Recently it was documented that a mummy - thought to be a man in his 50s - had numerous sclerotic spots throughout the bones of his pelvis and lower spine that were most consistent in appearance with metastases from prostate cancer (Prates et al., 2011).


3. Risk factors for prostate cancer

The etiological factors associated with prostate cancer are poorly studied compared to other common cancers. It is suggested that diet (Fair et. 1997; Schulman et al. 2001) and environmental differences (Muir et al. 1991) play important roles (Shimizu et al., 1991; Minami et al., 1993). For example, it is not known whether decreasing fat or increasing fruits and vegetables in the diet helps to decrease the risk of prostate cancer or death from prostate cancer. High intake of fat, especially total fat and saturated fat, is a risk factor for prostate cancer (Andersson et al. 1996; Kolonel, 2001). This has been explained by the evidence indicating that fat may be mediated through endogenous hormones (Bosland, 2000). Phytoestrogen metabolites have been studied, and dietary habits are probably an important factor contributing to the geographic variations observed in some Asian men compared to European men, which may explain the low incidence of prostate cancer in Asia (Adlercreutz et al., 1993).


4. Mechanism of prostate cancer cell

Living cells have three main systems for protection and repair under oxidative stress: (1) direct antioxidant enzymes (Superoxide dismutase (SOD), catalase, peroxidises), (2) proteases and phospholipases activated by oxidative modification of membranes, (3) lipid and water soluble antioxidants (Sies, 1997; Finkel and Holbrook, 2000). Normalization of malignant gene transcription in an organ requires dietary correction of the etiologic long-standing metabolic deficiency involving six or more inter-linked natural factors aided by hormonal equilibrium, enhanced by specific autologous immunotherapy. In bio-immunotherapy this therapeutic bio-modulation is aims to simulate specific leukaemia, adenocarcinoma or sarcoma regulatory codes, leading to cancer cure by forcing tumour cells back into healthy gene transcription, without apoptosis. According to Lukacs et al. (2010), prostate cancer can be initiated by so many different mutations, and if a key regulator of self-renewal can be found, then partially one may control the growth of the cancer, no matter what the mutation is. Their approach, which aims to attack the process that allows the cancer cells to grow indefinitely, may provide an alternative way of treating cancer by targeting the core mechanism of cancer cell self-renewal and proliferation (Lukacs et al.2010).

Cells are often exposed to a high load of oxidants and free radicals. Oxidative stress can occur as a result of increased metabolic rate, increased oxygen tension, compromise of normal cellular antioxidants and many others endogenous and exogenous factors (Figure 1). Cell motility is a complex biological process, involved in development, inflammation, homeostasis, and pathological processes such as the invasion and metastatic spread of cancer (Collins et al. 2006). Cancer metabolism is a factor that might be exploited as a potential therapeutic target for drug discovery also on how a cancer cell differs in its metabolism to that of a rapidly proliferating normal cell (Vander Heiden et al. 2009). By small interfering RNA–based functional screening of over 200 metabolic enzymes, transporters, and regulators to identify those selectively required for prostate cancer cell survival. Ros and co-workers showed that treatment with a chemical antioxidant rescued the viability of PFKFB4 (one of the genes identified) -deficient prostate cancer cells, further suggesting that PFKFB4 mediates ROS detoxification in cancer cells. Together, these findings reveal that prostate cancer cells are exquisitely sensitive to metabolic perturbations that affect the balance between glucose and the pentose phosphate pathway and implicate PFKFB4 as a potential therapeutic target (Ros et al 2012).

Under normal conditions, the antioxidant defence systems are probably capable of maintaining a low steady-state level of damage and thus protecting the cells (Zhou et al.2003). Among the risk factors for the development of prostate cancer are ageing and lifestyle. Under situations of oxidative stress and with increasing age the organism may not be able to maintain homeostasis with deleterious and potentially unfortunate consequences.

Figure 1.

The prostanoid system may belong to the adaptive mechanisms by which the cell reacts to its environment. The reaction may be triggered by chemical, mechanical and other stimuli. Prostacyclin (PGI2) and PGE2 stimulate ATPases and the formation of intracellular cyclic AMP, which usually stabilize the cell membrane. TXA2 among others may activate calcium-related processes which may lead to smooth muscle contraction, platelet aggregation and secretory events. PGE2 has the capacity for both excitatory and inhibitory activities and it is often released in stressful situations. (Parantainen et al.1988)


5. Inflammation and prostate cancer

Inflammation involves the induction of complex, coordinated chemical signals and associated physiological processes following injury that promote “healing” of damaged tissues (Balkwill and Mantovani, 2001; Rakoff-Nahoum, 2006; Mantovani et al, 2008). Early responses include increases in vascular permeability and activation, together with the directed migration of leukocytes (neutrophils, monocytes and eosinophils) towards the site of injury, where the ground-work is being laid for the formation of a new extracellular matrix. The directional migration is mediated by secreted chemokines that form a concentration gradient towards the site of inflammation (Koopmann and Krangel, 1997). The extracellular matrix provides the structure upon which cells (fibroblasts and endothelial cells) can migrate and proliferate, regenerating new tissue and a vascular network. In later stage of the inflammatory response, the macrophages are the dominant cell type, orchestrating and directing the healing process. Normally, inflammation is a self-limiting process due to the production of anti-inflammatory cytokines, which buffer the effect of pro-inflammatory cytokines. The cytokine/chemokine pattern persisting at the inflammatory site is important in the development of chronic disease. Deregulation of any of the cooperating factors can lead to prolonged inflammation with chronic exposure to cytotoxic mediators (Coussens and Werb, 2002). Chronic inflammation can be caused by a variety of factors, including bacterial, viral, and parasitic infections, chemical irritants, and non-digestible particles, but often the underlying cause is unknown. The longer the inflammation persists, the higher the risk of associated carcinogenesis (Shacter et al., 2002, Coussens and Werb, 2002).

