~Colorectal Cancer, Part 4 - Natural Therapies

Natural Therapies
  • Curcumin
  • Green Tea
  • Se-Methylselenocysteine
  • Coenzyme Q10
  • EPA and DHA Oils
  • Vitamins A, D, and E
  • Tocotrienols
  • Modified Citrus Pectin
Curcumin. Curcumin is extracted from the spice turmeric and is responsible for the orange-yellow pigment that gives the spice its unique color. Turmeric is a perennial herb of the ginger family and a major component of curry powder. It has been safely used for centuries by the Chinese and Indians in herbal medicine and in food preparation as a spice.

Curcumin has a number of biological effects within the body. However, one of the most important functions is curcumin's ability to inhibit angiogenic growth signals emitted by tumor cells eliciting angiogenesis (growth and development of new blood vessels).

In a study conducted by the International Institute of Anticancer Research in the 2001 edition of Anticancer Research, curcumin inhibited cell proliferation and induced G2/M (cell cycle phase) arrest in HCT-116 colon cancer cells. Furthermore, immunoblot analysis indicated that curcumin caused the induction of apoptosis as evidenced by cleavage of PARP, caspase-3, and reduction in Bcl-XL levels. Curcumin also stimulated the activity of caspase-8 which initiates the Ras signaling pathway of apoptosis. Curcumin therefore appears to exert its anticarcinogenic properties by inhibiting proliferation and inducing apoptosis in certain gastric and colon cancer cells.

The American Health Foundation's Nutritional Carcinogenesis and Chemoprevention Program investigated epidemiological data suggesting that dietary manipulations play an important role in the prevention of many human cancers. Curcumin has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries.

Additionally, this data confirmed curcumin is a naturally occurring powerful anti-inflammatory medicine. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 (COX-2) expression. Curcumin has been shown to inhibit the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin has also demonstrated inhibition of the promotion/progression stages of carcinogenesis. The antitumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and to the induction of apoptosis. Curcumin has also inhibited the growth of DNA mismatch repair-defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair-deficient and microsatellite-unstable phenotype. The American Health Foundation suggests curcumin should be considered a safe, nontoxic, and easy-to-use chemotherapeutic agent for colorectal cancers in the setting of chromosomal instability as well as microsatellite instability.

Curcumin inhibits the epidermal growth factor (EGF) receptor and is up to 90% effective in a dose-dependent manner. It is important to note that while curcumin has been shown to be up to 90% effective in inhibiting the expression of the epidermal growth factor receptor on cancer cell membranes, this does not mean it will be effective in 90% of cancer patients or reduce tumor volume by 90%. Since two-thirds of all cancers, however, overexpress the epidermal growth factor receptor and such overexpression frequently fuels the metastatic spread of the cancer throughout the body, suppression of this receptor is desirable.

Other mechanisms of curcumin include:
  • Inhibition of the induction of basic fibroblast growth factor (bFGF). bFGF is both a potent mitogen (growth signal) for many cancers and an important signaling factor in angiogenesis (Arbiser et al. 1998).
  • Inhibition of the expression of COX-2, the enzyme involved in the production of PGE-2, a tumor-promoting prostaglandin hormone (Zhang et al. 1999).
  • Inhibition of a transcription factor in cancer cells known as nuclear factor-kappa B (NF-KB). Many cancers overexpress NF-KB and use this as a growth vehicle to escape regulatory control (Bierhaus et al. 1997).
  • Increased expression of nuclear p53 protein in human basal cell carcinomas, hepatomas, and leukemia cell lines (perhaps others as well). This increases apoptosis (Jee et al. 1998).
  • Increased production of transforming growth factor-beta (TGF-beta) producing apoptosis (cell death). While TGF-beta is multifunctional and can either stimulate or inhibit cell proliferation when combined with curcumin, it functions as an antigrowth signal and does not promote the progression of cancer; rather, curcumin retards it (Sidhu et al. 1998; Sporn et al. 1998).
  • Inhibition of PTK (protein tyrosine kinases) and PKC (protein kinase C). PTK and PKC both help relay chemical signals through the cell. A wide range of precancerous activities relies on abnormally high levels of these substances for signal transduction. These include proliferation, cell migration, metastasis, angiogenesis, avoidance of apoptosis, and differentiation (Reddy et al. 1994; Davidson et al. 1996).
  • Inhibition of AP-1 (activator protein-1) through a nonantioxidant pathway. While curcumin is an antioxidant, it appears to inhibit the signal transduction pathway via protein phosphorylation, thereby decreasing cancer cell activity, regulation, and proliferation (Huang et al. 1991).
Based on these favorable, multiple mechanisms, high-dose curcumin would appear to be useful for cancer patients. However, as far as curcumin being taken at the same time as chemotherapy drugs, there are contradictions in the scientific literature.

