Apigenin, which is a flavone (ie, a class of flavonoids) that is present in fruits and vegetables (eg, onions, oranges, tea, celery, artichoke, and parsley), has been shown to possess anti-inflammatory, antioxidant, and anticancer properties. Many studies have confirmed the cancer chemopreventive effects of apigenin (Patel 2007). Apigenin stimulates apoptosis in breast cancer cells (Chen 2007). A 2012 study showed that apigenin slowed the progression of human breast cancer by inducing cell death, inhibiting cell proliferation, and reducing expression of a gene associated with cancer growth (Her2/neu). In another study, it was noted that blood vessels responsible for feeding cancer cells were smaller in apigenin-treated mice compared to untreated mice. This is significant because smaller vessels mean restricted nutrient flow to the tumours and may have served to starve the cancer as well as limit its ability to spread (Mafuvadze 2012). Apigenin has been proven to have a synergistic treatment effect when combined with the chemotherapy drug paclitaxel (Xu 2011). In a study, apigenin increased the efficacy of the chemotherapy drug 5-Fluorouracil against breast cancer cells (Choi 2009).
Astragalus, an herb used for centuries in Asia, has exhibited immune-stimulatory effects. Astragalus potentiates lymphokine-activated killer cells (Chu 1988). One study found that astragalus could partially restore depressed immune function in tumor-bearing mice (Cho 2007a), while another concluded that “…astragalus could exhibit anti-tumor effects, which might be achieved through activating the…anti-tumor immune mechanism of the host” (Cho 2007b). It was observed in a clinical trial that astragalus inhibited the proliferation of breast cancer cells. Authors of the study stated, “The antiproliferation mechanisms may be related to its effects of up-regulating the expressions of p53…” (Ye 2011). Similar findings were noted in a previous experiment (Deng 2009).
Blueberries are rich in anthocyanins (ie, dark pigments in fruits) and pterostilbenes (ie, antioxidant closely related to resveratrol). The anti-cancer effects of blueberries are mediated by multiple mechanisms: Blueberry extracts block DNA damage. Damage to cellular DNA underlies most forms of cancer. By preventing such damage, blueberry extracts can block the malignant transformation of healthy cells (Aiyer 2008). Blueberry extracts inhibit angiogenesis. Rapidly-growing cancers recruit new blood vessels to meet their ravenous appetites for nutrients and oxygen. Blueberry inhibits new tumour blood vessel growth, known as angiogenesis (Gordillo 2009; Liu 2011). Blueberry extracts trigger cancer cells’ suicide. If normal cells replicate too fast, they are programmed to die through apoptosis. Cancerous cells, by contrast, ignore that programming, constantly doubling their population unchecked. Blueberry components restore normal programming and induce apoptosis in cells from a variety of cancers, putting the brakes on their rapid growth (Katsube 2003; Yi 2005; Seeram 2006; Srivastava 2007; Alosi 2010). Blueberry extracts stop excessive proliferation. Uncontrolled cell reproduction results in formation of dangerous tumours, as cells ignore the normal signals to stop growing. By restoring normal cellular signalling, blueberry extracts stop such out-of-control proliferation (Yi 2005; Adams 2010; Nguyen 2010). In an experimental breast cancer cell line, blueberry significantly reduced breast cancer cell proliferation, leading the researchers to state that “blueberry anthocyanins … demonstrated anticancer properties by inhibiting cancer cell proliferation and by acting as cell anti-invasive factors and chemo-inhibitors” (Faria 2010). In rats with experimentally induced breast cancer, the volume of new breast tumour formation was reduced by 40% in the group of rats supplemented with blueberry compared to the control group (Srinivasan 2008).
Blueberry extracts slow tumor spread by invasion and metastasis. Solid cancers produce matrix metalloproteinases, which are “protein-melting” enzymes that help them invade adjacent tissues and that enable them to metastasize. Blueberry extracts block matrix metalloproteinases, thereby inhibiting cancer invasion and metastasis (Adams 2010a; Matchett 2005). In one experiment published in 2011, blueberry extract was administered to mice with breast cancer. Compared to the control group, tumour volume was 75% lower in mice fed blueberry extract. Moreover, mice fed blueberry extract developed 70% fewer liver metastases and 25% fewer lymph node metastases compared to the control group (Adams 2011).