At the site of inflammation, caused by either wounding or infection, phagocytic cells (e.g. neutrophils and macrophages) generate reactive oxygen and nitrogen substances (Atroshi et al. 1988; Gallin, 1992), but these cells also synthesize and secrete large quantities of growth factors and a number of potent angiogenic factors, cytokines, and proteases, all of which are important mediators in the tissue regeneration, but can also potentiate neoplastic tumorigenesis. Prostaglandins, cytokines, nuclear factor NFkB, chemokines and angiogenic factors are the main molecular players that link inflammation to genetic alterations. However, free radical species derived from oxygen (ROI) and nitrogen (RNI) are the main chemical effectors (Jackson et al. 1997; Baron and, Sandler, 2000; Federico et al. 2007). Various carcinomas (including cancers of the liver, bladder, colon, stomach, and oesophagus) have been shown to arise from areas of infection and inflammation (Federico et al. 2007). Over 15% of all malignancies worldwide are attributable to infectious agents, and inflammation is a major component of these chronic infections (Kuper et al., 2000; Ibrahim and Makkiya, 2011). Colon cancers arising in individuals with inflammatory bowel disease (e.g. chronic ulcerative colitis or Crohn’s disease) and stomach cancers caused by chronic Helicobacter pylori infection are among the most intensively studied and well established types of cancer associated with inflammation of different origins (Coussens and Werb, 2002).


6. The role of inflammation in the pathogenesis of prostate

Although it has been established that chronic inflammation plays a causative role in the development of many human cancers, the contribution of inflammatory processes to the development of prostate cancer has not been extensively studied. Bioactive food components are increasingly being evaluated as potential prostate chemopreventive agents (Barqawi et al. 2004; Chong and Rashid, 2005; Sonn, et al. 2005; Hsu et al 2010; Schellhammer, 2012). One such agent is resveratrol, a phytochemical which has been considered as a chemopreventive for human prostate cancer (Ratan et al. 2002; Stewart et al. 2003 ).

The contribution of inflammatory intermediates such as eicosanoids in cancer initiation and progression is another area of interest. These intermediates might form the link between inflammation and cancer. Interest in the relationship between chronic prostatic inflammation and prostate cancer is increasing. Proliferative inflammatory atrophy, or proliferative inflammatory atrophy (PIA), consists of lesions in the prostate characterized by atrophy of the epithelium and by an increased proliferative index (De Marzo et al. 1999). These lesions are common in older men and have been hypothesized to be a precursor of prostate cancer (Nelson et al. 2004; De Marzo et al. 2007). More knowledge about the risk factors could lead to better preventive measures together with better treatments.

Evidence suggests that inflammation is vital for the aetiology of prostate cancer and the pathogenesis of PCa reflects both hereditary and environmental components. These evidence stems from epidemiological, histopathological and molecular pathological studies (Ames et al., 1995; De Marzo et al. 1999; Coussens and Werb, 2002). More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with a reduce incidence of prostate cancer (Gupta et al. 2000). The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex.

Some studies have suggested that prostatitis, inflammation of the prostate gland that includes acute or chronic bacterial infection, may be linked to an increased risk of prostate cancer (Dennis et a. 2002; Roberts et al. 2004). This link was explained that chronic inflammation within the prostate due to the exposure of microbial agents stimulates the production of ROS and inflammatory cytokines leading to carcinogenesis (Coussens and Werb, 2002; De Marzo et al. 2007).

Chronic inflammation has been associated with the development of malignancy in several other organs such as the oesophagus, stomach, colon, liver and urinary bladder. Inflammation is thought to incite carcinogenesis by causing cell and genome damage, promoting cellular turnover, and creating a tissue microenvironment that can enhance cell replication, angiogenesis and tissue repair. Epidemiological data have correlated prostatitis and sexually transmitted diseases with an increased risk of prostate cancer and intake of anti-inflammatory drugs and antioxidants with a decreased risk. Evidence from genetic and molecular studies also supports the hypothesis that prostate inflammation and/or infection may be a cause of prostate cancer. In 1999 De Marzo et al proposed that proliferative inflammatory atrophy (PIA) is a precursor to PIN and cancer. Further research will provide opportunities for the discovery and development of strategies for treatment and prevention of prostate cancer (Sugar, 2006).

Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. Cancer lesions can develop in two different regions of the prostate gland, most commonly (in ~80% of cases) in the periphery zone, while most of the remaining lesions are found in the transition zone, which is located in the periurethral region (McNeal, 1968, 1988).


7. Possible interaction between prostaglandins and glutathione metabolism in prostate cancer

Prostaglandins (PGs) constitute a whole family of peroxidized lipids formed in most cells. Almost any kind of stimuli be it mechanical, chemical, physiological or traumatic, may initiate the formation of different kinds of PGs (Atroshi et al. 1986). Thus the particular importance of the local PG-impact is usually very difficult to evaluate. Some PGS, like PGEs and PGI2 (prostacyclin), are potent triggers of inflammatory symptoms. The main roles for PGEs and PGI2 in inflammation may in fact be in the generation of hyperalgesia, sensitization of the tissue to the irritant and pain producing activity of the amine and peptide type of mediators of inflammation (Ferreira and Nakamura, 1979; Ferreira 2002). On the other hand, these PGs have a marked tissue protective function, e.g. in preventing vasoconstriction and platelet aggregation. Other prostanoids (PG-like substances), like PGD2, PGF2α and thromboxane A2 (TXA2), are mostly vasoconstrictors. Their formation may be associated with allergic and other reactions of hypersensitivity, and TXA2 is a very potent aggregator of platelets.

Prostaglandins play a role in the regulation of several important physiological and pathological processes, and evidence (Marnett, 1992; Thun et al., 1991; Taketo, 1998; Samuelsson et al., 2007) suggests that they could be involved in tumour progression. Studies have demonstrated that PGE2 and its EP receptors are implicated in promoting carcinogenesis in different types of cancer (Wang and Klein, 2007). Arachidonic acid (AA) is the precursor for prostaglandin E2 (PGE2) synthesis and increases growth of prostate cancer cells (Van et al., 1998). However, the real sources of PGs are not well known and are a matter of speculation. For example we do not know for sure if the PGs originate in the blood, inflamed tissue, etc. There are several possibilities:

  1. Bacterial toxins might contribute to the PG-release (figure 2). This was clearly demonstrated by Giri and coworkers (1984), and similar mechanisms might operate in the spontaneous disease as well (Liu et al. 2011; Sanz-Motilva et al. 2012).