Please refer to the Cancer Chemotherapy protocol before considering combining curcumin with chemotherapy.

Curcumin's effects are a dose dependent response, and a standardized product is essential. Please note that curcumin may cause mild gastrointestinal distress. If distress occurs, curcumin can be taken with food. The recommended dose is four 900-mg capsules 3 times daily.

Green Tea. As a tumor grows, it elicits new capillary growth (angiogenesis) from the surrounding normal tissues and diverts blood supply and nutrients away from the tissue to feed itself. Unregulated angiogenesis can facilitate the growth of cancer throughout the body. Antiangiogenesis agents inhibit this new blood vessel growth, and green tea is one of these agents.

Green tea contains epigallocatechin gallate (EGCG), a catechin whose primary action blocks the induction of vascular endothelial growth factor (VEGF). VEGF is essential in angiogenesis and endo-thelial cell survival and has been established as the most potent angiogenic factor leading to metastasis of colorectal cancer. Therefore, it is the EGCG component of green tea that makes it a potentially effective adjunct therapy in the treatment of colorectal cancer. In vivo studies have shown green tea extracts to have the following actions on human cancer cells (Jung et al. 2001a):
  • Inhibition of tumor growth by 58%
  • Inhibition of microvessel density by 30%
  • Inhibition of tumor cell proliferation by 27%
  • Increased tumor cell apoptosis 1.9-fold
  • Increased endothelial cell apoptosis 3-fold
The most current research shows that green tea may have a beneficial effect in treating cancer. While drinking green tea is a well-documented method of preventing cancer, it is difficult for the cancer patient to obtain a sufficient quantity of anticancer components in that form. Standardized green tea extract is more useful than green tea itself because the dose of EGCG can be precisely monitored and greater doses can be ingested without excessive intake of liquids. We suggest that a person with colorectal cancer take 6 capsules of 350-mg, lightly caffeinated green tea extract 3 times a day with each meal. Each capsule should provide at least 100 mg of epigallocatechin gallate (EGCG), the most potent anticancer constituent of green tea.

Green tea extract is available in a decaffeinated form for persons who are sensitive to caffeine or who want to take the less-stimulating decaffeinated green tea extract capsules in their evening dose.

Se-Methylselenocysteine. A new and better form of selenium is Se-methylselenocysteine--a naturally occurring, organic selenium compound found to be an effective chemopreventive agent. SeMSC is a selenoamino acid that is synthesized by plants such as garlic and broccoli.

A recent study has demonstrated that Se-methyl-selenocysteine is one of the most effective selenium compounds in inducing apoptosis in HL-60 leukemic cell lines (Jung et al. 2001b). Some of the most impressive data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis (Ip et al. 2001). Se-methylselenocysteine has been shown to:
  • Produce a 33% better reduction of cancerous lesions than selenite
  • Produce a 50% decrease in tumorigenesis
  • Induce apoptosis in cancer cells
  • Inhibit cancer cell proliferation
  • Reduce intratumoral microvessel density and angiogenesis
  • Downregulate VEGF (vascular endothelial growth factor)
  • Be essential for angiogenesis
(Ip et al. 1992, 1999, 2001; Sinha et al. 1997, 1999; Dong et al. 2001)

Unlike selenomethionine, which is incorporated into protein in place of methionine, SeMSC is not incorporated into any protein, thereby offering a completely bioavailable compound. In animal studies, it has been shown to be 10 times less toxic than any other known form of selenium. Colon cancer patients may consider taking 200-400 mcg a day of Se-methylselenocysteine.

