Nederlands Русский Breast Cancer.
Health Strategy.

Alternative therapy for breast cancer (#1).

Epigenetic modulation.

The genes that each of us inherited from our parents may signal an increased risk of disease, but most of the biological processes that occur do not depend directly on the genetic code, but on the complex interaction of all proteins and cells that work with environmental factors. Tumor development is associated not only and not so much with genetic changes (i.e., modifications of the genome itself), but, for the most part, with epigenetic changes (i.e., modifications of gene expression without changes in the genome itself) *. Figuratively speaking, not only the text of the instruction recorded in DNA is important, but also how this text will be read and executed. Both the first and second are critically important for all biological processes in the body.

DNA structure Enlarge Image

The nuclear DNA molecule stores a library of matrices, according to which an innumerable number of different protein molecules can be imprinted – both parts of the organism itself and the enzymes that serve it. The clever molecular mechanism that allows you to find the right fragment in this library in order to produce the required molecule in sufficient quantity at the request of the customer remains a delightful mystery. This extremely delicate process is influenced by many seemingly completely unrelated factors.

Daylight hours lengthen or shorten, and in accordance with this, an order for the production of animal wool proteins comes in, the order for the production of its pigments changes. Some color genes are silenced, and others get free; as a result, seasonal molting and color changes occur. A warm spring comes, a huge order for the production of sex hormones comes, the rut and mating of animals begins. The autumn cold is coming; some animals receive an order to increase the production of hormones that push them on thousands of kilometers of flights. And for others, orders for metabolic costs decrease, orders for sleep hormones and for the production of substances that allow the body not to freeze increase; such animals hibernate. In each of these cases, under the influence from outside, some of the genes get a chance to be realized, while others, on the contrary, are blocked.

Cancer is a multi-step process resulting from a combination of crosstalk between genetic changes and epigenetic influences through various environmental factors * *. But if the possibilities of genetic correction are difficult for us and expensive, then epigenetic changes can be largely regulated by many modifiable factors. In particular, it can be inexpensive natural *, including food substances *.

With their help, the expression of some genes can be weakened, while the expression of other genes can be increased. If the activated gene is a gene that prevents/suppresses the development of a tumor, or a gene that triggers the self-destruction of defective cells, then the cancer process will be delayed. If the activated gene is a gene that stimulates tumor growth, then the cancer process will be accelerated.

Thus, epigenetically it is possible either to stimulate, or vice versa, to suppress the cancerous process, especially at its earliest stages. In addition, age-related epigenetic changes (including changes in methylation) presumably underlie the aging process * *. It forces you to look at your diet from a new perspective. Many of the supplements discussed in the topic sections below also act through epigenetic mechanisms, among other things.

More specifically, certain additives can affect the following mechanisms to ensure the stable and correct operation of the genetic apparatus and counteract the tumor:

DNA integrity. Damage to the DNA molecule occurs under the influence of various destructive factors, including hard radiation and chemicals. The main threat to the DNA molecule comes from free radicals, so all substances that can suppress free radicals by donating the missing electron to them protect DNA and serve as a good prophylactic. These substances are called antioxidants and are discussed in more detail in the «Anti-Inflammatory Therapy» section . You can add to their list: coenzyme Q10 (300 mg/day) * *, lycopene (equiv. 350 mg/day) * *, melatonin (10-20 mg/day) *, N-acetylcysteine (equiv. 800 mg/day) *.

Control of regulatory genes. The main goal of epigenetic intervention is to silence the expression of pro-tumor genes and to activate the expression of anti-tumor genes. Chemical processes called histone hypermethylation and deacetylation lead to structural changes in the DNA molecule, and can unblock unwanted epigenetic expression, or vice versa, block desirable regulatory genes.

Substances that normalize methylation include: folic acid (1-10 mg/day); vitamins В2 (25-100 mg/day), В6 (50-100 mg/day), В12 (0.1-2 mg/day); betaine (100-300 mg/day); as well as zinc (15-50 mg/day); EGCG (1'500 mg/day), especially with supplements of selenium (from 200 μg/day) * and magnesium (400-800 mg/day) *; sulforaphane (400-800 mg/day) *; diallyl disulfide (2'500 mg/day) *; genistein (20-50 mg/day) *; boswellic acid (500 mg/day). The degree of methylation in the body can be indirectly assessed through the level of homocysteine in the blood, which should not exceed 7.5 µM.