  2. The production of PGs is greatly increased by polymorphonuclear leukocytes. Neutrophil invasion is a typical feature in inflammation (Atroshi et al. 1988).

  3. Changes in tissue protein and electrolyte contents are factors that have marked effects on PG-production (atroshi et al. 1988). Albumin is a typical factor increasing the formation of PGs, particularly that of PGF2α.

  4. Inflammatory mediators are factors that might contribute to the formation of PGs. (e.g. monoamines and peptide hormones).

Figure 2.

Possible interaction between erythrocyte and inflamed tissue during infection/inflammation. Oxygen free radicals produced by hypoxia, bacterial toxins and phagocytosis increase lipid peroxidation and peroxidative stress in the erythrocyte. Pyogenic bacteria as well as white cells may stimulate the synthesis of mucoproteins. The pus formed has antioxidant activity and the formation of oxygen free radicals is needed. GSH and other antioxidant enzymes represent the intracellular charged compounds, potential sources of reducing equivalents. The intracellular enzymes (GSH, GSHPX etc.) may greatly affected by oxygen free radicals and lipid peroxidation associated e.g. in infection, hypoxia and cancer. Destruction of erythrocytes is one possible source of GSH and other antioxidant enzymes which are elevated in the inflamed tissue. (Atroshi et al.1986)


8. Possible importance of leukotrienes

Leukotrienes (LTs) are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid through the 5-lipoxygenase pathway (Matsuyama et al. 2010; Haeggström and Funk, 2011). Leukotrienes and other lipoxygenase products are synthesized from the same precursor fatty acids as PGs, and substantial changes in PG/LT balance are possible during inflammation and infection (Figure 3). LTs are highly vasoactive, and together with PGs they may contribute to the local haemodynamic changes in the inflamed tissue. Moreover, some LTs are very active leukotactic agents, and LTB4 in particular could contribute to the massive invasion of neutrophils in the inflammatory area. PGE2 and LTB4 are involved in inflammation and carcinogenesis in several tissues. PGE2 and inflammation may be associated to stromal benign prostatic hyperplasia whereas LTB4 may play a role in prostate carcinogenesis; cancerous samples had higher LTB4 levels than pericancerous samples, but there was no difference in PGE2 levels (Larré et al. 2008).

Figure 3.

Enzymes with peroxidase activity are needed to reduce the endoperoxide PGG2 to PGH2 (1), and specific isomerases resembling GSH-S-transferase (2) reduce PGH2 further to PGs and prostacyclin (3). GSH and GSH-enzymes are involved in the formation of leukotrienes as well. One molecule of GSH (4) is attached to LTA 4 to form LTC4, the first of the cysteinyl leukotrienes (C, D, E). The peroxidative capacity of erythrocytes may participate in the conversion of LTA 4 to LTB4. Peroxidases are also needed to reduce other lipid hydroperoxides to corresponding alcohols (6) to prevent the enzyme destruction caused by oxygen free radicals (7). The activity of LTB4 may be mediated by PGs (5). (Atroshi et al. 1986)

Lipoxygenase-like activities are seen in the phagocytosis and bacterial killing. Lipid peroxidation as such is a source of oxygen free radicals. On the other hand, the radicals are among the most potent triggerers of lipid peroxidation. Some free radicals, particularly the hydroxyl radical (•OH) are very toxic to the tissues. During reduction of the 15-hydroperoxide, to the corresponding alcohol •OH is formed and the enzyme systems that form PGI2 may be injured. Leukotriene B4 (LTB4) has been implicated in prostate and colon carcinogenesis. The anticancer effect of celecoxib is COX-2-independent in HT-29 and PC-3 cells and in HT-29 cells primarily via down-regulating LTB4 production (Gao et al., 2010). Matsuyama and co-workers (2010) have demonstrated that CysLT1R expressed in urological cancer may play a crucial role in carcinogenesis and may therefore be a novel target in the treatment of urological cancer. An increasing body of evidence supports an acute role for 5-LO products already during the earliest stages of pancreatic, prostate, and colorectal carcinogenesis (Steinhilber et al., 2010).


9. The role of GSH-enzymes in the metabolism of arachidonic acid

The tissue content of GSH is normally very high, in some tissues the level is up to the 5 mM. The functions of GSH are often tissue protective, and there are numerous enzymes in which GSH plays a central role as a cofactor.

Typical GSH-enzymes include GSH-peroxidase (GSH-Px), located in the circulation almost exclusively in the red cells, various GSH-transferases that have peroxidise-like activity and bind chemicals and γ-glutamyl transferase which reflects the function of the liver and is involved in the transport of amino acids across the cell membrane. GSH is also consumed by some cytochromes, most notably cytochrome P-450.

Several steps in the metabolism of arachidonic acid may be normally regulated by GSH-enzymes (Rouzer et al. 1982). It was an early observation that GSH may function as a chemical cofactor or coenzyme in the formation of some PGs, particularly PGEs (Mimata et al. 1988). Specific, atypical GSH-S-transferases are needed in the isomeration of PG-endoperoxides (the intermediary step) to PGEs and PGDs (Hubatsch et al. 2002). Ghosh (2004) demonstrated that selenium significantly reduced the incidence of clinical prostate cancer. A high intake of dietary fat containing arachidonic acid or its precursor fatty acids should be administered when selenium is used for the management of prostate cancer, as it has been suggested that a combination of selenium and 5-lipoxygenase inhibitors may be an effective regimen for prostate cancer control (Ghosh and Myers, 1998; Ghosh, 2004). A low prostatic arachidonic acid level was found in patients undergoing prostate surgery for either benign or malignant disease. Showed a low prostatic arachidonic acid level, which was explained as a result of the increased use of arachidonic acid for the production of prostaglandins and/or leukotrienes (Faas et al. 2003; Tilg and Moschen, 2006; Calder 2012 ).