Coenzyme Q10 (CoQ10). Since the 1960s, studies have shown that cancer patients often have decreased blood levels of CoQ10 (Lockwood et al. 1995; Folkers 1996; Ren et al. 1997; Portakal et al. 2000; NCCAM 2001). These findings sparked interest in the compound as a potential anticancer agent (NCCAM 2001). Cellular and animal studies have found evidence that CoQ10 stimulates the immune system and can increase resistance to illness (Bliznakov et al. 1970; Hogenauer et al. 1981; NCCAM 2001).

Although there are only a few studies, the safe nature of CoQ10 coupled with this promising research suggests that cancer patients should take at least 100mg daily. It is important to take CoQ10 with some kind of oil such as fish or flaxseed because dry powder CoQ10 is not readily absorbed without it.

There are more promising results for the use of CoQ10 to protect against heart damage related to chemotherapy. Many chemotherapy drugs can cause damage to the heart (UTH 1998; ACS 2000; Dog et al. 2001), and initial animal studies found that CoQ10 could reduce the adverse cardiac effects of these drugs (Folkers et al. 1996; Combs et al. 1977; Choe et al. 1979; Lubawy et al. 1980; Usui et al. 1982; Shinozawa et al. 1993).

Some studies indicate that CoQ10 should not be taken at the same time as chemotherapy. If this were true, it would be disappointing, since CoQ10 is so effective in protecting against adriamycin-induced cardiomyopathy. Adriamycin is a chemotherapy drug sometimes used as part of a chemotherapy cocktail. Until more research is done, it is not possible to make a definitive recommendation regarding whether to take CoQ10 during chemotherapy (for more information please see the Cancer Chemotherapy protocol).

EPA and DHA Oils. The omega-3 fatty acids have demonstrated several different anticancer mechanisms, including inhibition of tumor development and metastasis. Large doses of fish oil can inhibit cell proliferation and tumor growth through a free-radical-mediated mechanism, while at more moderate doses, omega-3 fatty acids inhibit inflammation, angiogenesis, and Ras protein activity or invasion enzymes (McCarty 1996; Collett et al. 2001; Grimm et al. 2002).

If one ingests flaxseed or perilla oil, the body usually breaks down the alpha-linolenic acid found in these oils to the biologically active EPA and DHA fraction. A more efficient and consistent way of obtaining high concentrations of EPA and DHA is to consume a standardized fish oil supplement. Cancer patients often ingest about 3200 mg of EPA and 2400 mg of DHA a day from a standardized fish oil supplement.

Vitamins A, D, and E. Combined, vitamin A and vitamin D3 have been shown to inhibit tumor-induced angiogenesis. Additionally, vitamin D3 has demonstrated the ability to inhibit liver cancer cell growth (Majewski et al. 1996). Cancer patients should take 4000-6000 IU of vitamin D3 every day on an empty stomach. Water-soluble vitamin A can be taken in doses of 100,000-300,000 IU every day. Monthly blood tests are needed to make sure toxicity does not occur in response to these relatively high daily doses of vitamin A and vitamin D3. After 4-6 months, the doses of vitamin D3 and vitamin A can be reduced.

Vitamin E succinate (d-alpha tocopheryl succinate) has been shown to inhibit tumor cell growth in vitro and in vivo. For instance, in mice with colon cancer xenografts, vitamin E succinate suppressed tumor growth by 80%. This study epitomizes the cancer cell killing effects of this form of vitamin E which has no known side effects (Neuzil et al. 2001).

It is critically important that cancer patients use the alpha tocopheryl succinate form of vitamin E as opposed to standard vitamin E preparations. A study compared two different forms of vitamin E using nude mice with colon cancer xenografts. While standard vitamin E (alpha tocopherol) exerted modest antitumor activity, tocopheryl succinate showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. The scientists who conducted this study concluded by stating: "Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential" (Weber et al. 2002).

The suggested dose of d-alpha tocopheryl succinate is 800-2000 mg daily along with at least 200 mg of gamma tocopherol.

When taking doses of vitamin D3 in excess of 1400 IU a day, regular blood chemistry tests should be taken to monitor kidney function and serum calcium metabolism.

