Prostate Cancer Inflammation and Antioxidants

Marika Crohns, Tuomas Westermarck and Faik Atroshi

Additional information is available at the end of the chapter

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 chemothera-peutic 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. Un der situations of oxidative stress and with increasing age the organism may not be able to maintain homeostasis with deleterious and potentially unfortunate consequences.

a Dietary habits a Free radicals a Lipid peroxidation a Hypoxia =

a Anaemia a SH, redox changes E a Covalent binding a Protein damage a Health status a Genetic polymorphisms [



Na*, K* electrolyte changes Cyclic AMP Ca" transport others

• replication errors •chemical carcinogens

• other factors

DNA damage apoptosis _

Cell growth i!

I mechanical stimuli I chemical (hormones) I Genes

I Infectious agents

polyunsaturated fatty*. ^^

f] ~ """"antioxidants

V prostaglandin yy formation PGG2

citotoxicity tisuue destruction oxygen free radicals

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