Breast cancers that are estrogen-receptor positive can grow and be exacerbated in the presence of estrogen in the body. One aim of drug therapy for estrogen-receptor positive breast cancer is to decrease the levels of estrogen in the body. To that end, drugs used to block the enzyme (ie, aromatase) that converts testosterone into estrogen (ie, aromatase inhibitors) are widely used in women with estrogen-receptor positive breast cancer. Chrysin, a flavonoid, is a natural aromatase inhibitor (Campbell 1993; Mohammed 2011).
Coffee, especially brews enriched with chlorogenic acid, protect cells against the DNA damage that leads to aging and cancer development (Bakuradze 2011; Hoelzl 2010; Misik 2010). Growing tumours develop the ability to invade local and regional tissue by increasing their production of “protein-melting” enzymes called matrix metalloproteinases. Chlorogenic acid—present in coffee—strongly inhibited matrix metalloproteinase activity (Jin 2005; Belkaid 2006). A 2011 study reported that postmenopausal women who drank 5 cups of coffee daily exhibited a 57% decreased risk of developing estrogen-receptor negative (non-hormone-responsive) breast cancer (Li 2011). Chlorogenic acid and other polyphenols are the likely beneficial agents in such cancers (Bageman 2008).
Curcumin is extracted from the spice turmeric and is responsible for the orange/yellow pigment that gives the spice its unique colour. Turmeric is a perennial herb of the ginger family and a major component of curry powder. Chinese and Indian people, both in herbal medicine and in food preparation, have safely used it for centuries. Curcumin has a number of biological effects in the body. However, one of the most important functions is curcumin's ability to inhibit growth signals emitted by tumour cells that elicit angiogenesis (growth and development of new blood vessels into the tumour). Curcumin inhibits the epidermal growth factor 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 tumour volume by 90%. However, because two-thirds of all cancers 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.
There are several other anticancer mechanisms of curcumin and based on the favourable results, higher-dose curcumin would appear to be useful for cancer patients to take. However, as far as curcumin being taken at the same time as chemotherapy drugs, there are contradictions in the scientific literature. Therefore, caution is advised. 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. The recommended dose is four 900-mg capsules 3 times per day, preferably with food.
As a tumour 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 tumour angiogenesis can facilitate the growth of cancer throughout the body. Anti-angiogenesis agents, including green tea, inhibit this new tumour blood vessel (capillary) growth.
Green tea contains epigallocatechin gallate EGCG, a polyphenol that helps to block the induction of vascular endothelial growth factor (VEGF). Scientists consider VEGF essential in the process of angiogenesis and tumour endothelial cell survival. It is the EGCG fraction of green tea that makes it a potentially effective adjunct therapy in the treatment of breast cancer. In vivo studies have shown green tea extracts to have the following actions on human cancer cells (Jung et al. 2001b; Muraoka et al. 2002):
- Inhibition of tumour growth by 58%
- Inhibition of activation of nuclear factor-kappa beta
- Inhibition of microvessel density by 30%
- Inhibition of tumour-cell proliferation in vitro by 27%
- Increased tumour-cell apoptosis 1.9-fold
- Increased tumour endothelial-cell apoptosis threefold
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 EGCG anticancer components in that form. Standardized green tea extract is more useful then green tea itself because the dose of EGCG can be precisely monitored and greater doses can be ingested without excessive intake of liquids. A suggested dose for a person with breast cancer is 5 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 EGCG. It may be desirable to take a decaffeinated version of green tea extract in the evening to ensure that the caffeine does not interfere with sleep. Those patients that are sensitive to caffeine may also use this decaffeinated form for all treatment. However, there are benefits to obtaining some caffeine. Studies show that caffeine potentiates the anticancer effects of tea polyphenols, including the critical EGCG. Caffeine will be discussed in further detail later in this protocol. Green tea extract is available in a decaffeinated form for those sensitive to caffeine or those who want to take the less-stimulating decaffeinated green tea extract capsules for their evening dose.
