Agents with Anti-lnflammatory Properties in Chemoprevention of Colorectal Neoplasia

Immunomodulation (reduced T cell activation)

Inhibition of cyclooxygenase (COX) activity

Production of novel anti-inflammatory lipid mediators, e.g. resolvins

Direct fatty acid signaling via GPCRs

Alteration of membrane dynamics and cell surface receptor function

Alteration of cellular redox state

Anti-angiogenesis

Evidence is strongest for a role for inhibition of COX-2-dependent synthesis of prostaglandin (PG) E₂ in the anti-CRC activity of ω-3 PUFAs. EPA can act as an alternative substrate for COX-2, instead of the usual substrate, arachidonic acid, leading to a reduction in formation of protumorigenic PGE₂ in favour of PGE₃ in several cell types including CRC cells (Smith 2005). Recently, a ‘PGE₂ to PGE₃ switch’ has been demonstrated in colorectal mucosa of rats treated with fish oil (Vanamala et al. 2008). However, reduction of PGE₂ synthesis and/or generation of PGE₃ following EPA treatment remains to be demonstrated in mouse or human CRC tissue.

It is known that DHA also binds the substrate channel of COX-2 and inhibits COX-2 activity (Vecchio et al. 2010).

In the presence of aspirin, which irreversibly acetylates the COX enzyme, EPA drives COX-2-dependent production of resolvin (Rv) E1 (5S,12R,18R-trihydroxyeicosapentaenoic acid; Serhan et al. 2008). 18R-RvE1 has been detected in plasma of healthy volunteers in ng/ml quantities after aspirin and EPA ingestion [31]. The precursors of E-series resolvins may also be produced independent of COX by direct CYP450 metabolism of EPA (Serhan et al. 2008). Metabolism of DHA can produce D-series resolvins, 17S-docosatrienes termed protectins or 14-lipoxygenase-derived products termed maresins. These newly described families of EPA- and DHA-derived lipid mediators all share anti-inflammatory and inflammation resolution activity in animal models of acute inflammation (Serhan et al. 2008). RvE1 is a ligand for ChemR23 and BLT1 G protein-coupled receptors (GPCRs). It is currently not known whether ω-3 PUFA-derived resolvins exhibit anti-neoplastic activity. However, it is known that ChemR23-dependent RvE1 signalling inhibits NFκB activation in leukocytes (Serhan et al. 2008).

EPA and DHA can also act as direct ligands for GPCRs including Gpr120 and Gpr40 (Oh et al. 2010). Gpr120 is not expressed by intestinal epithelial cells, including several human CRC cell lines (Oh et al. 2010). However, Gpr120 activation decreases adipose tissue macrophage M1 polarisation in mice (Oh et al. 2010) suggesting that direct ω-3 PUFA signaling via GPCRs could negatively affect pro-tumourigenic tumour-associated macrophage activity or modulate the systemic host anti-tumour response.

There is some evidence that the incorporation of ω-3 PUFAs into cell phospholipid membranes alters the fluidity, structure and/or function of lipid rafts or calveolae (Schley et al. 2007). The localisation of cell surface receptors, such as epidermal growth factor receptor (EGFR), in lipid rafts is believed to be crucial for downstream receptor signalling controlling proliferation and apoptosis, which in turn could be altered by ω-3 PUFA incorporation (Schley et al. 2007).

PUFAs are highly peroxidisable, generating reactive oxygen species such as the superoxide radical. Therefore, ω-3 PUFAs may have anti-neoplastic activity through alteration in the cellular redox state and increased oxidative stress, leading to cancer cell apoptosis (Sanders et al. 2004).

3.2 Curcumin

Curcumin (diferuloylmethane) is a polyphenolic phytochemical, which is extracted from turmeric, a rhizomatous plant of the Ginger family used widely in Asian cooking (Aggarwal et al. 2007). Turmeric has been used for medicinal purposes for many centuries. Curcumin powder consists of approximately 75 % curcumin in combination with curcuminoid derivatives that are metabolised to the parent curcumin in vivo. Curcumin is stable in acidic conditions, which are generally observed in the gastrointestinal tract.

