Alternative Approaches to Prostate Cancer Prevention

Back in 2013, Dr. Anne E. Cress (Univ. Arizona Cancer Center) was commissioned to write a chapter for the 3rd edition of Fundamentals of Cancer Prevention. Dr. Cress, who besides being my boss in her lab is also my personal training client, knew about my interest in phytonutrients in cancer prevention, so she asked me to write a small section of the chapter on Alternative Approaches to Prostate Cancer Prevention. Below is that section.

It's pretty basic stuff, and not very in-depth--nor is it, by itself, firmly grounded in the molecular mechanisms at play. It has been my plan to update it and expand it into a full-length article. But, since then, there have been many, many grants to write/edit, and three first-author papers I have been assigned (two already published - Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers; The Cohesive Metastasis Phenotype in Human Prostate Cancer). Let's just say it was back-burnered.

I post it here in hope that someone might benefit from the information. And, perhaps, as impetus to get off my arse and write a new version.

Fundamentals of Cancer Prevention (2014); edited by David Alberts, Lisa M. Hess. Springer-Verlag Berlin Heidelberg; Heidelberg Germany. DOI: 10.1007/978-3-642-38983-2

Chapter 16: Prevention of Prostate Cancer, Amit M. Algotar, M. Suzanne Stratton, William L. Harryman, and Anne E. Cress

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16.4 Alternative Approaches to Prostate Cancer Prevention (pgs. 501-504)

The natural health industry has a reputation for making unsubstantiated health claims for various herbs, foods, and spices. However, clinical research offers an avenue to evaluate these claims, offering the hope of finding the next aspirin in terms of health benefits versus risks. A few of these supplements show potential in cancer treatment and prevention, most notably curcumin, and resveratrol, and manipulation of lifestyle factors should also be considered as an alternative approach.

16.4.1 Curcumin

Curcumin is one of the rising stars in the alternative health market and has been touted as a treatment for arthritis via regulation of 5-LOX and COX-2 pathways (Rao 2007), as a cancer prevention agent (Rao 2007; Khan et al. 2008), to support liver health (Vitaglione et al. 2005; Reuter et al. 2008), for life extension (Naik et al. 2004), and for a host of other health issues. Curcumin [1,7-bis(4-hydroxy- 3-methoxyphenyl)-1,6-hepatadiene-3,5-dione] is the primary constituent of turmeric (Curcuma longa), a spice used in cooking and folk medicine throughout Southeast Asia, a region evidencing low incidence for most cancer types (Salvioli et al. 2007). Over the last 20 years, researchers have been assembling a considerable body of evidence that curcumin may be a powerful tool in the fight against cancer—via apoptosis (Vitaglione et al. 2005; Khan et al. 2008) and due to its antitumor and anti-inflammatory properties (Piper et al. 1998; Ravindran et al. 2009)—and in slowing the progression of cancer (Plummer et al. 2001; Aggarwal et al. 2006; Bae et al. 2006). Curcumin induces apoptosis in both androgen-dependent and metastatic hormone refractory prostate cancer cells (Yoysungnoen et al. 2006), as well as demonstrating antimetastatic activity (Dorai et al. 2000; Kuttan et al. 2007).

In addition to its own antioxidant activity (Killian et al. 2012), curcumin increases glutathione S-transferase, which upregulates the creation of glutathione (Rao 2007; Basnet and Skalko-Basnet 2011), the body’s master antioxidant [accordingly, researchers are studying curcumin as a liver detoxification supplement (Naik et al. 2004; Vitaglione et al. 2005)]. Curcumin affects several cell-signaling pathways identified as tumor growth and survival mechanisms for several types of cancer, including prostate cancer (Sharma et al. 2001, 2005). Furthermore, curcumin demonstrates androgen receptor-binding capabilities, downregulating the expression of AR (Dorai et al. 2000; Aggarwal 2008). Finally, curcumin promotes PSA inhibition, while one of its constituent curcuminoids also serves as an AR antagonist (Nakamura et al. 2002; Tsui et al. 2008).

Despite these demonstrated chemopreventive benefits of curcumin, researchers remain unclear about the specific mechanisms of action (Shi et al. 2009). Turmeric contains, in addition to curcumin, several minor fractions such as demethoxycurcumin (curcumin II), bisdemethoxycurcumin (curcumin III), and cyclocurcumin (Shen and Ji 2012b). Most commercially available products contain three major curcuminoids: 77 % curcumin, 17 % demethoxycurcumin, and 3 % bisdemethoxycurcumin (Kiuchi et al. 1993). Ravindran et al. propose that the presence of these methoxy groups accounts for curcumin’s anti-inflammatory and antiproliferative activity (Ravindran et al. 2009), while the hydroxyl groups provide the antioxidant activity. One of the ongoing issues with curcumin pharmacology is its minimal in vivo bioavailability, resulting in low serum levels and miniscule presence in tissues (Karunagaran et al. 2005; Anand et al. 2007; Aggarwal and Sung 2009). The low absorption and bioavailability of curcumin led some researchers to propose the mechanism of action is not only in the curcuminoids but also in the metabolites and degradation products (Anand et al. 2007; Aggarwal and Sung 2009; Shen and Ji 2012a). Nonetheless, several labs are seeking to isolate specific curcumin compounds according to which pathways they affect. The goal is to develop alternative delivery systems, leading to better absorption, which includes nanoparticle conjugation (Shen and Ji 2012a), β-cyclodextrin, fibrinogen, liposome, and hydrogel (Shankar and Srivastava 2012).