Tocotrienols. Vitamin E is the term used to describe eight naturally occurring essential fat-soluble nutrients: alpha, beta, delta, and gamma tocopherols plus a class of compounds related to vitamin E called alpha, beta, delta, and gamma tocotrienols.

Tocotrienols possess the ability to stimulate the killing of cancer cells selectively through programmed cell death (apoptosis) in order to reduce cancer cell proliferation, while leaving normal cells unaffected (Kline et al. 2001). One of the mechanisms by which tocotrienols are thought to suppress cancer is related to the isoprenoid side chain.

Isoprenoids are plant compounds that have suppressed the initiation, growth, and progression of many types of cancer in experimental studies (Block et al. 1992). Isoprenoids are common in fruits and vegetables, which may explain why diets rich in these foods have consistently been shown to reduce the incidence of cancer.

The antiproliferative effect of isoprenoids is thought to be due to suppression of the mevalonate pathway, through which mutated Ras proteins transform healthy cells into cancer cells. Mutated Ras is the most common cellular defect found in human cancers. The mevalonate pathway escapes regulatory control in tumor tissue but remains highly sensitive to regulation by tocotrienols. Tocotrienols are at least 5 times more powerful than farnesol, the body's regulator of the mevalonate pathway (Elson et al. 1994).

Among the tocotrienols, delta-tocotrienol has been shown to be the most potent inducer of apoptosis (programmed cell death) in both estrogen-responsive and estrogen-nonresponsive human breast cancer cells, followed by gamma- and alpha-tocotrienol. (Beta-tocotrienol was not tested.) Interestingly, delta-tocotrienol is more plentiful in palm tocotrienols than in tocotrienols derived from rice. Of the natural tocopherols, only delta-tocopherol showed any apoptosis-inducing effect, although it was less than one-tenth of the effect of palm and rice delta-tocotrienol (Yu et al. 1999).

While healthy people normally take about 60 mg a day of palm-oil tocotrienols, cancer patients may consider taking 240 mg daily for a period of 3-6 months.

Modified Citrus Pectin. Adhesion molecules called E-selectin are present on blood vessel cells, and several types of cancer cells use the carbohydrate groups called Lewis antigens (Lewis X and Lewis A.4) that are found on their surface to bind to E-selectin. Once the Lewis antigens on the cancer cell bind to the E-selectin adhesion molecule on the blood vessel cell, the initiation of a metastatic tumor is established.

Modified citrus pectin is a free sugar that has been demonstrated to inhibit metastasis by binding to the E-selectin adhesion molecules.

Note: Please note that free sugar is not to be confused with dietary sugars, which will be discussed later.

Research has demonstrated that if all E-selectin sugar-binding sites are filled with free sugars, the E-selectin is not able to bind to other cells, specifically cancer cells. This would reduce the initial binding of tumor cells to the vascular wall as they travel through the circulation. The effect of filling sugar-binding sites has been shown to reduce colon cancer growth by 70% (Hayashi et al. 2000). Based on these findings, 15 grams of modified citrus pectin is recommended daily in 3 divided doses.

Diet

Cancer has an appetite for sugar. Tumors are primarily obligate glucose metabolizers. Simply stated, cancer requires sugar for survival. Sugars play an active role in reducing the immune response and energizing cancer. Ingestion of certain sugars also provokes an insulin spike that further induces cancer cell division.

There is a relationship between lactic acid, insulin, and angiogenesis. In tumors, hypoxic conditions occur through inflammation, which reduces blood flow, promotes anemia, and induces the chaotic development of blood vessels within tumors. These hypoxic conditions alter the pathways by which immune cells and tumor cells burn fuel (glucose) for energy. This creates excessive buildup of toxic lactic acid.

In an oxygen-rich (aerobic) environment, glucose is burned in an efficient process that produces a maximum amount of energy and a minimal amount of lactic acid. However, tumor cells in chronic hypoxic conditions produce excessive lactic acid and inefficient utilization of glucose. Thus, there is a vicious cycle in which the reduced energy output stimulates the tumor cells to burn more glucose which in turn produces more lactic acid. Tumor cells consume glucose at a rate 3-5 times higher than normal cells, creating a highly stimulated glycolysis (glucose-burning) pathway.