3.2.1 Anti-Inflammatory Activity of Curcumin

Curcumin is believed to have anti-inflammatory activity via several mechanisms (Hanai and Sugimoto 2009; Irving et al. 2011). These include attenuation of NFκB signalling, via poorly understood mechanisms including inhibition of IκB kinase, and inhibition of synthesis of multiple pro-inflammatory mediators including PGs, nitric oxide (NO) and chemokines (Irving et al. 2011). Curcumin has efficacy in animal models of inflammatory bowel disease (Sugimoto et al. 2002; Billerey-Larmonier et al. 2008). Curcumin also exhibits immunomodulatory properties in vitro and in vivo including modulation of intestinal lymphocyte infiltration in Apc^Min/+ mice (Churchill et al. 2000).

3.2.2 Preclinical Studies of the Anti-CRC Activity of Curcumin

Preclinical evidence for the CRC chemopreventative activity of curcumin has been obtained from chemical carcinogenesis and Apc^Min/+ rodent models. Dietary curcumin supplementation has been demonstrated to reduce AOM-induced ACF and CRC incidence in mice and rats by 40–60 % (Huang et al. 1994; Rao et al. 1995; Pereira et al. 1996). Rao and colleagues also provided evidence for inhibition of intestinal COX and lipoxygenase (LOX) activity by curcumin (Rao et al. 1995). More recently, similar effects on Apc^Min/+ mouse adenoma multiplicity have been reported (Perkins et al. 2002).

3.2.3 Pharmacokinetics of Curcumin

Curcumin has limited systemic bioavailability following oral dosing. It is poorly absorbed with the majority of the parental molecule and related curcuminoids excreted in faeces (Irving et al. 2011). Curcumin also has a short half-life and is preferentially excreted in bile, with poor renal excretion. Whether the low nanomolar concentrations of curcumin detected in human plasma are sufficient for possible systemic activity of curcumin, or whether local intestinal bioactivity of curcumin restricts anti-neoplastic properties to the gastro-intestinal tract, is not clear (Dhillon et al. 2008). Tissue curcumin levels reach nmol/g concentrations in normal colorectal mucosa and CRC following oral dosing in humans (Garcea et al. 2005). The above pharmacokinetic properties of curcumin have hampered clinical evaluation because of uncertainty regarding appropriate dosing. New pharmacodynamic assays should provide greater understanding of the systemic bioavailability of curcumin and its bioactive metabolites (Ponnurangam et al. 2010).

3.2.4 Clinical Data Supporting the CRC Chemopreventative Activity of Curcumin

Phase I and II trials of curcumin in the setting of colorectal adenoma or CRC have used daily dosing from 450 mg to 4 g daily (reviewed in Irving et al. 2011). In all cases, curcumin was well tolerated with few adverse events, mainly minor gastrointestinal disturbances. Higher doses have been administered in clinical studies although adverse events were higher in these studies suggesting a possible limit to tolerable daily dosing. Uncertainty about the relative importance of systemic versus topical delivery of curcumin for activity in the intestine means that dosing frequency remains an open question.

A dose of 1440 mg curcumin daily for six months has been tested in 5 patients with FAP, in combination with another polyphenol quercetin (Cruz-Correa et al. 2006). In this open-label study, there was a significant 50–60 % reduction in colorectal adenoma number and size leading to early termination of the trial (Cruz-Correa et al. 2006). These results have prompted ongoing randomized evaluation of 1–3 g curcumin daily for 12 months in FAP patients. In a separate non-randomised, open-label study, 41 individuals undergoing colonoscopic screening for CRC received either 2 or 4 g curcumin daily for one month prior to measurement of rectal ACF multiplicity. There was a significant 40 % reduction in ACF number in the group taking 4 g daily compared with the 2 g daily group (Carroll et al. 2011).

3.2.5 Mechanisms of the Anti-CRC Activity of Curcumin

Several different modes of the anti-neoplastic activity of curcumin have been proposed. However, the contribution of these individual mechanisms to activity in vivo is currently unclear. For example, reduction in intestinal mucosal PGE₂ levels previously observed in rodent models (Rao et al. 1995) has not been observed in endoscopically normal rectal mucosa or ACFs following curcumin administration in humans (Carroll et al. 2011).

Curcumin can scavenge or trap oxygen and nitrogen free radicals, which are believed to contribute to DNA mutagenesis during carcinogenesis (Weber et al. 2005). In addition to the anti-inflammatory mechanisms attributed to curcumin noted in Sect. 3.2.1, particularly NFκB signalling inhibition and COX/LOX downregulation, several other effects relevant to anti-neoplastic activity have been reported including CRC cell cycle arrest and apoptosis via p53-dependent and -independent mechanisms, anti-angiogenic activity and modulation of the host immune response to tumourigenesis (Irving et al. 2011). It will be important in future clinical trials to measure biomarker end-points relevant to these putative mechanisms of action in order to develop predictive biomarkers of chemoprevention activity in order to personalise treatment (particularly dose) with curcumin.