There is little data available on these parameters in the prostate. Richie et al (2012), working with age related changes in selenium and glutathione levels in different lobes of the rat prostate found an increased level of oxidative stress together with decreases in selenium and the major cellular antioxidant glutathione (GSH). They compared the levels of selenium, GSH and protein-bound GSH (GSSP) in blood and prostate tissues in rats. Their findings of age-related changes in GSSP and selenium in the DL prostate are consistent with the sensitivity of this lobe to carcinogenesis and, thus, may be playing a mechanistic role (Richie et al. 2012). Selenium is an integral part of GSH peroxidase, the enzyme that mediates antioxidants by glutathione (Parantainen et al. 1988). Studying the metabolic profiles of human prostate cancer tissues it was shown a significant decrease in reduced glutathione (GSH) during cancer progression from low- to high-grade Gleason scores (Sreekumar et al. 2009; Pavlou and Diamandis, 2009). Some studies found a lower Se concentration in the whole blood and plasma in benign prostatic hyperplasia (BPH) patients compared to healthy controls was observed by Eichholzer et al. (2012); also they found a lower activity of erythrocyte GPx. A significant inverse association between serum Se concentrations and the risk of BPH was shown (Eichholzer et al. 2012).

The formation of PGs is a very specific form of lipid peroxidation, and in these processes GSH-Px may have a central regulatory role. Some pGs inhibit the formation of lipid peroxides, while a certain level of peroxides is needed to maintain normal PG-production (Hemler and Land, 1980; Sugino et al. 2001). Such a “peroxide tone” is a crucial factor in the regulation of the metabolism of arachidonic acid in toto. Peroxidases may have a key role in eliminating the oxygen free radical during the conversion of endoperoxides to corresponding alcohols. The hydroxyl radical formed from 15-HPETE may thus be trapped (Chance et al. 1979; Flohé and Ursini, 2008).

Considering the circulatory peroxides, the functioning of the erythrocyte GSH-Px may have a crucial role. During infection and inflammation there may be a marked reduction in the erythrocyte count. Such anaemia may be due to haemolytic processes in which lipid peroxidation and the formation of free radicals may be the key event.

In the formation of leukotrienes, the GSH-enzymes γ-GT and GSH-S-transferases have a key role. The whole group of cysteinyl leukotrienes are formed by adding GSH to LTA4, which gives rise to LTC4 and, when the GSH is split, to LTD4, LTE4 and LTF4. In the formation of the other type, LTB4, GSH does not have a direct role (Morris et al.1981). However, LTA4 is reduced to LTB4 on contact with erythrocytes, which points to a certain importance of the peroxidise-like mechanisms, possibly GSH-Px, so abundant in the red cell. Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, implicated in numerous diseases including prostate cancer. An LTB4 tissue level was shown to play a role in in benign and cancerous prostates. Cancerous from patients’ sample had higher LTB4 than pericancerous samples (Larre et al. 2008).


10. Diet, inflammation and prostate cancer

The causes of cancer have been largely attributed to genetic and environmental factors, including lifestyle, and are generally thought of as either avoidable or unavoidable. Dietary habits have been considered for years in epidemiological and case controlled studies to have an impact on cancer development and prevention. However, this association between diet and cancer has never been as clear as the correlation between smoking and cancer. Differences in diet and lifestyle may account for the variability of prostate cancer rates in different countries (Manolio et al. 2009). Good nutrition may reduce the incidence of prostate cancer and help reduce the risk of prostate cancer progression (Miller et al 2012). Several studies suggest a relationship between diet and prostate cancer risk; however, nutritional studies are difficult to perform because of the inherent heterogeneity of any study population (Klein et al.2006), the variations in individual lifestyles, and the quantitative and qualitative complexity in food and food products (Giovannucci et al, 1993; Huang, 2006). Therefore, randomized and carefully controlled studies can address the relation between prostate cancer and nutrition.

The importance of nutrition in disease prevention and treatment has gained much attention in recent years. Diet may represent a modifiable prostate cancer risk factor, but a vegetable-based prostate-healthy diet is a major change for most men (Carmody et al. 2008). Other study suggest that keeping the appropriate body mass and level of cholesterol by proper diet and physical exercises may be the prophylaxis of prostate cancer (Pilch et al 2012). The cancer preventive activity of vitamin E has been suggested by many epidemiologic studies. Yang and co-workers suggested that vitamin E, as ingested in the diet or in supplements that are rich in γ- and δ-tocopherols, is cancer preventive; whereas supplementation with high doses of α-tocopherol is not (Yang et al 2012). It has been suggested that intake of vegetables and fruit plays a role in protecting against prostate cancer development (Chan and Giovannucci, 2001; Key et al., 2004). Furthermore, vitamins and trace elements have been studied for their roles in prostate cancer pathogenesis (Chanand Giovannucci, 2001; Moyad et al. 2002; Tallberg and Atroshi, 2011).

In order to disentangle the association of diet and prostate carcinogenesis better understanding of the human genome will further accelerate nutrigenomics applications and the development of nutritional modifications including personalized nutrition for our well-being and will also present a strong influence on future drug discovery (Lundstrom,2012). However, antioxidant supplements so far tested seem to offer little improvement over a well-balanced diet, possibly because of the choice of the substances tested or of an excessive dosage (Fair and Wynder, 1996; Dolara et al. 2012). Future trials of nutritional medication might help to disentangle the association of diet and prostate carcinogenesis.

The effect of diet can be direct, via the cumulative effect of exposure to nutrients and carcinogens in foods; in this case, the balance of cancer-promoting and -protective substances may contribute in defining cancer risk (Antila et al. 1996; Adhami and mukhtar, 2012; Adhami et al.2012). There are also indirect ways by which diet affects the cancer process. These include the effects of diet on energy balance and risk of obesity and the hormonal and metabolic responses related to energy balance.

