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Colorectal Cancer

Folate

Folic acid is necessary for the synthesis of both S-adenosylmethionine (SAMe) and deoxythymidine monophosphate (dTMP). dTMP and SAMe are needed in the synthesis and function of DNA, respectively. Therefore, a deficiency of folic acid may disrupt proper DNA synthesis or function. A pooled analysis of 13 studies involving over 725,000 participants, found a 2% risk reduction for every 100 mcg/day increase of total folic acid intake (Kim 2010). In a large population study, those taking the highest amount of folate from diet and supplements (>900mcg/d) had a 30% reduced risk of developing colon cancer versus those with the lowest consumption (<200mcg/d) (Gibson 2011).

Alcohol consumption increases the risk of colon cancers, and evidence suggests this may be potentiated by polymorphisms in genes that produce enzymes involved in folate metabolism (Giovannucci 2003). Maintaining adequate levels of folate, and its co-nutrient methionine, may offer protection from colon adenoma development, particularly in those consuming alcohol or those with genetic polymorphisms in folate metabolism (Giovannucci 2002).

Green Coffee and Chlorogenic Acids

Greater coffee consumption has been linked with a lower rate of a variety of cancers, including colon cancer (Galeone 2010: Je 2009).

Coffee contains powerful antioxidant compounds, called chlorogenic acids, which have been shown to exert several potentially chemopreventive effects, including favorably modulating glucose metabolism, and quelling inflammation (dos Santos 2006; van Dijk 2009). In fact, a recent study found that chlorogenic acids were able to interfere with a variety of cellular processes that drive colon cancer metastasis, including NF-kB signaling (Kang 2011).

However, the roasting process used to prepare conventional coffee beverages destroys the majority of these beneficial chlorogenic acids. Therefore, drinking coffee is an inefficient means of obtaining these bioactive compounds.

Recent scientific innovation has led to the availability green coffee bean extract standardized to 50% chlorogenic acids. Supplementation with green coffee bean extract is a viable option for obtaining robust quantities of bioactive chlorogenic acids.

Garlic

Consumption of garlic has been linked with lower colon cancer risk (Fleischauer 2000). Garlic has been shown to reduce the carcinogenic potential of compounds such as nitrosamines, as well as exert anti-proliferative effects (Milner 2001a; Milner 2001b). Components that may be responsible for the cancer protective effects of garlic include organosulfur compounds and flavonoids.

There are many mechanisms that can explain how garlic reduces carcinogenesis in the colon and rectum.

  • Inhibition of cell growth and proliferation directly
  • Inhibition of new blood vessel growth
  • Increased cell death (apoptosis)
  • Increased detoxification of carcinogens
  • Suppression of carcinogen activating enzymes
  • Inhibition of cyclooxygenase-2 (thereby inhibition of inflammation)
  • Antioxidant action, squelching free radicals in the bowel (Ngo 2007)

One clinical trial showed that supplementing with aged garlic extract reduced the formation of pre-cancerous adenomas in patients with a history of adenomas (Tanaka 2006).

Ginger

Like garlic, ginger has been a mainstay of traditional medicine for more than 2,500 years. Ginger’s multiple chemopreventive benefits have been reported in a wide range of experimental models (Shukla 2007). Key compounds in ginger and its extracts limit the oxidative damage to cells caused by free radicals. They also lower levels of signaling molecules called cytokines, specifically those that provoke an inflammatory response. This dual mode of action may inhibit initiation of carcinogenesis and limit expansion of existing malignancies (Murakami 2002; Pan 2008). Some ginger components also increase the activity of vital enzymes that detoxify carcinogens present in the body (Nakamura 2004; Brandin 2007).

Indian researchers provided direct evidence of ginger’s chemopreventive power in rats with chemically induced colon cancers in two recent studies (Manju 2005; Manju 2006). After injection with a potent carcinogen, animals were either supplemented with ginger or given normal diets. In both studies the incidence of cancers and the number of individual tumors was significantly reduced in the supplemented groups. The first study also detected lower levels of oxidative agents and higher levels of natural antioxidants in supplemented animals, while the second study further showed a decrease in the activity of bacterial enzymes that release intestinal toxins and damage the colon’s natural protective mucous layer.

In recent clinical trial, 30 healthy subjects consumed 2 grams of ginger or a placebo each day for 28 days. Colon biopsies were taken at baseline and at day 28 and assessed for levels of inflammatory markers. The subjects that received ginger displayed significantly lower levels of PGE-2 and 5-HETE, two inflammatory fatty acid metabolites, in their tissue samples than those who received a placebo (Zick 2011). These findings are encouraging due to the role of inflammation in driving colon cancer growth.