Conjugated Linoleic Acid (CLA)
Conjugated linoleic acid (CLA) found naturally, as a component of beef and milk, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA is essential for the transport of dietary fat into cells, where it is used to build muscle and produce energy. CLA is incorporated into the neutral lipids of mammary fat (adipocyte) cells, where it serves as a local reservoir of CLA. It has been proposed that CLA may be an excellent candidate for prevention of breast cancer (Ip et al. 2003). Low levels of CLA are found in breast cancer patients but these do not influence survival. Nevertheless, it has been hypothesized that a higher intake of CLA might have a protective effect on the risk of metastasis (Chajes et al. 2003).
CLA was shown to prevent mammary cancer in rats if given before the onset of puberty. CLA ingested during the time of the "promotion" phase of cancer development conferred substantial protection from further development of breast cancer in the rats by inducing cell kill of pre-cancerous lesions (Ip et al. 1999b). It was determined that feeding CLA to female rats while they were young and still developing conferred life-long protection against breast cancer. This preventative action was achieved by adding enough CLA to equal 0.8% of the animal's total diet (Ip et al. 1999a).
CLA inhibits the proliferation of human breast cancer cells (MCF-7), induced by estradiol and insulin (but not EGF). In fact, CLA caused cell kill (cytotoxicity) when tumour cells were induced with insulin (Chujo et al. 2003). The antiproliferative effects of CLA are partly due to their ability to elicit a p53 response that leads to growth arrest (Kemp et al. 2003). CLA elicits cell killing effects in human breast tumour cells through both p53-dependent and p53 independent pathways according to the cell type (Majumder et al. 2002). Refer to Cancer Treatment The Critical Factors, for more information on determining the p53 status of cancer. The effects of CLA are mediated by both direct action (on the epithelium) as well as indirect action through the stroma. The growth suppressing effect of CLA may be partly due to changes in arachidonic distribution among cellular lipids and an altered prostaglandin profile (Miller et al. 2001). Intracellular lipids may become more susceptible to oxidative stress to the point of producing a cytotoxic effect (Devery et al. 2001). CLA has the ability to suppress arachidonic acid. Since arachidonic acid can produce inflammatory compounds that can promote cancer proliferation, this may be yet another explanation for CLA's anticancer effects.
The recommended dose for CLA is a dose of 3000-4000 mg daily, which is approximately 1% of the average human diet. The suggested amount required to obtain the overall cancer-preventing effects is only 3000-4000 mg daily in divided doses.
Caffeine occurs naturally in green tea and has been shown to potentiate the anticancer effects of tea polyphenols. Caffeine is a model radio-sensitizing agent that is thought to work by abolishing the radiation-induced G2-phase checkpoint in the cell cycle. Caffeine can induce apoptosis of a human lung carcinoma cell line by itself and it can act synergistically with radiation to induce tumour cell kill and cell growth arrest. The cancer cell killing effect of caffeine is dependent on the dose (Qi et al. 2002).
Caffeine enhances the tumour cell killing effects of anticancer drugs and radiation. A preliminary report on radio-chemotherapy combined with caffeine for high-grade soft tissue sarcomas in 17 patients, (treated with cisplatin, caffeine, and doxorubicin after radiation therapy) determined complete response in six patients, partial response in six and no change in five patients. The effectiveness rate of caffeine-potentiated radio-chemotherapy was therefore 17%, and contributed to a satisfactory local response and the success of function-saving surgery for high-grade soft tissue sarcomas (Tsuchiya et al. 2000).
In a randomized, double blind placebo-controlled crossover study, the effects of caffeine as an adjuvant to morphine in advanced cancer patients was found to benefit the cognitive performance and reduce pain intensity (Mercadente et al. 2001). To ascertain the inhibitory effects of caffeine, mice at high risk of developing malignant and non-malignant tumours (SKH-1), received oral caffeine as their sole source of drinking fluid for 18-23 weeks. Results revealed that caffeine inhibited the formation and decreased the size of both non-malignant tumours and malignant tumours (Lou et al. 1999). Consumption of coffee, tea, and caffeine was not associated with breast cancer incidence in a study of 59,036 Swedish women (aged 40-76 years) (Michels et al. 2002).
Lignans are found in high concentrations in flaxseed and sesame. Once consumed, lignans are converted in the intestines into enterolactone.Enterolactone has been shown to inhibit angiogenesis and promote cancer cell apoptosis (Bergman 2007; Chen 2007). Enterolactone inhibits the aromatase enzyme, which converts testosterone into estrogen (Brooks 2005; Wang 1994). Researchers conducted an analysis of breast cancer risk and dietary lignan intake in 3158 women. They determined that premenopausal women with the highest lignan intake had a 44% reduced risk of developing breast cancer (McCann 2004).
