Breast Cancer.
Health Strategy.

Therapeutic arsenal.

There are many therapeutic agents, including over-the-counter ones, that reduce the risk of breast cancer, aid in its treatment, and increase patient survival *. These are, for example, metformin, chloroquine, aspirin, statins, cimetidine, methotrexate, valproic acid, nitroxoline, coenzyme Q10, beta-andrenoblockers, disulfiram, mebendazole, benztropine, diclofenac and others *. They can act alone * or in various combinations *.

A small number of agents of therapeutic interest will be discussed below. The list is limited to those who have been able to show in clinical studies a significant reduction in tumor growth, disease stabilization or reversal. In the absence of contraindications, and with the approval of the attending physician, they could provide significant assistance to the patient. The problem is that the evidence for their effectiveness is incomplete, because obviously non-patentable substances have no hope of finding a sponsor for Phase III clinical trials.

Epigenetic agents.

Epigallocatechin gallate (EGCG)is the main polyphenol in green tea * *.

One randomized, double-blind, placebo-controlled, phase II clinical trial in 1'075 healthy postmenopausal women showed that daily consumption of 4 caffeine-free capsules for a year of an extract containing 1'315 mg of mixed catechins, including 843 mg of EGCG, inexpressively (~ 5%) reduced the percentage of mammographic density in young women *. Significantly exceeding this dosage does not seem to increase the benefit, but may adversely affect liver function *.

Green tea extract (2'175 mg containing about 940 mg EGCG, equivalent to 8-10 cups of green tea) consumed daily for a month showed a reduction in proliferation markers in both benign and malignant cells in breast tissue samples received during operation *.

Green tea may improve the condition of breast cancer patients undergoing radiation therapy. Taking 3×400 mg EGCG capsules for 2-8 weeks produced several notable changes in proliferation-related markers * *. In breast cancer patients receiving radiation therapy after tumor removal, an EGCG solution sprayed onto the affected areas reduced the symptoms of radiation dermatitis *.

Consuming at least 3 cups of green tea a day significantly reduces the risk of recurrence of breast cancer *, especially in women diagnosed in the early stages of the disease *. Women with TNBC who regularly drank green tea within five years of diagnosis had a 46% lower risk of cancer recurrence than those who did not drink it *.

In premenopausal women with benign uterine tumors, daily intake of 800 mg of green tea extract (380 mg EGCG) for 4 months resulted in a 33% reduction in tumor volume and also reduced the severity of disease symptoms without any negative side effects *.

Experimental studies suggest a synergistic interaction of green tea catechins with tamoxifen or raloxifene in the treatment of ER-positive and ER-negative breast cancer through estrogen-dependent and estrogen-independent mechanisms *.

Diindolylmethane (DIM) is a natural substance with broad antitumor activity. It reduces acetylation of genes that promote tumor progression * * * * *, prevents strong estrogens from binding to estrogen receptors (ER) *, and also helps to transform stronger types of estrogens into less strong ones *.

In targeted therapy, DIM enhances the effect of monoclonal antibodies *. And in women with a mutation in the BRCA1 gene, which predisposes to breast cancer, oral DIM was associated with an increase in BRCA1 mRNA expression by an average of 24% *.

Dosage: 150-300 mg/day DIM * *; low dosages give little effect *. DIM, in the form of its metabolic precursor indole-3-carbinol (I3C), is found in cruciferous vegetables (cabbage, cauliflower, kale, bok choy, mustard greens, Peruvian maca, Brussels sprouts, and especially broccoli). DIM is fat soluble, so it is best to mix it with vegetable oil for better absorption. However, it is difficult to achieve a therapeutically meaningful blood concentration of DIM through a purely plant-based diet.

Sulforaphane inhibits breast CSC at concentrations (0.5-5 μm), which are approximately 10 times lower than required for the manifestation of its antiproliferative effect. TNBC tumor-grafted mice (SUM159) treated with sulforaphane (50 mg/kg intraperitoneally daily for 2 weeks) had half as much tumor growth as controls. Moreover, when the sulforaphane-treated tumor was re-inoculated into a new group of mice, it showed no growth *. Patients with ductal carcinoma in situ who took 3×60 mg sulforaphane for 2-8 weeks had a significant decrease in Ki-67, a marker of cell proliferation *.