There is an emerging consensus that situations of acute or chronic imbalance between the antioxidative capacity of cells and tissues, and the production of pro oxidative species, is associated with the development of a number of human diseases. Despite enormous interest in the area of antioxidants as therapeutic tools, the development of foreign compounds as therapeutic antioxidants has provided little therapeutic benefit.

  1. Many important physiological functions, such as the regulation of cell cycle (mitogenesis and apoptosis), are known to be tightly coupled to the induction of controlled episodes of oxidative stress in biological systems. This entails problems in terms of potential side effects for antioxidant therapy, which have been largely ignored in most clinical use of antioxidants. This may have serious implications for the choice of antioxidant principle to be used.

  2. The actual choice of antioxidant therapy is it xenobiotic or endogenous, should be indicated based on sound molecular knowledge of the involvement of oxidative stress in the actual pathology.

  3. Dietary habits are probably an important factor that contributes to the geographic variations in prostate cancer rates. A large number of epidemiological studies have investigated the association between dietary factors and prostate cancer. Epidemiologic studies on prostate cancer have extensively investigated dietary risk factors (Kolonel, 2001; Park et al. 2007). Suggesting that diet and environmental differences play important roles in prostate cancer (Shimizu et al., 1991; Minami et al.,1993).

11. Conclusion

Cancer is due to the accumulation of DNA mutations that confer a growth advantage and invasive properties on clones of cells. A variety of external factors including nutrients in the environment interacting with genetic susceptibility influence the accumulation of mutations in cells. Nutrition is important at every stage of carcinogenesis from initiation to promotion to progression and metastasis. In spite of the fact that prostate cancer is the most common male cancer in many countries in the developed world, little is known of risk factors and predisposing conditions.

The number of prostate cancer cases around the world is increasing. Its incidence has been associated with ageing, environmental factors and changes in lifestyle. Based on some research in animals and people, certain dietary measures have been suggested to prevent the progression of prostate cancer. However, there is no solid evidence that a healthy diet can prevent people from developing prostate cancer. The reasons that patients with prostate cancer are using the dietary supplements are to enhance their health. Such dietary elements may also limit drug efficiency.

Oxidative stress has been suggested to play a key role in carcinogenesis. Free radicals have been shown to mediate the anti-cancer actions of many chemotherapeutic regimens. Despite active investigation, knowledge is lacking concerning the local and systemic effects of free radical-generating treatments in cancer. Free radicals are among the environmental factors that might contribute to cancer process (Atroshi et al. 2010). While it has not been conclusively determined whether free radicals are a cause or an effect of prostate cancer, it is clear that characteristic types of free radical damage increase with cancer. However, understanding the nature of that particular tumour can help us to optimize therapy or to design therapeutic approaches. Recently, Maddams and co-workers have shown that a large increase in cancer can be expected in the oldest age groups in the coming decades, and therefore there is an increased demand upon the right treatment and health services (Maddams et al. 2012).