3.3 Resveratrol

Resveratrol (trans-3,4′,5-trihydroxystilbene) is another phytochemical polyphenol with well-recognised anti-oxidant properties (Patel et al. 2010). Predominant dietary sources are grapes, peanuts and cranberries. The anti-inflammatory properties of resveratrol are less well characterized than curcumin (Patel et al. 2010), but dietary supplementation with resveratrol does attenuate dextran sodium sulphate (DSS)-induced colitis in mice (Sanchez-Fidalgo et al. 2010; Cui et al. 2010). Unlike curcumin, it is rapidly and efficiently absorbed along the gastrointestinal tract with predominant metabolism in the liver (Patel et al. 2010).

3.3.1 Preclinical Studies of the Anti-CRC Activity of Resveratrol

Resveratrol has been demonstrated to have chemopreventative efficacy in AOM-induced ACF and Apc^Min/+ mouse models in a similar manner to curcumin (Tessitore et al. 2000; Schneider et al. 2001). Resveratrol also has efficacy against colitis-associated cancer in the DSS–AOM mouse model (Cui et al. 2010). Pharmacokinetic evaluation of an oral resveratrol preparation in CRC patients is ongoing and data from these studies should inform design of Phase II biomarker studies more relevant to CRC chemoprevention.

3.3.2 Mechanisms of the Anti-CRC Activity of Resveratrol

The majority of mechanistic studies with resveratrol have provided in vitro data using human CRC cells, which suggest effects on cancer cell cycling and apoptosis (Patel et al. 2010). Alterations in expression levels of cell cycle proteins (D cyclins) and the pro-apoptotic protein Bax have been confirmed in vivo (Tessitore et al. 2000; Schneider et al. 2001).

3.4 Other Dietary Polyphenols

Many other dietary polyphenols have been demonstrated to have anti-neoplastic activity but are beyond the scope of this review as they have not been tested in ‘nutraceutical’ form (Ricciardiello et al. 2011). For example, a complex apple polyphenol extract has recently been demonstrated to have efficacy in the Apc^Min/+ mouse (Fini et al. 2011). In a recent perspective, Ricciardiello and colleagues have argued that the mixture of naturally occurring anti-inflammatory phytochemical compounds found in high fruit and vegetable diets, particularly polyphenols, may have greater anti-neoplastic efficacy than higher quantities of single agents in nutraceutical form (Ricciardiello et al. 2011).

One promising preparation with anti-inflammatory properties that requires detailed assessment for anti-CRC activity is green tea, which contains a complex mixture of polyphenols termed tea catechins (Chow and Hakim 2011). Administration of green tea extract for 12 months has been demonstrated to reduce incidence of colorectal adenoma (15 vs. 31 % in a non-supplemented control group) in individuals with a past history of colorectal adenoma in a randomised trial of 136 patients (Shimizu et al. 2008). A placebo-controlled colorectal polyp prevention trial testing decaffeinated green tea extract of Camellia Sinensis, containing 300 mg (-)epigallocatechin 3-gallate (EGCG) daily in gelatin capsules, is currently underway in patients with previous colorectal neoplasia (NCT01360320).

3.5 Other Natural Anti-Inflammatory Agents with CRC Chemopreventative Efficacy

3.5.1 Vitamin D

A large amount of epidemiological evidence is suggestive that vitamin D intake protects against CRC, although the complex relationship between existing vitamin D status (as measured by serum 25-hydroxy-vitamin D) and the dose required for efficacy is poorly understood (Zhang and Giovannucci 2011; Touvier et al. 2011). More recently, it has become recognised that the active moiety calcitriol (1α,25-dihydroxyvitamin D₃) has potent anti-inflammatory activity and that this mechanism of action may contribute to anti-cancer activity of vitamin D (Krishnan and Feldman 2011). Calcitriol may decrease COX-2-PG signalling during carcinogenesis via suppression of COX-2 expression, induction of 15-PG dehydrogenase and reduced expression of PG receptors (Krishnan and Feldman 2011). Calcitriol has also been demonstrated to inhibit NFκB signalling and have anti-angiogenic activity (Krishnan and Feldman 2011).

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