Modified Citrus Pectin

Modified Citrus Pectin (MCP) is a type of soluble dietary fiber derived from citrus fruits that has been modified by pH and heat to form smaller units of absorbable galactose residues that are able to bind to cancer cells. Specifically, MCP binds to Galectin-3, a protein expressed by cancer cells that is involved in cell to cell adhesion, survival and spread to distant organs (metastasis) (Takenaka 2004; Nakahara 2005). Nullifying the effects of galectin-3 by finding agents to bind to it is one means of inhibiting these pro-cancerous mechanisms (Ingrassia 2006; Glinsky 2009). MCP has been shown to effectively bind galectin-3 and inhibit growth and metastasis of various cancers (Nangia-Makker 2002), including colon cancer (Liu 2008).

Interfering with galectin-3 and preventing metastasis is particularly important in colorectal cancer, where spread to the liver means a much worse prognosis than limited or local disease. Galectin-3 levels appear to be increased in colon cancer, and are associated with advanced disease stage (Irimura 1991; Schoeppner 1995), confirming that galectin-3 is an important molecule in the growth and spread of colon cancers.

Additional discussion on the role of MCP in combatting cancer metastasis can be found in the Life Extension Magazine article entitled “Fighting Cancer Metastasis and Heavy Metal Toxicities With Modified Citrus Pectin”.

Curcumin

Curcumin is derived from the spice turmeric (Curcuma longa), an ancient spice used throughout Asia. Cultures in which diets high in turmeric are consumed have much lower rates of colon cancer than Western cultures (Sinha 2003). Curcumin is a powerful anti-inflammatory compound that acts on NF-kB, a proinflammatory mediator that influences hundreds of genes involved in the growth and spread of cancer. In addition, curcumin regulates tumor suppressor pathways and triggers mitochondrial-mediated death in cancer cells (Ravindran 2009; Cheng 2010).

Despite aggressive surgical care and chemotherapy, nearly 50% of people with colorectal cancers develop recurrent tumors (Patel and Majumdar 2009). This may be due in part to the survival of dangerous colon cancer stem cells that resist conventional chemotherapy and act as “seeds” for subsequent cancers (Subramaniam 2010). There is evidence that combining curcumin with FOLFOX, the first line chemotherapy drug combination of 5-fluorouricil, leukovorin and oxaliplatin, eliminates the persistent pool of colon cancer stem cells (Yu 2009), and potentiates the lethality of FOLFOX on cancer cells (Sengupta 2008).

Finally, curcumin interferes with tumor invasiveness and blocks molecules that would otherwise open pathways to penetration of tissue (Anand 2008). It also helps to starve tumors of their vital blood supply and it can oppose many of the processes that permit metastases to spread (Bar-Sela 2010). These multi-targeted actions are central to curcumin’s capacity to block multiple forms of cancer before they manifest (Bachmeier 2010).

Curcumin also creates a gastrointestinal environment more favorable to optimal colon health by reducing levels of so-called secondary bile acids, natural secretions that contribute to colon cancer risk (Han 2009). That has a direct effect, inhibiting proliferation of cancer cells and further reducing their production (Wang 2009).

A novel feature of curcumin is its ability to bind to and activate vitamin D receptors (VDR) in colon cells (Bartik 2010). Binding to VDR elicits a host of anti-proliferative and anti-inflammatory actions.

Curcumin given to patients undergoing treatment for colon cancer led to weight gain, decreased circulating inflammatory mediator TNF-a, and increased apoptosis (He 2011).

Omega-3 Fatty Acids

There is a substantial amount of experimental, population-based studies and clinical trials showing that risk of colorectal cancer is reduced with higher intakes of omega-3 fatty acids (Anti 1992; Fernandez 1999; Rao 2001; Bancroft 2003; Cheng 2003; Hall 2008; Kim 2010).

EPA (2 grams/d for 3 months) reduced crypt cell proliferation and promoted proper apoptosis of colonic epithelial cells in patients with a history of colonic adenomas (Courtney 2007). Separately, a large population study of physicians found that those who consumed fish oil supplements during a 10-year period had a 35% reduction in the risk of developing colon cancer (Satia 2009).

Omega-3 fatty acids may prevent colorectal cancer through supporting normal turnover of the epithelial cells by encouraging apoptosis (Cheng 2003). Fish oils reduce the pro-tumor effects of many molecules involved in the growth and spread of colon cancer, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PDECGF), cyclo-oxygenase 2 (COX-2), prostaglandin-E2 (PGE2), nitric oxide, nuclear factor kappa B (NF-kB), matrix metalloproteinases and beta-catenin (Spencer 2009).