Substances that normalize acetylation include: sodium butyrate (300-4'000 mg/day) * * *; ω-3 fatty acids (1'400 mg/day EPA and 1'000 mg/day DHA) *; EGCG (1'500 mg/day) *; sulforaphane (400-800 mg/day) * *; diindolylmethane (1'600 mg/day) * *.

Regulation of proliferation genes. The cell cycle is tightly regulated by signals from genes called tumor suppressor genes (antioncogenes) and apoptosis genes *. Suppressor genes turn on in response to an abnormal signal and prevent cell division from getting out of control. Weakening or loss of this signal leads to uncontrolled cell division. Many nutrients are able in vitro and in vivo to block the continuous cycle of cell division, slowing the growth of cancer. These are, for example, apigenin (25-50 mg/day) *, aspirin *, indole-3-carbinol (I3C) * *, melatonin *, sulforaphane  * *.

Regulation of apoptosis genes. Apoptosis, or programmed cell death, is a powerful means of controlling cell growth. Normal cells have the ability to self-destruct if they receive signals that they are dividing too quickly. Malignant cells lose this signaling, which removes the limitation on their growth rate. A number of nutrients have the ability to restore the ability of breast cancer cells to apoptosis, including the following: apigenin * * *, conjugated linoleic acid (CLA) *, curcumin * * *, EGCG * *, indole-3-carbinol (I3C) * *, N-acetyl cysteine (NAC) *, pomegranate * *, quercetin *, silibinin *, soy isoflavones *, tocotrienols *, melatonin and vitamin D *.

Regulation of angiogenesis genes. The formation of a network of blood vessels allows tumor cells to receive sufficient nutrients, which contributes to their growth. Inhibition of angiogenesis, forcing the tumor to starve, inhibits its development. Substances that regulate angiogenesis-related genes are believed to include: apigenin  * * *, coenzyme Q10 (CoQ10*, conjugated linoleic acid (CLA) *, curcumin  *, grape seed extract (100 mg/day) *, green tea extract (725 mg/day) *, N-acetylcysteine (NAC, 600 mg/day) * *, ω-3 fatty acids (1'400 mg/day EPA and 1'000 mg/day DHA) *, pomegranate extract (500 mg/day) *, quercetin (500 mg/day) *, silibinin (750 mg/day) *, vitamin D3 (2'000-10'000 IU) *, vitamin E (400 mg/day).

Regulation of invasion and metastasis genes. Some natural substances show the ability to regulate genes associated with invasiveness and metastasis. These are, for example, coenzyme Q10 (CoQ10, 200 mg/day) *, chlorogenic acid (chlorogenic acid) *, conjugated linoleic acid (CLA) *, sulforaphane and isocyanates (400-800 mg/day) *, curcumin (400 mg/day) *, green tea polyphenols * * *, melatonin *, silibinin * *.

Regulation of genes associated with immunity. Serum vitamin D [25(OH)D] has been reported to affect DNA methylation and transcription of genes that are associated with immune function *.

Differentiation of immature cells. Differentiated cells eventually die or stop growing. This fact can be used to contain the tumor.

Even after cells have undergone malignant transformation, there is a chance to reverse this process, forcing them to differentiate back into normal tissue-forming cells. Nutrients that promote breast cancer cell differentiation through epigenetic mechanisms include: butyric acid (sodium butyrate) *, propionic acid (sodium propionate) *, retinoic acid *, conjugated linoleic acid (CLA) *, N-acetyl cysteine (NAC) *, vitamin D * *.

For clarity, all the above data can be summarized in one table.

Effects of nutrients on cancer cell characteristics Open in new window

In addition to estrogen, progesterone, and HER2, breast cancer cells are affected by a number of other growth factors. Inhibition or epigenetic modification of these growth factors is one of the goals of breast cancer chemoprevention, which may be facilitated by the following nutrients: apigenin *, conjugated linoleic acid (CLA) * *, curcumin *, γ-tocotrienol *, green tea polyphenols * *, indole-3-carbinol (I3C) *, melatonin *, ω-3 fatty acids *, silibinin *, vitamin D *.

Clinical studies using a combination of DNA methylation and HDAC inhibition show that this therapy is safe and appears to increase the efficacy of common chemotherapeutic cytotoxins such as doxorubicin/cyclophosphamide *. Thus, the addition of hydralazine (83-182 mg/day) and magnesium valproate (2'000 mg/day) to the doxorubicin/cyclophosphamide treatment protocol resulted in a complete clinical response in 31%, a partial response in 50%, and stabilization in 19% patients with breast cancer who were at the stage of development of the disease IIB and IIIA *. This same protocol has shown similar results in other cancers and with other chemotherapy drugs *.