Thirty-two women awaiting surgery for breast cancer were randomized to receive either a muffin containing 25 grams of flaxseeds or no flaxseed (control group). Post-operative analysis of the cancerous tissue revealed that markers of tumor growth were reduced by 30-71% in the flaxseed group versus no reduction in the control group (Thompson 2005). Scientists concluded that “dietary flaxseed has the potential to reduce tumor growth in patients with breast cancer.” In order to examine the relationship between dietary lignan intake and breast cancer, researchers assessed the diets of 1122 women in the 1-2 years before breast cancer diagnosis. They noted that postmenopausal women with the highest dietary intake of lignans had a 71% decreased risk of death from breast cancer (McCann 2010).
One of the most important supplements for a breast cancer patient is the hormone melatonin. Melatonin inhibits human breast cancer cell growth (Cos et al. 2000) and reduces tumour spread and invasiveness in vitro (Cos et al.1998). Indeed, it has been suggested that melatonin acts as a naturally occurring anti-estrogen on tumour cells, as it down-regulates hormones responsible for the growth of hormone-dependent mammary tumours (Torres-Farfan 2003). A high percentage of women with estrogen-receptor-positive breast cancer have low plasma melatonin levels (Brzezinski et al. 1997). There have been some studies demonstrating changes in melatonin levels in breast cancer patients; specifically, women with breast cancer were found to have lower melatonin levels than women without breast cancer (Oosthuizen et al. 1989). Normally, women undergo a seasonal variation in the production of certain hormones, such as melatonin. However, it was found that women with breast cancer did not have a seasonal variation in melatonin levels, as did the healthy women (Holdaway et al. 1997).
Low levels of melatonin have been associated with breast cancer occurrence and development. Women who work predominantly at night and are exposed to light, which inhibits melatonin production and alters the circadian rhythm, have an increased risk of breast cancer development (Schernhammer et al. 2003). In contrast, higher melatonin levels have been found in blind and visually impaired people, along with correspondingly lower incidences of cancer compared to those with normal vision, thus suggesting a role for melatonin in the reduction of cancer incidence (Feychting et al. 1998).
Light at night, regardless of duration or intensity, inhibits melatonin secretion and phase-shifts the circadian clock, possibly altering the cell growth rate that is regulated by the circadian rhythm (Travlos et al. 2001). Disruption of circadian rhythm is commonly observed among breast cancer patients (Mormont et al. 1997; Roenneberg et al. 2002) and contributes to cancer development and tumor progression. The circadian rhythm alone is a statistically significant predictor of survival time for breast cancer patients (Sephton et al. 2000).
Melatonin differs from the classic anti-estrogens such as tamoxifen in that it does not seem to bind to the estrogen receptor or interfere with the binding of estradiol to its receptor (Sanchez-Barcelo 2003). Melatonin does not cause side effects, such as those) caused by the conventional anti-estrogen drug tamoxifen. Furthermore, when melatonin and tamoxifen are combined, synergistic benefits occur. Moreover, melatonin can increase the therapeutic efficacy of tamoxifen (Lissoni et al.1995) and biological therapies such as IL-2 (Lissoni et al. 1994).
How melatonin interferes with estrogen signaling is unknown, though recent studies suggest that it acts through a cyclic adenosine monophosphate (cAMP)-independent signaling pathway (Torres-Farfan 2003). It has been proposed that melatonin suppresses the epidermal growth factor receptor (EGF-R) (Blask et al. 2002) and exerts its growth inhibitory effects by inducing differentiation (“normalizing” cancer cells)(Cos et al. 1996). Melatonin directly inhibits breast cancer cell proliferation (Ram et al. 2000) and boosts the production of immune components, including natural killer cells (NK cells) that have an ability to kill metastasized cancer cells.