  1. 1. Abate-Shen C and Shen MM. Molecular genetics of prostate cancer. Genes Dev. 2000 14: 2410-2434.
  2. 2. Adhami VM, Mukhtar H. Human Cancer Chemoprevention: Hurdles and Challenges. Top Curr Chem. 2012 Jul 12. [Epub ahead of print.
  3. 3. Adhami VM, Syed DN, Khan N, Mukhtar H. Dietary flavonoid fisetin: A novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem Pharmacol. 2012 Jul 25. [Epub ahead of print
  4. 4. Adlercreutz H, Markkanen H, Watanabe S. Plasma concentrations of phytooestrogens in Japanese men. Lancet, 1993, 342:1209-1210.
  5. 5. Ames, B. N., Gold, L. S. & Willett, W. C. The causes and prevention of cancer. Proc. Natl Acad. Sci. USA ,92, 5258–5265, 1995.
  6. 6. Andersson SO, Wolk A, Bergstrom R, et al. Energy, nutrient intake and prostate cancer risk: a population-based case-control study in Sweden. Int J Cancer 1996;68:716–22.
  7. 7. Andreoiu M, Cheng L. Prostatic cancer multifocality makes accurate clinical staging difficult, and repeated revisions have been undertaken in an effort to optimize prognostic accuracy. Hum Pathol. 2010 ;41(6):781-93.
  8. 8. Antila E, Mussalo-Rahamaa H, Kantola M, Atroshi F, Westermarck T. Association of cadmium in human breast cancer. Sci. Total Environ. 1996, 186:251-256.
  9. 9. Atroshi F, Parantainen J, Sankari S, Österman,T. Prostaglandin and glutathione peroxidase in bovine mastitis. Res. Vet. Sci., 1986, 40:361-366.
  10. 10. Atroshi F., Sankari S., Työppönen J. and Parantainen J. Inflammation related changes in trace elements, GSH-metabolism, prostaglandins and sialic acid. In: Trace Elements in Man and Animals 6 (Hurly LS ; Keen CL; Lonnerdal Bo, & Rucker RB, Editors), Plenum Press, New York & London, 1988, pp.97-99.
  11. 11. Atroshi, F., Tallberg Th, Abdulla VM, Westermarck T. The Impact of Heavy Metals on Health with special emphasis on Cadmium Carcinogenesis. In: Natural Resource Conservation and Environment Management (Bhagirathi Behera, S.P.Panda, Editors), APH Publishing Corporation, New Delhi, pp. 1-12,2010
  12. 12. Balkwill F.& Mantovani A. Inflammation and cancer: back to Virchow? Lancet 357, 539-545,2001.
  13. 13. Baron JA, Sandler RS. Nonsteroidal anti-inflammatory drugs and cancerprevention. Annu Rev Med 2000; 51: 511–23.
  14. 14. Barqawi, A., Thompson, I. M., Crawford, E. D.: Prostate cancer chemoprevention, an overview of United States trials. J. Urol., 2004, 171 , 5–9.
  15. 15. Bosland MC. The role of steroid hormones in prostate carcinogenesis. Journal of the National Cancer Institute Monographs, 2000, 27:39-66.
  16. 16. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: Nutrition or pharmacology? Br J Clin Pharmacol. 2012 Jul 6. doi: 10.1111/j.1365-2125.2012.04374.x
  17. 17. Carmody J, Olendzki B, Reed G, Andersen V, Rosenzweig P. A dietary intervention for recurrent prostate cancer after definitive primary treatment: Results of a randomized pilot trial. Urology. 2008;72(6): 1324-1328.
  18. 18. Chan JM, Giovannucci EL. Vegetables, fruits, associated micronutrients, and risk of prostate cancer. Epidemiol Rev, 2001, 23:82-86.
  19. 19. Chance B, Sies H, Boveris A. Hydroperoxide Metabolism in Mammalian Organs. PHYSIOLOGICAL REVIEWS, 1979, 59 (3): 527-605.
  20. 20. Chong, P. and Rashid, P. Can we prevent prostate cancer? Aust Fam Physician, 34: 265-267, 2005.
  21. 21. Collins CS, Jiyong Hong J, Sapinoso L, Zhou Y, Liu Z, Micklash K, Schultz PG, and Hampton GM. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci U S A. 2006; 103(10): 3775–3780.
  22. 22. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature, 2002, 420, 860–867.
  23. 23. Crohns M, Saarelainen S, Kankaanranta H, Moilanen E, Alho H, Kellokumpu-Lehtinen P. Local and systemic oxidant/antioxidant status before and during lung cancer radiotherapy. Free Radic Res 2009;43:646–657.
  24. 24. Crohns M, Saarelainen S, Erhola M, Alho H, Kellokumpu-Lehtinen P. Impact of radiotherapy and chemotherapy on biomarkers of oxidative DNA damage in lung cancer patients. Clin Biochem 2009;42:1082–1090.
  25. 25. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007; 7: 256–69.
  26. 26. De Marzo AM, Marchi VL, Epstein JI, NelsonWG. Proliferative inflammatory atrophy of the prostate. Am J Path 1999;155:1985–92.
  27. 27. Dolara P, Bigagli E, Collins A. Antioxidant vitamins and mineral supplementation, life span expansion and cancer incidence: a critical commentary. Eur J Nutr. 2012 Jun 9. [Epub ahead of print]cancer. Urology 60: 78–83
  28. 28. Eichholzer M, Steinbrecher A, Kaaks R, Teucher B, Linseisen J, Rohrmann S. Effects of selenium status, dietary glucosinolate intake and serum glutathione S-transferase α activity on the risk of benign prostatic hyperplasia. BJU Int. 2012 Aug 9. doi: 10.111148–54
  29. 29. Faas FH, Dang AQ, White J, Schaefer RF, Johnson DE. Decreased prostatic arachidonic acid in human prostatic carcinoma. BJU Int. 2003;92(6):551-4.
  30. 30. Fair WR, Wynder EL (1996) Editorial: prostate cancer—nutrition adjunct therapy. J Urol 156:1364–1365
  31. 31. Fair WR, Fleshner NE, Heston W. Cancer of the prostate: a nutritional disease? Urology 1997;50:840–8.
  32. 32. Federico A, Morgillo F, Tuccillo C, Ciardiello F & Loguercio C. Chronic inflammation and oxidative stress in human carcinogenesis .Inter J Cancer. 121(11): 2381–2386, 2007.
  33. 33. Finkel, T; Holbrook, NJ. "Oxidants, oxidative stress and the biology of ageing". Nature,2000, 408 (6809): 239–47
  34. 34. Ferreira SH. Peripheral analgesic sites of action of anti-inflammatory drugs. Int J Clin Pract Suppl. 2002;(128):2-10
  35. 35. Ferreira SH and Nakamura MI (1979) Prostaglandin hyperalgesia, a cAMP/å2+ dependent process. Prostaglandins 18: 179-190.
  36. 36. Flohé L and Ursini F. Peroxidase: A Term of Many Meanings. Antioxid. Redox Signal. 10 (9), 1485–1490, 2008.
  37. 37. Gao P, Guan L, Zheng J. Role of leukotriene B4 in celecoxib-mediated anticancer effect. Biochem Biophys Res Commun. 2010;402(2):308-11