16.4.2 Resveratrol

The headline proclaims, “Daily dose of red wine compound backed for cancer fight” (Gray 2012), but does the research support these claims? Resveratrol (3, 5, 4′ trihydroxy-trans-stilbene) is a natural phytochemical with cardioprotective, antiinflammatory, and anticancer properties (Jang et al. 1997). There is no definitive research confirming resveratrol as a first-line chemopreventive strategy, but there is growing evidence to support continued research.

Pezzuto’s review of the literature, as well as his own research, suggests that resveratrol shows potential as a carcinogenesis inhibitor (Pezzuto 2008). Kraft et al. suggest resveratrol is a promising chemopreventive agent due to its ability to decrease metabolism of phase-I enzyme genes (CYP2E1 and CYP1A1), which are pro-carcinogenic, and/or by increasing the metabolism of phase-II detoxifying enzymes (Kraft et al. 2009) [glutathione S-transferases, uridine diphosphateglucuronosyltransferases, and quinone reductase enzymes (Hebbar et al. 2005)]. Kai, Samuel, and Levenson examined the ability of resveratrol to enhance p53 acetylation and apoptosis in prostate cancer by inhibiting the MTA1/NuRD complex, which then allows the activation of proapoptotic genes (Kai et al. 2010). The expression of MTA1 protein is higher in androgen-independent metastatic tumors in relation to early-stage localized disease and benign prostatic tissues (Hofer et al. 2004). These authors suggest their research identifies MTA1 as a new target in prostate cancer treatment and prevention.

16.4.3 Lifestyle Factors

Based on the research presented for curcumin and resveratrol, there are a few generalizations that can act as guiding principles for prostate cancer prevention. What follows might be considered an ecological approach in that it takes into account the whole ecology of tumorigenesis in the human body [see also (Pienta et al. 2008) for an ecological approach focused on the environment of the tumor itself], where the body is the ecosystem we seek to manipulate. It seems possible now to create an inhospitable environment for the survival of cancer cells in the body.

Estimations from the World Health Organization (WHO) are that 300 million adults are obese and more than a billion adults are overweight (Faloia et al. 2012). This has implications for prostate cancer. Gong et al. identified a 29 % increased risk for high-grade prostate cancer (Gleason ≥7) and an 18 % decreased risk of low-grade tumors in men with a body mass index ≥30 in comparison to men with body mass index <25 [ n = 10,258, 1,936 prostate cancers] (Gong et al. 2006). The consensus in meta-analyses of the connection between obesity and high-grade prostate cancer supports the findings of Gong and colleagues (Gong et al. 2006; Rodriguez et al. 2007; Wright et al. 2007). Burton et al. have correlated obesity with unusually high levels of adipocyte-derived peptides (adipokines), sex hormones [including estrogen, which may be the initiating driver of prostate adenocarcinoma progression (Singha et al. 2008)], and inflammatory cytokines, with both in vitro and epidemiological studies showing that adipokines influence prostate carcinogenesis (Burton et al. 2010). As suggested by Gong et al., Burton et al. found that testosterone levels are lower in obesity, which may select for more aggressive, androgen-independent tumors. However, there is no connection between moderate and high-normal levels of testosterone and prostate cancer (Stattin et al. 2004).

One of the comorbidities of obesity is low-grade or “smoldering” inflammation (Balkwill et al. 2005), which contributes to various forms of disease, including prostate cancer. COX-2 expression, a pro-inflammatory enzyme and the primary target of nonsteroidal anti-inflammatory drugs (NSAIDs), is highly increased in several cancers, including prostate cancer (Gupta et al. 1999). There is some evidence that aspirin use may offer COX-2-mediated protection against esophageal, lung, stomach, and ovarian cancers (Fosslien 2000). In a follow-up for patients in a vascular event prevention study, with randomized trials of daily aspirin versus control, those in the aspirin group had a 40 % reduction in cancer deaths from the 5-year mark forward and consistent death-rate reductions for certain cancers at the 20-year follow-up (Rothwell et al. 2011). Through a review of the records from the United Kingdom’s five large randomized trials of daily aspirin versus no aspirin (cardiovascular event prevention), all participants who showed incident cancers had a 30–40 % risk reduction for distant metastasis and nearly a 50 % risk reduction for metastatic adenocarcinoma (Rothwell et al. 2012).

The major recommendation for lifestyle factors in prostate cancer prevention is that men need to be more physically active (Orsini et al. 2009), which helps prevent obesity, another risk factor for prostate cancer (Rodriguez et al. 2007; Burton et al. 2010). In addition, men must reduce their reliance on the current Western diet, which is high in processed foods, low in fresh fruit and vegetables (sources of phytonutrients), and nearly void of omega-3 fats (anti-inflammatory) while containing abundant omega-6 fats, including arachidonic acid, a powerful driver of the inflammatory process (Matsuyama and Yoshimura 2008). The research has not revealed the definitive diet, and each person processes food a little differently. Consuming more fresh fruits and vegetables [especially cruciferous vegetables, which offer chemoprevention for the prostate (Beaver et al. 2012)], lean meats (chicken, fish, turkey), and nuts and seeds (walnuts, almonds, pumpkin seeds, hemp seed), as part of a diet also rich in curry, would offer a solid foundation for general health.

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