In tumorigenesis studies, melatonin reduced the incidence and growth rate of breast tumors and slowed breast cancer development (Subramanian et al. 1991). Furthermore, prolonged oral melatonin administration significantly reduced the development of existing mammary tumors in animals (Rao et al. 2000). Melatonin can be safely taken for an indefinite period of time. The suggested dose of melatonin for breast cancer patients is 3-50 mg at bedtime. Initially, if melatonin is taken in large doses vivid dreams and morning drowsiness may occur. To avoid these minor side effects melatonin may be taken in low doses nightly and the dose slowly increased over a period of several weeks.
Pomegranate, which is rich in antioxidants, has gained widespread popularity as a functional food (i.e., for its health benefits). The health benefits of the fruit, juice(s), and extract(s) have been studied in relation to a variety of chornic diseases, including cancer (Syed 2012; Johanningsmeier 2011). Researchers discovered that consumption of whole pomegranate seed oil and juice concentrate (Kim 2002) resulted in dramatic growth inhibition of estrogen-dependent breast cancer cells. The same study showed inhibition of tumor formation in rodent cells exposed to known breast carcinogens. Using different methods, another research group found a 42% reduction in tumor formation with whole pomegranate juice polyphenols and an 87% reduction with pomegranate seed oil (Mehta 2004).
Pomegranate seed oil is a potent inhibitor of aromatase, the enzyme that converts testosterone into estrogen (Adams 2010). This enzymatic blockade contributes to pomegranate seed oil’s ability to inhibit growth of estrogen-dependent breast cancer cells. Pomegranate extract has also been shown to enhance the effects of the estrogen blocking drug tamoxifen, with the authors of a study stating that “…pomegranate combined with tamoxifen may represent a novel and a powerful approach to enhance and sensitize tamoxifen action” (Banerjee 2011). Pomegranate also increases apoptosis, even in cancer cells that lack estrogen receptors (Kim 2002).
Cancer cells need to grow new blood vessels to support their rapid growth and tissue invasion (angiogenesis). They typically do this by ramping up production of a variety of growth factors, including VEGF and inflammatory interleukins. Pomegranate seed oil powerfully inhibits production of VEGF while upregulating production of migratory inhibitory factor (MIF) in breast cancer cells. In a laboratory model of vessel growth, these modulations translated into a significant decrease in new blood vessel formation (Toi 2003). Pomegranate seed oil’s capacity to block breast cancer development was also demonstrated in an organ culture model of mouse breast cancer (Mehta 2004).Treating the glands with pomegranate seed oil prior to exposure to a powerful carcinogen resulted in a 87% reduction in the number of cancerous lesions compared with controls.
Pomegranate seed oil contains a number of unique chemical constituents with potent biological effects. Punicic acid, an omega-5 polyunsaturated fatty acid that inhibits both estrogen-dependent and estrogen-independent breast cancer cell proliferation in lab cultures (Grossmann 2010), also induced apoptosis at rates up to 91% higher than those in untreated cell cultures—effects which appear to be related to fundamental regulation of cancer cell signaling pathways (Grossmann 2010).
PSK, which is a specially prepared polysaccharide extract from the mushroom Coriolus versicolor, has been studied extensively in Japan where it is used as a non-specific biological response modifier to enhance the immune system in cancer patients (Koda 2003; Noguchi 1995; Yokoe 1997). PSK suppresses tumor cell invasiveness by down-regulating several invasion-related factors (Zhang 2000). PSK has been shown to enhance NK cell activity in multiple studies (Ohwada 2006; Fisher 2002; Garcia-Lora 2001; Pedrinaci 1999). In a study investigating the use of PSK in women with stage 2 breast cancer, post-operative participants received Tamoxifen with PSK (3 g daily) or Tamoxifen alone. The 5-year survival was 89.9% in the PSK group compared to 86.9% in the group receiving Tamoxifen only (Morimoto 1996).
Pterostilbene, a polyphenol found in blueberries, grapes, and in the bark of the Indian Kino Tree, is closely related to resveratrol (but with unique attributes). Pterostilbene’s mechanisms of action include blocking enzymes that activate carcinogens (Mikstacka 2006, 2007), inducing apoptosis (Tolomeo 2005) and cell cycle arrest (Wang 2012), and enhancing nitric oxide-induced cell death (Ferrer 2007). Researchers observed that pterostilbene markedly inhibited the growth of breast cancer cells in the laboratory by inducing apoptosis and cell cycle arrest (Wang 2012).