Both of these drugs are already used in clinical practice: hydralazine – in cardiovascular diseases (to dilate blood vessels), and magnesium valproate – in the treatment of epilepsy; and the dosages used here are very close to therapeutic dosages for the corresponding non-cancer diseases. Unfortunately, this study was not placebo-controlled, so the results of treatment efficacy could only be compared with the average.

The use of a combination of azacitidine (30-40 mg/m2) and entinostat (7 mg), inhibitors of DNA methylation and histone deacetylation, respectively, has also shown high efficacy in the treatment of certain types of cancer *.

Entinostat is an acetylation modulator, it exhibits an epigenetic effect that promotes apoptosis and activates the immune system *. Entinostat has a long half-life and can be taken by mouth once a week. In clinical studies, entinostat (5mg per week during chemotherapy) increased the survival rate of patients with breast cancer by 1.4 times *, however, this positive effect was observed only in hormone-positive subtypes of breast cancer *.

Among food sources, the most significant beneficial epigenetic effects are: ellagitannin (pomegranate; raspberry; walnut) *; EGCG (green tea) * *; curcumin (turmeric root) *; genistein (soy products) *; resveratrol (peanut; red wine extract) *; diindolylmethane, indole-3-carbinol * and sulforaphane (cruciferous vegetables; especially broccoli) *; organoselenium compounds (Brazil nuts) *; organosulfur compounds (garlic) * *; quercetin (onions, apples, buckwheat) *; rosmarinic acid (rosemary, thyme) * *; taken on their own or in various combinations * *.

One in vitro study investigating the epigenetic effect of pomegranate shell alcohol extract on breast cancer focused on gene expression changes occurring in ER MCF-7 cancer cells. It was found that the decrease in cancer cell proliferation under the action of the extract was accompanied by a change in the expression of 903 genes, 505 of which were activated and 398 were suppressed. Most of the activated genes were involved in the regulation of apoptosis, and most of the suppressed genes were involved in mitosis, chromosome organization, response to DNA damage and its repair *. Thanks to the latter, the cell cycle was delayed, and the proliferation of cancer cells was inhibited *.

Other plant sources are much weaker. However, by targeting different epigenetic targets, they can give a noticeable overall result. The active ingredients of these plants are valproic acid (valerian) *, biochanin (clover) and daidzein (soy) *, caffeic and chlorogenic acids (coffee) *, catechin and epicatechin (black tea, cat's claw) *, pomiferin (maclura) *, lycopene (tomato) *, thymoquinone (kalinji) * and others *. Due to the fact that epigenetic influences are reversible, only the systematic consumption/alternation of the above foods can constantly create a favorable epigenetic background.

The ω-3 and ω-6 fatty acids have different effects on the BRCA1 and BRCA2 genes, which maintain genetic stability. Long-chain ω-3 molecules (alpha-linolenic acid, EPA, DHA) protect against cancer, while ω-6 fats (linoleic acid, arachidonic acid), on the contrary, contribute to the development of cancer. Short-chain fatty acids (acetate, propionate, butyrate), whether they are ingested in the diet or produced enzymatically by intestinal bacteria, also have an anti-cancer effect *.

Some chemical elements such as selenium * *, zinc * and magnesium * * also contribute to positive epigenetic correction; vitamins such as D and E; as well as some hormones such as melatonin *.

Epigenetic disorders occur in response to external factors such as unhealthy diet, toxins, stress, and hormone imbalances. Changing all these conditions is easily implemented. Normalization of weight and diet after 6-12 months lead to positive changes in DNA methylation in patients who survived after breast cancer *.

Epigenetic features of an organism can be so long-term that they can be passed on to subsequent generations. However, despite their completely identical genetics, identical twins suffer from different diseases and die from different causes if they are affected by different epigenetic interventions, such as hormone disruptors or diet.

Despite its simplicity and attractiveness, epigenetic therapy also has a possible fundamental drawback. Ideally, methylation/acetylation processes should only affect the target genes, normalizing their expression, but not increasing the expression of oncogenes. However, there remains some risk that active epigenetic interference may activate not only genes associated with apoptosis and cell differentiation, but also genes associated with cell proliferation.

The problem is compounded by the fact that it is almost impossible to fully determine which genes are silenced/overexpressed in a given patient. A wide variety of lateral subclones of tumor-initiating cells makes the targeted epigenetic impact unrealistic. In addition, epigenetic therapy alone, like any other monotherapy, is unable to destroy the tumor and reverse the cancer process. However, its combination with other therapies may make the treatment more effective *.


Next chapter