  38. 38. Gallin JJ (eds.): Disorders of phagocytic cells, in Inflammation: Basic Principles and Clinical Correlates, 2d ed, edited by JJ Gallin et al, pp. 859–875. Raven Press, New York, 1992.
  39. 39. Giri, S.N., Z. Chen, E.J. Carroll, R. Mueller, M.J. Schiedt, and L. Panico. 1984. Role of prostaglandins in pathogenesis of bovine mastitis induced by Escherichia coli endotoxin. Am. J.Vet. Res. 45: 586.
  40. 40. Ghosh J. Rapid induction of apoptosis in prostate cancer cells by selenium: reversal by metabolites of arachidonate 5-lipoxygenase. Biochem Biophys Res Commun. 2004;315(3):624-35
  41. 41. Ghosh J, Myers CE. Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci U S A. 1998;95(22):13182-7.
  42. 42. Giovannucci E, Rimm EB, Colditz GA, Stampfer MJ, Ascherio A, Chute CC, et al. A prospective study of dietary fat and risk of prostate cancer. J Natl Cancer Inst, 1993;85(19):1571-9.
  43. 43. Gupta S, Srivastava M, Ahmad N, Bostwick DG, Mukhtar H. Overexpression of cyclooxygenase-2 in human prostate adenocarcinoma. Prostate 42:73–78, 2000.
  44. 44. Haeggström JZ, Funk CD. Lipoxygenase and leukotriene pathways: biochemistry, biology, and roles in disease. Chem Rev. 2011;111(10):5866-98.
  45. 45. Hemler, M.E., Lands, W.E.M., 1980. Evidence of peroxide-initiated free radical mechanism of prostaglandin. biosynthesis. J. Biol. Chem. 225, 6253–6261.
  46. 46. Huang HY. Customized diets for cancer prevention according to genetic polymorphisms: are we ready yet? J Natl Cancer Inst, 2006; 98(22):1590-1.
  47. 47. Hubatsch I, Mannervik B, Gao L, Roberts LJ, Chen Y, Morrow JD. The cyclopentenone product of lipid peroxidation, 15-A(2t)-isoprostane (8-isoprostaglandin A(2)), is efficiently conjugated with glutathione by human and rat glutathione transferase A4-4. Chem Res Toxicol. 2002;15(9):1114-8
  48. 48. Hsu A, Bray TM, Ho E. Anti-inflammatory activity of soy and tea in prostate cancer prevention. Exp Biol Med (Maywood). 2010 ;235(6):659-67.
  49. 49. Ibrahim MA and Makkiya A . Consequences of Chronic Bacterial Infections on Development of Cancer. Research Journal of Microbiology,2011, 6: 310-321.and roles in disease. Chem. Rev., 111, 5866–5898 (2011).
  50. 50. Jackson JR, Seed MP, Kircher CH, Willoughby DA,Winkler JD. The codependence of angiogenesis and Chronic inflammation. FASEB J 1997; 11: 457–65.
  51. 51. Key TJ, Allen N, Appleby P, Overvad K, Tjonneland A, Miller A, Boeing H, Karalis D, Psaltopoulou T, Berrino F, Palli D, Panico S, Tumino R, Vineis P, Bueno-De-Mesquita HB, Kiemeney L, Peeters PH, Martinez C, Dorronsoro M, Gonzalez CA, Chirlaque MD, Quiros JR, Ardanaz E, Berglund G, Egevad L, Hallmans G, Stattin P, Bingham S, Day N, Gann P, Kaaks R, Ferrari P, Riboli E. Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer, 2004, 109:119-124.
  52. 52. Klein EA, Casey G, Silverman R. Genetic susceptibility and oxidative stress in prostate cancer: integrated model with implications for prevention. Urology, 2006;68(6):1145-51.
  53. 53. Kolonel LN. Fat, meat, and prostate cancer. Epidemiol Rev, 2001, 23:72-81.
  54. 54. Koopmann W and Krangel MS. Identification of a Glycosaminoglycan-binding Site in Chemokine Macrophage Inflammatory Protein-1α. The Journal of Biological Chemistry, 1997, 272: 10103-10109.
  55. 55. Kuper, H., Adami HO and Trichopoulos D . Infections as a major preventable cause of human cancer. J. Intern. Med.,2000, 248: 171-183.
  56. 56. Larré S, Tran N, Fan C, Hamadeh H, Champigneulles J, Azzouzi R, Cussenot O, Mangin P, Olivier JL. PGE2 and LTB4 tissue levels in benign and cancerous prostates. Prostaglandins Other Lipid Mediat. 2008;87(1-4):14-9.
  57. 57. Liu YW, Su YW, Ong WK, Cheng TH, Tsai YC. Oral administration of Lactobacillus plantarum K68 ameliorates DSS-induced ulcerative colitis in BALB/c mice via the anti-inflammatory and immunomodulatory activities.Int Immunopharmacol. 2011;11(12):2159-66.
  58. 58. Lukacs RU, Goldstein AS, Devon A Lawson DA, Cheng D & Witte ON. Isolation, cultivation and characterization of adult murine prostate stem cells. Nature Protocols 5,702 –713,2010.
  59. 59. Lundstrom K. Past, Present and Future of Nutrigenomics and its Influence on Drug Development. Curr Drug Discov Technol. 2012 Jun 25. [Epub ahead of print]
  60. 60. Lu-Yao GL, Albertsen P, Warren J, Yao SL. Effect of age and surgical approach on complications and short-term mortality after radical prostatectomy—a population-based study. Urology 1999;54:301–7.
  61. 61. Maddams J, Utley M and Møller H. Projections of cancer prevalence in the United Kingdom, 2010–2040. British Journal of Cancer advance online publication 14 August 2012; doi: 10.1038/bjc.2012.366.
  62. 62. Mahan L.K., Escott-Stump S. Krause’s Food, Nutrition & Diet Therapy. 11th. Saunders; Philadelphia, PA, USA: 2004.
  63. 63. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature, 2008, 454(7203):436-44.
  64. 64. Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Res 1992;52:5575-89.
  65. 65. Matsuyama M, Yoshimura R. Cysteinyl-leukotriene1 receptor is a potent target for the prevention and treatment of human urological cancer. Mol Med Report. 2010 ;3(2):245-51.
  66. 66. McNeal JE: Regional morphology and pathology of the prostate. Am J Clin Pathol 1968, 49:347-357
  67. 67. McNeal JE. Normal histology of the prostate. Am J Surg Pathol. 1988 Aug;12(8):619–633.
  68. 68. Miller PE, Morey MC, Hartman TJ, Snyder DC, Sloane R, Cohen HJ, Demark-Wahnefried W. Dietary patterns differ between urban and rural older, long-term survivors of breast, prostate, and colorectal cancer and are associated with body mass index.J Acad Nutr Diet. 2012;112(6):824-31
  69. 69. Mimata H, Tanigawa T, Ogata J, Takeshita M. Regulation of prostaglandin synthesis by reduced glutathione in urinary bladder epithelium. J Urol. 1988;139(3):616-20.
  70. 70. Minami Y, Staples MP, Giles GG. The incidence of colon, breast and prostate cancer in Italian migrants to Victoria, Australia. Eur J Cancer, 1993, 29A:1735-1740.
  71. 71. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM..Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.