Quercetin is a flavonoid found in a broad range of foods, from grape skins and red onions to green tea and tomatoes. Quercetin’s antioxidant and anti-inflammatory properties protect cellular DNA from cancer-inducing mutations (Aherne 1999). Quercetin traps developing cancer cells in the early phases of their replicative cycle, effectively preventing further malignant development and promoting cancer cell death (Yang 2006). Furthermore, quercetin favorably modulates chemical signaling pathways that are abnormal in cancer cells (Morrow 2001; Bach 2010). In breast cancer cells, quercetin induces apoptosis and cell cycle arrest (Choi 2001; Chou 2010). Querctin inhibited the growth of tumors (Zhong 2003) and prolonged survival of mice with breast cancer (Du 2010).
Se-methylselenocysteine (SeMSC), a naturally occurring organic selenium compound found to be an effective chemopreventive agent, is a new and better form of selenium. SeMSC is a selenoamino acid that is synthesized by plants such as garlic and broccoli. Methylselenocysteine (MSC) has been shown to be effective against mammary cell growth both in vivo and in vitro (Sinha et al. 1999) and has significant anticancer activity against mammary tumor development (Sinha et al. 1997). Moreover, Se-methylselenocysteine was one of the most effective selenium chemoprevention compounds and induced apoptosis in human leukemia cells (HL-60) in vitro (Jung et al. 2001a). Exposure to MSC blocks expansion of cancer colonies and premalignant lesions at an early stage by simultaneously modulating pathways responsible for inhibiting cell proliferation and enhancing apoptosis (Ip et al. 2000a).
Se-methylselenocysteine has been shown to:
- Produce a 33% better reduction of cancerous lesions than selenite.
- Produce a 50% decrease in tumor development.
- Induce cell death (apoptosis) in cancer cells.
- Inhibit cancer-cell growth (proliferation).
- Reduce density and development of tumor blood vessels.
- Down-regulate VEGF (vascular endothelial growth factor). (Ip et al. 1992; Sinha et al. 1997; Sinha et al. 1999; Ip et al. 2000a, b; Dong et al. 2001)
Unlike MSC, 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, SeMSC has been shown to be 10 times less toxic than any other known form of selenium. Breast cancer patients may consider taking 400 mcg of SeSMC daily.
Sulforaphane, which is an isothiocyanate, is most highly concentrated in broccoli as well as in other cruciferous vegetables (eg, brussels sprouts, cabbage and cauliflower). Sulforaphane detoxifies potential carcinogens, promotes apoptosis, blocks the cell cycle that is required for cancer cell replication, prevents tumor invasion into healthy tissue, enhances natural killer cell activity, and combats metastasis (Zhang 2007; Nian 2009; Traka 2008; Thejass 2006). Research has also demonstrated that sulforaphane is among the plant chemicals most potently capable of blocking the cancer-producing effects of ultraviolet radiation (Dinkova-Kostova 2008).
It has been observed that sulforaphane activated apoptosis (Pledgie-Tracy 2007) and inhibited the proliferation of breast cancer cells in culture (Ramirez 2009; Jo 2007). The binding of estrogen hormones to estrogen receptor alphapromotesbreast cell proliferation, which can promote the progression of breast cancer. Researchers have also noted that sulforaphane down-regulates the expression of estrogen receptor alpha in breast cancer cells (Ramirez 2009). In another clinical trial, mice injected with breast cancer cells developed 60% less tumor mass when treated with sulforaphane compared to untreated mice (Jackson 2004).
Coenzyme Q10 (CoQ10) is synthesized in humans from tyrosine through a cascade of eight aromatic precursors. These precursors require eight vitamins, which are vitamin C, B2, B3 (niacin) B6, B12, folic acid, pantothenic acid, and tetrahydrobiopterin as their coenzymes. Since the 1960s, studies have shown that cancer patients often have decreased blood levels of coenzyme Q10 (Lockwood et al. 1995; Folkers 1996; Ren et al. 1997). In particular, breast cancer patients (with infiltrative ductal carcinoma) who underwent radical mastectomy were found to have significantly decreased tumour concentrations of CoQ10 compared to levels in normal surrounding tissues. Increased levels of reactive oxygen species may be involved in the consumption of CoQ10 (Portakal et al. 2000). These findings sparked interest in the compound as a potential anticancer agent (NCCAM 2002). 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 2002). CoQ10 may induce protective effect on breast tissue and has demonstrated promise in treating breast cancer. Although there are only a few studies, the safe nature of CoQ10 coupled with this promising research of its bioenergetic activity suggests that breast cancer patients should take 100 mg up to 3 times a day. It is important to take CoQ10 with some kind of oil, such as fish or flax, because dry powder CoQ10 is not readily absorbed.
