Breast Cancer-9

CoQ10

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 tumor 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 tumor 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 D-3 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 D-3 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: Refer to the symptoms of vitamin A toxicity in Appendix A: Avoiding 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.


Tocotrienols
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, tumor formation, and of cell damage. Animals exposed to carcinogens that were fed corn oil- or soybean oil-based diets had significantly more tumors 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 (Kline et al. 2001). Tocotrienols are thought to suppress cancer through the isoprenoid side chain.

Isoprenoids are plant compounds that have been shown to suppress the initiation, growth, and progression of many types of cancer in experimental studies (Block et al. 1992). They 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.

Isoprenoids induce cell death (apoptosis) and arrest cell growth in human breast adenocarcinoma cells (MCF-7) (Mo et al.1999). Isoprenoids may suppress 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 five times more powerful than farnesol, the body's regulator of the mevalonate pathway. Interestingly, human breast cancer cells have been shown to respond very well to treatment with tocotrienols (Parker et al. 1993).

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).

In vitro studies have demonstrated the effectiveness of tocotrienols as inhibitors of both estrogen-receptor-positive (estrogen-responsive) and estrogen-receptor-negative (nonestrogen-responsive) cell proliferation. The effect of palm tocotrienols on three human breast cancer cells lines, estrogen-responsive and estrogen-nonresponsive (MCF7, MDA-MB-231, and ZR-75-1), found that tocotrienols inhibited cell growth strongly in both the presence and absence of estradiol. The gamma- and delta-fractions of tocotrienols were most effective at inhibiting cell growth, while alpha-tocopherol was ineffective. Tocotrienols were found to enhance the effect of tamoxifen (Nesaretnam et al. 2000).

Delta-tocotrienol was 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).

Tocotrienols effectively arrested the cell cycle and triggered cell death of mammary cancer cells (from mice) whereas tocopherols (alpha, gamma, and delta) did not cause inhibition of tumor cell growth. Highly malignant cells were most sensitive to the antiproliferative effects of tocotrienols, whereas less aggressive precancerous cells were the least sensitive (McIntyre et al. 2000).

Tocotrienols were found to be far more effective than alpha-tocopherol in inhibiting breast cancer cell growth. Tocotrienols in combination with tamoxifen proved more effective than either compound alone in both estrogen-responsive and nonresponsive breast cancer cells. The synergism between 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.


PREVENTING BREAST CANCER CELL METASTASIS
Bone Remodeling
Bone Metastases Affects Remodeling
Bone Loss and Fatty Acids
Hormone Therapy and Metastasis
Breast cancer cells frequently metastasize to the bone, where they cause severe degradation of bone tissue. Metastatic cancer affects more than half of all women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcemia (abnormally high levels of calcium in blood plasma), and spinal cord compression. The bisphosphonates, including alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), ibandronate, and zoledronic acid (Zometa), are a class of drugs that protect against the degradation of bone, primarily by inhibiting osteoclast-mediated bone resorption (bone breakdown).

Bisphosphonates are analogs of a naturally occurring compound, called pyrophosphate, which serves to regulate calcium and prevent bone breakdown. Bisphosphonates are a major class of drugs used for the treatment of bone diseases as they have a marked ability to inhibit bone resorption. Bisphosphonates are considered standard care for tumor-associated hypercalcemia and have been shown to reduce bone pain, improve quality of life, and to delay and reduce skeletal events (Hortobagyi 1996; Roemer-Becuwe et al. 2003).


Bone Remodeling
The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). This process is called bone remodeling. Healthy bone is continually being remodeled. Two main types of cells are responsible for bone renewal: the osteoblasts involved in bone formation and the osteoclasts involved in bone resorption. There are several stages involved in bone remodeling. The first is activation. This process involves preosteoclasts that are stimulated and differentiated under the influence of cytokine and growth factors to mature into active osteoclasts. The next step is resorption, in which osteoclasts digest mineral matrix (old bone). The third step is reversal, which ends resorption and signals for the final phase, formation. During this stage, osteoblasts are responsible for bone matrix synthesis (collagen production). Two other noncollagenous proteins are also formed: osteocalcin and osteonectin, together they form new bone.