Melatonin takes a diverse part in epigenetic processes *:
- affects the transcriptional activity of nuclear receptors (ERα, GR and RAR) involved in the regulation of breast cancer cell growth;
- suppresses the expression of genes responsible for the local synthesis or activation of estrogens, including aromatase;
- reduces the activity of telomerase;
- modulates the cell cycle by inhibiting the expression of cyclin D1;
- attenuates circadian rhythm disturbances that deregulate the PER2 protein, which acts as a tumor suppressor gene. Women with the lowest melatonin levels have the highest rates of breast cancer growth *.

In metastatic patients with various types of cancer, a partial response was observed in 12% of cases, and stabilization of the disease was observed in another 52% of cases after melatonin supplementation (20 mg at bedtime) *. In addition, melatonin (3-6 mg 1 hour before bedtime) subjectively improves the depth and quality of sleep in patients * * *.

Valproic acid is able to enhance the expression of the melatonin receptor in vivo *. Dosage: up to 2'000 mg/day *.

Defeat of the tumor volume.

Herbal remedies.

White mistletoe (Viscum album). The main active ingredient contained in the fruits and leaves of the plant is the toxic lectin viscumin, which belongs to the ribosome-inactivating proteins (RIP), but other components of the plant may increase its effect *. Viscumin interferes with protein synthesis in the affected cell. As a result of the cellular response to this stress, cytokines are released, high levels of which cause the death of cancer cells through apoptosis *. In in vitro studies, mistletoe had little effect on ER+ cells, but moderately inhibited the growth of ER– cells *, which seems to be expected in patients.

In one of the most successful experiments, stage II-IIIA patients received incremental injections of mistletoe extract as monotherapy. According to sonographic results, after 6 months the overall response rate was 50%, the median tumor size decreased from 3 cm to 2 cm, the median area from 8 cm2 to 3 cm2, while 8% of patients had a complete remission. The degree of development of the disease according to histological assessment decreased in patients by one stage. However, no further results or dosage of the extract were reported in this report *.

In another publication by the same author, it was reported that the average daily dosage of subcutaneous injections of the extract for patients with stage IV disease gradually increased from 0.02 to 20 mg (up to 8 ampoules) within six months with constant monitoring of the blood count *. Here, in 77% of patients, the quality of life improved – sleep normalized, pain and depression decreased, and tumor markers decreased. These were only two isolated cases of such a high success rate of mistletoe treatment.

In all other reports, the results were more modest, even when mistletoe was combined with traditional treatment. However, patients with non-metastatic breast cancer who received subcutaneous injections of mistletoe extract (0.01 to 5 mg Iscador®, 1 to 50 mg Helixor®) 3 times a week for 18 weeks of chemotherapy tended to improve neutropenia, improved pain and appetite scores *, and a marked reduction in negative side effects caused by major chemotherapy drugs *.

A standardized water extract of mistletoe, administered subcutaneously twice a week for 15 consecutive weeks, mitigated the side effects of chemotherapy and improved the quality of life of patients with breast, ovarian, and non-small cell lung cancer * *.

In a multicenter clinical trial, subcutaneous injections of mistletoe extract were used as an adjunct to conventional therapy. After a mean duration of treatment with mistletoe extract of 52 months, significantly fewer patients in the treatment group (16.3%) than those in the control group (54.1%) developed one or more adverse reactions associated with conventional therapy. At the same time, mild general adverse reactions associated with treatment with mistletoe extract were observed in 0.8%, and local adverse reactions in 17.3% of patients *. Side effects included skin redness, allergic and inflammatory skin reactions, fever, and itching at the injection site.

Prospective studies show a 40% increase in survival time in patients treated with additional Iscador® * therapy, as well as a slight reduction in the risk of metastasis * and an increase in time to recurrence and metastasis, both lymphatic and distant *. The main side effects of mistletoe therapy were local reactions at the injection site.

In a review of 26 randomized clinical trials, 22 of them confirmed the benefit of using mistletoe extract *. A review of studies on the use of mistletoe against breast cancer found that most (but not all) of them confirm the antitumor effect of the plant *. The tolerability of mistletoe extract was rated as good or very good in 91% of patients, and efficacy as good or very good in 94% *.

A multicenter clinical study in women with primary breast cancer confirmed the safety and efficacy of mistletoe extract *. Additional treatment of breast cancer patients with mistletoe extract during a 5-year rehabilitation period after completion of standard therapy resulted in a significant reduction in patient complaints (~ 56% in the study group vs. 70% in the control group). There was a decrease in the number of signs/symptoms associated with the disease/therapy (mucositis, fatigue, pain, headache), and with it a significant improvement in the quality of life.