DHA, an omega-3 fatty acid found in fish oil, disrupts cell signaling in colon cancer and is synergistic with butyrate in inducing apoptosis (Kolar 2007; Chapkin 2008).

Fish oil (2.5 grams/d) normalized abnormal rectal proliferation patterns in patients with a history of adenomas, and this is thought to be through lessening the availability of the inflammatory omega-6 fatty acid arachidonic acid and modifying vitamin E availability (Anti 1994;Bartoli, Palozza 1993).

Chemotherapies induce cell death by inducing DNA damage in quickly dividing cells, tipping the death/survival pathways toward cellular self-destruction (apoptosis). Experiments have shown EPA and DHA can make cancer cells more vulnerable to damage from chemotherapy and radiation, thus encouraging the cells to turn on cell death pathways in lieu of repair pathways (Benais-Pont 2006; Dupertuis 2007; Slagsvold 2010). Eventual resistance of colon cancer cells to the cytotoxic effects of chemotherapy may also be lessened with EPA/DHA (Kuan 2011).

PSK

PSK is a mushroom polysaccharide complex used more commonly in other countries such as Japan and Australia for immune support in cancer care. Pure PSK cannot be obtained in the United States, but the mushroom Trametes versicolor (formerly called Coriolus versicolor) is high in this polysaccharide and is often substituted. Many mushrooms have some immune enhancing properties, but PSK can also suppress activation of NF-kB, therefore reducing the expression of hundreds of pro-cancerous genes (Yamashita 2007).

A review of three clinical trials in patients who had surgery and chemotherapy for their colon cancer showed that overall survival was improved by 29% with the addition of PSK (Sakamoto, Morita 2006).

A group of colon cancer patients were randomized to receive chemotherapy alone or chemotherapy plus PSK, which was taken for two years. The group receiving PSK had an exceptional 10-year survival of 82%. The group receiving chemotherapy alone had a 10-year survival of only 51% (Sakai 2008). In a similar trial reported in the British Journal of Cancer in 2004, colon cancer patients received chemotherapy alone or combined with PSK (3 grams per day) for two years. In the group with Stage 3 colon cancer, the five-year survival was 75% in the PSK group. This compared to a five-year survival of only 46% in the group receiving chemotherapy alone (Ohwada 2004).

Sulforaphane

Sulforaphane is a compound that is found in cruciferous vegetables, like broccoli and kale. It improves the elimination of toxic substances by the liver. It also may have a more direct role in thwarting the growth of cancers, including colorectal cancer, through re-activation of tumor suppressor genes that were formerly silenced (Myzak 2006; Dashwood 2007).

Sulforaphane inhibited the formation of colon tumors in an animal model (Myzak 2006). It is also able to induce apoptosis in colon cancer cells with impaired apoptosis capability (Rudolf 2011).

Sulforaphane appears to protect normal colon cells while encouraging self-destruction of colon cancer cells (Reuter 2008). When added to oxaliplatin, sulforaphane improved the ability of the drug to kill colon cancer cells (Kaminski 2011).

In one study, sulforaphane was synergistic with indole-3-carbinol, another compound from cruciferous vegetables. Together the compounds resulted in greater toxicity to colon cancer cells than either compound alone (Pappa 2007).

Resveratrol

Resveratrol is a polyphenol found in grapes, peanuts and mulberries. Resveratrol suppresses colitis and colitis associated colon cancer in mice (Cui 2010). Grape powder and resveratrol inhibited the carcinogenic Wnt pathway in normal colonic mucosa (Hope 2008; Nguyen 2009). Resveratrol also inhibits the COX-2 enzyme, suppressing inflammation (Zykova 2008). Resveratrol may synergize with butyrate in the colon as well (Wolter 2002).

Resveratrol has been shown to lessen aberrant crypt formation (Tessitore 2000; Sengottuvelan 2006) and adenoma formation (Schneider 2001) as well as induce apoptosis of colon cancer cells (Mahyar-Roemer 2002; Vanamala 2011).

A small study of twenty patients scheduled for colon resection to remove malignancy showed that a dose of 0.5-1.0 grams/day for eight days prior to surgery resulted in adequate levels of resveratrol in the tumors to have biological effects. This was particularly true for tumors on the right (proximal) side (Patel 2010).

Resveratrol may also increase the sensitivity of colon cancer cells to the killing effects of chemotherapy (Santandreu 2011).

Green Tea Extract

Green tea contains potent antioxidants known as catechins, the most well studied of which is epigallocatechin-3-gallate (EGCG), which has been found to inhibit carcinogenesis in various cancers, including colorectal cancers (Yang 2002; Issa 2007; Kumar 2007).