This glucose consumption can waste the cancer patient's energy reserves and the increased production of lactic acid can stimulate increased production of angiogenic factors. Lactic acid itself is an angiogenic factor that causes macrophages, the predominant immune cell at tumor sites, to produce other angiogenic factors, and of these, TNF (tumor necrosis factor) may be the most active. A common belief is that immune activities inhibit cancer development; however, this does not accurately describe what occurs within the body.

The macrophage-mediated angiogenesis creates a complex interplay between opposing regulators. It is believed that when normal wound healing has concluded, the macrophages responsible for promoting angiogenesis, switch modes and inhibit angiogenesis. However, at tumor sites, it appears that the signals that cause the angiogenesis-promoting mode to switch to an angiogenesis-inhibiting mode are lacking and the angiogenesis-promoting mode continues unabated.

Insulin plays an active role in promoting angiogenesis. Insulin is a growth factor that stimulates glycolysis and the proliferation of many cancer cell lines. Insulin is thought to facilitate angiogenesis by increasing lactic acid production in hypoxic tumor cells and by stimulating the proliferation of vascular cells. In cancer patients, elevated levels of insulin are common in cancerous tissue and blood plasma. It would follow that obesity and early stages of noninsulin-dependent diabetes Type II (NIDDM) have been implicated as risk factors in a variety of cancers.

Therefore, based on cancer's sugar dependency, a sugar deprivation diet is strongly recommended. An effective tool in eliminating sugar is to know the glycemic index. The index is a list that rates the speed at which different foods are digested and raise blood sugar levels. The ratings are based on the rate at which a measured amount of pure glucose affects the body's blood sugar curve. Glucose itself has a rating of 100, and the closer a food item is to a rating of 100, the more rapidly it raises blood glucose levels. Only foods with very low glycemic index values such as vegetables and protein and to a lesser extent whole grains and beans are suggested.

Regarding depleting sugar from one's diet, the following ideas should be considered:
  • Avoid all white foods, including but not limited to sugar, flour, rice, pasta, breads, crackers, and cookies.
  • Read labels. Sugar has many names, including brown sugar, corn syrup, honey, molasses, maple syrup, high-fructose corn syrup, dextrin, raw sugar, fructose, polyols, dextrose, hydrogenated starch, galactose, glucose, sorbitol, fruit juice concentrate, lactose, brown rice syrup, xylitol, sucrose, mannitol, sorghum, maltose, and turbinado, to mention only a few.
  • Avoid all fruit juices. Per glass, fruit juices contain the juice of many pieces of fruit and a large amount of fructose (fruit sugar), but no fiber. Instead, infrequently eat low-glycemic-rated fruit in small portions.
Natural compounds have also been reported to inhibit cancer-promoting effects of insulin. For example, vitamin C has been reported to increase oxygen consumption and reduce lactic acid production in tumor cells. In addition, some natural compounds may help reduce insulin production by reducing insulin resistance. Insulin resistance occurs when cells are no longer sensitive to insulin and thus more insulin is produced in an effort to reduce glucose levels.

Insulin resistance has been implicated as a risk factor for cancer, and diets high in saturated fats and omega-6 fatty acids promote insulin resistance. Although the exact pathway is unknown, it is thought that the mechanism of action is via chronic activation of protein kinase C (PKC). Some of the known natural compounds that can reduce insulin resistance include omega-3 fatty acids, curcumin, flavonoids, selenium, and vitamin E.

Dietary risk factors must be managed. Therefore, besides restricting dietary sugars, individuals should eat an adequate amount of fruits and vegetables because phytochemicals in fruits and vegetables act as potent anticancer agents.

In addition, high-fat foods and animal proteins should only be consumed moderately. Studies have found that dietary beef induces and dietary rye bran prevents formation of intestinal polyps. Studies suggested that obesity, rather than fat intake per se, predisposed an individual to colon cancer (Stemmermann et al. 1985; Murphy et al. 2000). It is therefore suggested that both a low sugar and a low saturated fat diet be followed.

Continued . . .


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