In a clinical study, 32 patients were treated with CoQ10 (90 mg) in addition to other antioxidants and fatty acids; six of these patients showed partial tumor regression. In one of these cases the dose of CoQ10 was increased to 390 mg and within one month the tumor was no longer palpable, within two months the mammography confirmed the absence of tumor. In another case, the patient took 300 mg of CoQ10 for residual tumor (post non-radical surgery) and within 3 months there was non residual tumor tissue (Lockwood et al. 1994). This overt complete regression of breast tumors in the latter two cases coupled with further reports of disappearance of breast cancer metastases (liver and elsewhere) in several other case (Lockwood et al. 1995) demonstrates the potential of CoQ10 in the adjuvant therapy of breast cancer. There are promising results for the use of CoQ10 in protecting against heart damage related to chemotherapy. Many chemotherapy drugs can cause damage to the heart (UTH 1998; ACS 2000; NCCAM 2000; Dog et al. 2001), and initial animal studies found that CoQ10 could reduce the adverse cardiac effects of these drugs (Combs et al. 1977; Choe et al. 1979; Lubawy et al. 1980; Usui et al. 1982; Shinozawa et al. 1993; Folkers 1996).
Caution: Some studies indicate that CoQ10 should not be taken at the same time as chemotherapy. If this were true, it would be disappointing, because 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 known, it is not possible to make a definitive recommendation concerning taking CoQ10 during chemotherapy. For more information please see the Cancer Chemotherapy protocol.
EPA and DHA
Dietary polyunsaturated fatty acids (PUFAs) of the omega-6 (n-6) class, found in corn oil and safflower oil, may be involved in the development of breast cancer, whereas long chain (LC) omega-3 (n-3) PUFAs, found in fish oil can inhibit breast cancer (Bagga et al. 2002). A case control study examining levels of fatty acids in breast adipose tissue of breast cancer patients has shown that total omega-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that omega-3 PUFAs, derived from fish oil, may have a protective effect (Bagga et al. 2002). A higher omega-3:omega-6 ratio ((n-3)):(n-6) ratio) may reduce the risk of breast cancer, especially in premenopausal women (Goodstine et al. 2003). In a prospective study of 35,298 Singapore Chinese women aged 45-74 years, it was determined that high levels of dietary omega-3 fatty acids from marine sources (fish/shellfish) were significantly associated with reduced risk of breast cancer. Furthermore, women who consumed low levels of marine omega-3 fatty acids had a statistically significant increased risk of breast cancer (Gago-Dominguez et al. 2003). Omega-3 fatty acids, primarily eicosapentanoic acid (EPA) and docosahexaneoic acid (DHA) found naturally in oily fish and fish oil, have been consistently shown to retard the growth of breast cancer in vitro and in animal experiments, inhibit tumor development and metastasis. Fish oils have antiproliferative effects at high doses, which means they can inhibit tumour cell growth, through a free radical-mediated mechanism, while at more moderate doses omega-3 fatty acids inhibit, Ras protein activity, angiogenesis, and inflammation. The production of pro-inflammatory cytokines can be modified by dietary omega-3 PUFAs (Mancuso et al. 1997).
High consumption of fatty fish is weakly associated with reduced breast cancer risk (Goodstine et al. 2003). Flaxseed, the richest source of alpha-linoleic acid inhibited the established growth and metastasis of human breast cancer implanted in mice. This effect was found to be due to its down-regulation of insulin-like growth factor I (IGF-1) and epidermal growth factor receptor (EGF-R) expression (Chen et al. 2002). The recommended dosage is to consume a fish-oil concentrate supplement that provides 3200 mg of EPA and 2400 mg of DHA a day taken in divided doses.