Green tea extract is well established to have anti-cancer actions on growth, survival, angiogenesis and metastatic processes of cancer cells (Yang, Lambert 2007; Singh 2011) and favorable effects on immune function (Butt 2009). Green tea has also been shown to reduce the carcinogenicity of nitrosamines, carcinogenic compounds from cooked meats (Dashwood 1999).

A meta-analysis of consumption of green tea across populations found that those consuming the highest levels of green tea had an 18% lower risk of developing colorectal cancer compared to those consuming the lowest amounts (Sun 2006). In a clinical study, green tea extract (equivalent of >10 cups/day, or about 150mg EGCG) lessened adenoma formation, both number and severity, in those with a prior history of adenomas (Shimizu 2008).

Milk Thistle

Milk thistle (Silybum marianum) contains silibinin and silymarin, flavonoid compounds shown to have numerous anticancer effects. Milk Thistle is generally used to improve the break down and elimination of chemicals and toxins, so it is not surprising that silymarin was able to prevent chemically induced colon cancer in mice (Kohno 2002). In another animal study, silymarin, along with quercitin, curcumin, rutin, all independently reduced aberrant crypt formation, an early process in colon cancer formation (Volate 2005). Silymarin also inhibits angiogenesis (Yang 2003), a necessary process for tumor growth.

Silibinin has been shown to inhibit colorectal carcinogenesis directly (Sangeetha 2010). Silibinin blocks proliferation, reduces new blood vessel growth and induces cell death (apoptosis) of colorectal cancer cells (Hogan 2007; Singh 2008; Kaur 2009; Kauntz 2011). It may achieve some of these anti-tumor effects through disruption of signaling pathways within cancer cells as well as by blocking activation of NF-kB (Li 2010).

Quercetin

Quercetin belongs to a class of potent antioxidants called flavonoids. These are what give apples their color. Onions, garlic, tea, red grapes, berries, broccoli, and leafy greens are also rich sources of quercetin.

It’s well known to nutritional scientists as a potent free radical-scavenger (Murakami 2008). Quercetin also happens to possess a singular cancer-fighting feature: it can prevent cancer caused by chemicals. Its unique molecular structure enables it to block receptors on the cell surface that interact with carcinogenic chemical compounds. This makes it a perfect anticancer agent for the colon, where carcinogenic chemicals tend to accumulate (Murakami 2008).

Researchers in Greece have also discovered that quercetin dramatically suppresses one particular cancer-causing gene in colon cells. This makes quercetin supplementation an ideal form of early prevention for individuals with a family history of colon cancer (Psahoulia 2007).

Dutch scientists uncovered even more evidence of its cancer-preventive power at the genetic level. In an animal study, quercetin reduced “cancer gene” activity and increased “tumor-suppressor gene” activity in colon cells after 11 weeks (Dihal 2008).

In yet another promising animal study, scientists in South Carolina were able to halt the development of aberrant crypts. Cancer-prone rats fed a diet high in quercetin (Mahmoud 2000) underwent a four-fold reduction in the number of aberrant crypts compared to a control group. Similar research has yielded additional evidence of quercetin’s capacity to reduce emerging aberrant crypts — a vital first step in preventing colon cancer from developing at all (Gee 2002).

In 2006, scientists at the Cleveland Clinic evaluated patients suffering from familial adeno-matous polyposis. They discovered that a combination of curcumin and quercetin could cause these growths to diminish substantially. The researchers supplemented the patients with 480 mg of curcumin and 20 mg of quercetin orally, three times a day, for six months. Every single patient experienced a remarkable decrease in polyp numbers and size, with average reductions of 60% and 51%, respectively (Cruz-Correa 2006).

N-Acetylcysteine

NAC is a slightly modified version of the sulfur-containing amino acid cysteine.

When taken internally, NAC replenishes intracellular levels of the natural antioxidant glutathione (GSH), helping to restore cells’ ability to avoid damage from reactive oxygen species. NAC suppresses the NF-kB, which in turn prevents activation of multiple inflammatory mediators (Kim 2000; Chen 2008). NAC also regulates the gene for COX-2, the enzyme that produces pain- and inflammation-inducing prostaglandins in a wide array of chronic conditions (Origuchi 2000).

NAC (800mg/day) lessened the rate of proliferation of the cells in the colonic crypts in patients with a history of adenomatous polyps (Estensen 1999). This is in keeping with a study that showed that those with a history of polyps had a 40% reduction in recurrence of their polyps using 600 mg of NAC daily (Ponz de Leon 1997).

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