  72. 72. Muir CS, Nectoux J, Staszewski J. The epidemiology of prostatic cancer: geographical distribution and time-trends. Acta Oncol 1991; 30:133–40.
  73. 73. Nelson WG, De Marzo AM, and Isaacs WB . Prostate Cancer. N Engl J Med 2003; 349:366-381.
  74. 74. Parantainen J., Sankari S. & Atroshi F. (1988) Biological functions of silicon, selenium and glutathione peroxidase (GSH-Px) explained in terms of semicoduction. In: Trace Elements in Man and Animals 6 (Hurly LS ; Keen CL; Lonnerdal Bo, & Rucker RB, Editors), Plenum Press, New York & London, pp.359-360.
  75. 75. Park S, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Fat and meat intake and prostate cancer risk: the multiethnic cohort study. Int J Cancer 2007;1339–45.
  76. 76. Pavlou M and Diamandis EP. The Search for New Prostate Cancer Biomarkers Continues. Clinical Chemistry, 2009, 55(7): 1277-1279.
  77. 77. Pilch P, Radziszewski P, Maciukiewicz P. Prostate cancer dependance upon cholesterol, statins and diet. Wiad Lek. 2012;65(1):31-7.
  78. 78. Prates C , Sousa S, Oliveira C, Ikram S. Prostate metastatic bone cancer in an Egyptian Ptolemaic mummy, a proposed radiological diagnosis. International Journal of Paleopathology, 1(2): 98–103,2011
  79. 79. Rakoff-Nahoum S. Why Cancer and Inflammation? Yale journal of biology and medicine, 2006, 79: 123-130
  80. 80. Ratan, H. L., Steward, W. P., Gescher, A. J., and Mellon, J. K. Resveratrol—a prostate cancer chemopreventive agent? Urol Oncol, 7: 223-227, 2002.
  81. 81. Richie JP Jr, Das A, Calcagnotto AM, Aliaga CA, El-Bayoumy K. Age related changes in selenium and glutathione levels in different lobes of the rat prostate. Exp Gerontol. 2012;47(3):223-8.
  82. 82. Ros S, Santos CR, Moco S, Baenke F, Gavin Kelly G, Howell M, Zamboni N and Schulze A. Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival. Cancer Discovery 2012 2; (4):328-43.
  83. 83. Rouzer CA, Scott WA, Griffith OW, Hamill AL, and Cohn ZA. Arachidonic acid metabolism in glutathione-deficient macrophages. Proc Natl Acad Sci U S A. 1982; 79(5): 1621–1625.
  84. 84. Samuelsson B, Morgenstern R and Jakobsson P-J. Membrane Prostaglandin E Synthase-1: A Novel Therapeutic Target. Pharmacological Reviews ,2007 , 59(3): 207-224.
  85. 85. Sanz-Motilva V, Nagore E, Martorell-Calatayud A. Non-Steroidal Anti-Inflammatory Drugs and Melanoma. Curr Pharm Des. 2012
  86. 86. Schaeffer AJ (2003) Epidemiology and demographics. of prostatitis. Andrologia 35:252-257.
  87. 87. Schulman CC, Ekane S, Zlotta AR. Nutrition and prostate cancer: evidence or suspicion? Urology 2001;58:318–34.
  88. 88. Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology. 2002;16:217–226.
  89. 89. Sies, Helmut. "Oxidative stress: Oxidants and antioxidants". Experimental physiology, 1997,82 (2): 291–5.
  90. 90. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM. Cancers of the prostate and breast among Japanese and white immigrants in Los Angeles County. Br J Cancer, 1991, 63:963-966.
  91. 91. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ, Haas GP. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo. 1994 May-Jun;8(3):439-43.
  92. 92. Schellhammer P. Life after failure of traditional androgen deprivation therapy. Urol Oncol. 2012 ;30(4 Suppl):S10-4
  93. 93. Sonn, G. A., Aronson, W., Litwin, M. S., Chong, P., and Rashid, P. Impact of diet on prostate cancer: a review Can we prevent prostate cancer? Prostate Cancer Prostatic Dis, 8: 304-310, 2005.
  94. 94. Sreekumar A, Poisson LM, Rajeniran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009;457:910-914
  95. 95. Steinhilber D, Fischer AS, Metzner J, Steinbrink SD, Roos J, Ruthardt M, Maier TJ. 5-lipoxygenase: underappreciated role of a pro-inflammatory enzyme in tumorigenesis. Front Pharmacol. 2010;1:143
  96. 96. Stewart, J. R., Artime, M. C., and O'Brian, C. A. Resveratrol: a candidate nutritional substance for prostate cancer prevention. J Nutr, 133: 2440S-2443S, 2003.
  97. 97. Sugar LM. Inflammation and prostate cancer. Can J Urol. 2006 Suppl 1:46-7
  98. 98. Sugino N, Karube-Harada A, Kashida S, Takiguchi S and Kato H. Reactive oxygen species stimulate prostaglandin F2α production in human endometrial stromal cells in vitro. Human Reproduction, 2001, 16(9): 1797-1801.
  99. 99. Tallberg Th and Atroshi F. Prostate Cancer, the Long Search for Etiologic and Therapeutic Factors: Dietary Supplementation Avoiding Invasive Treatment. In “Prostate Cancer: From Bench to Bedside”( Philippe E. Spiess ed.), pp. 33-52, 2011. INTECH Publisher, Croatia.
  100. 100. Tallberg T, Westermarck T, Atroshi F. Cancer Treatment, Based on Active Nutritional Bio-Modulation, Hormonal Therapy and Specific Autologous Immunotherapy.In: Heavy Metals in the Environment (editors: Zueng-Sang Chen, Dar-Yuan Lee, Tser-Sheng Lin). Publisher, National Taiwan University Taipei, Taiwan, November 2008.
  101. 101. Taketo MM. Cyclooxygenase-2 inhibitors in tumorigenesis (part 1). J Natl Cancer Inst 1998;90:1529-36.
  102. 102. Thun MJ, Namboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 1991;325:1593-6.
  103. 103. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-83.
  104. 104. Vander Heiden, MG, Cantley, LC and Thompson, CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009. 324(5930): p. 1029-33
  105. 105. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97–120.
  106. 106. Wang X, Klein RD. Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. Mol Carcinog. 2007 ;46(11):912-23.
  107. 107. Yancik R. Population aging and cancer: a cross-national concern.Cancer J 2005; 11(6):437-441.
  108. 108. Yang CS, Suh N, Kong AN. Does vitamin E prevent or promote cancer? Cancer Prev Res (Phila). 2012;5(5):701-5.
  109. 109. Zhou Y,Elizabeth EO. Hileman, HW, Keating MJ, and Huang P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood, 2003, 101 (10): 4098-4104.

Written By

Marika Crohns, Tuomas Westermarck and Faik Atroshi

Published: January 16th, 2013