Vitamins A, D, and E
Vitamin A and vitamin D3 inhibit breast cancer cell division and can induce cancer cells to differentiate into mature, noncancerous cells. Vitamin D3 works synergistically with tamoxifen (and melatonin) to inhibit breast cancer cell proliferation. The vitamin D3 receptor as a target for breast cancer prevention was examined. Pre-clinical studies demonstrated that vitamin D compounds could reduce breast cancer development in animals. Furthermore, human studies indicate that both vitamin D status and genetic variations in the vitamin D3 receptor (VDR) may affect breast cancer risk. Findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer (Welsh et al. 2003). Daily doses of vitamin A, 350,000 to 500,000 IU were given to 100 patients with metastatic breast carcinoma treated by chemotherapy. A significant increase in the complete response was observed; however, response rates, duration of response and projected survival were only significantly increased in postmenopausal women with breast cancer (Israel et al. 1985).
Breast cancer patients may take between 4000 to 6000 IU, of vitamin D3 every day. 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 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 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. Vitamin E from dietary sources may provide women with modest protection from breast cancer.
Vitamin E succinate, a derivative of fat-soluble vitamin E, has been shown to inhibit tumor cell growth in vitro and in vivo (Turley et al. 1997; Cameron et al. 2003). In estrogen receptor-negative human breast cancer cell lines vitamin E succinate inhibited growth and induced cell death. Since vitamin E is considered the main chain breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemopreventative agent and its use in the adjuvant treatment of aggressive human breast cancers appears reasonable. Those with estrogen-receptor-negative breast cancers should consider taking 800-1200 IU of vitamin E succinate a day. Vitamin E supplementation, 800 IU daily for 4 weeks, was shown to significantly reduce hot flashes in breast cancer survivors (Barton et al. 1998).
Caution: it is possible to get Vitamin A Toxicity. 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. Vitamin E has potential blood thinning properties, individuals taking anticoagulant drugs should inform their treating physician if supplementing with vitamin E and have their clotting factors monitored regularly.
When vitamin E was isolated from plant oils, the term tocopherols was used to name the initial four compounds that shared similar structures. Their structures have two primary parts--a complex ring and a phytyl (long-saturated) side chain--and have been designated as alpha, beta, delta, and gamma tocopherol. Tocopherols (vitamin E) are important lipid-soluble antioxidants that can protect the body against free radical damage. However, there are four additional compounds related to tocopherols--called tocotrienols that are less widely distributed in nature. The tocotrienol structure, three double bonds in an isoprenoid (unsaturated) side chain, differs from that of tocopherols. While tocopherols are found in corn, olive oil, and soybeans, tocotrienols are concentrated in palm, rice bran, and barley oils.
Tocotrienols elicit powerful anticancer properties, and studies have confirmed tocotrienol activity is much stronger than that of tocopherols (Schwenke et al. 2002). Tocotrienols provide more efficient penetration into tissues such as the brain and liver. Because of the double bonds in the isoprenoid side chain, tocotrienols move freely and more efficiently within cell membranes than tocopherols, giving tocotrienols greater ability to counteract free radicals. This greater mobility also allows tocotrienols to recycle more quickly than alpha-tocopherol. Tocotrienols are better distributed in fatty cell membranes and demonstrate greater antioxidant and free-radical-scavenging effects than that of vitamin E (alpha-tocopherol) (Serbinova et al. 1991; Theriault et al. 1999). Tocotrienol's antioxidant function is associated with lowering DNA damage, tumour formation, and of cell damage. Animals exposed to carcinogens that were fed corn oil- or soybean oil-based diets had significantly more tumours than those fed a tocotrienol-rich palm oil diet. Tocotrienol-rich palm oil did not promote chemically induced breast cancer (Sundram et al. 1989). Tocotrienols possess the ability to stimulate the selective killing of cancer cells through programmed cell death (apoptosis) and to reduce cancer cell proliferation while leaving normal cells unaffected. Tocotrienols cause growth inhibition of breast cancer cells in culture independent of estrogen sensitivity and have great potential in the prevention and treatment of breast cancer (Nesaretnam et al. 1998). tamoxifen and tocotrienols may reduce the risk of adverse side effect from tamoxifen (Guthrie et al. 1997). Tocotrienols are considered important lipid-soluble antioxidants, with potent anticancer and anti-inflammatory activity. Therefore, a daily dose of 240 mg of tocotrienols should be considered as an adjuvant breast cancer therapy.