Another 5-year study also showed that adding mistletoe extract to chemotherapy improves the quality of life of early-stage breast cancer patients and may prevent neutropenia. No negative effect of mistletoe on the effectiveness of chemotherapy has been identified. But the improvement in the rates of recurrence and metastasis within 5 years after chemotherapy in the experimental group compared to the control group was also not noticeable *.

In all cases described above, standardized aqueous extracts of fermented mistletoe (Iscador®, Helixor® and the like) were used. The method of extracting bioactive substances fundamentally affects the biochemical composition and therapeutic properties of the resulting extract *. For practical use, it is better to take ready-made standardized extracts for injection, and not to prepare a drink for ingestion by cold infusion of mistletoe leaves and berries. The extraction of viscumin from vegetable raw materials with hot water or a solvent leads to the fact that this protein is denaturalized and loses its properties.

Alcohol solutions of mistletoe contain biologically active substances that inhibit key glycolytic enzymes in vitro: hexokinase, phosphofructokinase, pyruvate kinase * *. Thus, in addition to cytotoxic and immunomodulatory, mistletoe also has an anti-glycolytic effect.

Baikal skullcap (Scutellaria baicalensis). The plant contains several highly potent chemical compounds such as apigenin, wogonin, baicalin, and baicalein, however the whole extract of the plant exhibits a stronger cytotoxic effect than any of these alone. Bioactive substances of skullcap reduce oxidative stress, inhibit β-glucuronidase, inhibit growth, invasion, adhesion and migration of cancer cells.

In one clinical study, the treatment of patients with metastatic breast cancer consisted of 350 mL/day oral administration of an aqueous extract of the aerial part of skullcap (Scutellaria barbata) as monotherapy. This dosage is a quarter of the maximum tolerant. Simplified, the extract was prepared as follows: 180 g of raw material powder was infused in 1'800 mL of water at a temperature of 70 °С for 1 hour, then the filtered solution was evaporated 5 times by volume – up to 350 ml and stored in a refrigerator at +4 °С.

As a result of taking this extract, 28% of patients had stabilization of the disease within 180 days; and some showed slight regression of the primary tumor *. The more pre-chemotherapy courses there were, the worse was the response to this treatment. The most commonly reported side effects included: nausea (38%), diarrhea (24%), headache (19%), flatulence (14%), vomiting (10%), constipation (10%) and fatigue (10%) *.

Turkey tail (Trametes versicolor) contains a polysaccharide peptide (PSP), which is used in Japan in the treatment of breast cancer. While oral PSP can enhance innate immunity and the effects of chemotherapy as an adjunctive treatment, it is rarely effective on its own. Dosage used in clinical studies: 3×340 mg for 4 weeks *.

Red sage (Salvia Miltiorrhiza) has vasodilating and antioxidant effects; and Turkey tail modulates various immunological functions. Together, they improve immune markers in patients with stage I-III non-metastatic breast cancer who have completed anti-cancer treatment within the past 3 years *.

Daily intake of tinder (50 mg/kg) and sage (20 mg/kg) capsules by patients for 6 months markedly improved their immunological profile. The number of T-helper lymphocytes (CD4+); the ratio of T-helpers to T-suppressors; the ratio of T-helpers to cytotoxic lymphocytes (CD4+:CD8+); as well as the percentage and number of B-lymphocytes were significantly increased; while the plasma concentration of soluble interleukin receptor (sIL-2R) was significantly reduced. Quality of life indicators such as fatigue, sleep pattern, appetite, stool and emotional status of the patients were also significantly improved.

Ashwagandha (Withania somnifera) contains withaferin A, which exhibits selective cytotoxicity against ERα-positive cancer cells *. An aqueous extract or root powder is able to enhance the therapeutic effect of both radiation therapy * (due to mitochondrial dysfunction and an increase in the level of oxidants in cancer cells *); and chemotherapy (by improving immune function * *).

In one study, plant root powder (3×2 g) was given to patients with stage II and III breast cancer throughout the course of chemotherapy (6 cycles in total). In the experimental group, patient fatigue scores were improved and overall 2-year survival at 24 months was 72% versus 56% in the control group *.

Other clinically proven effects of ashwagandha include the reduction of anxiety symptoms * and the protection of brain cells from chemical damage.

Aloe ( Aloe vera) exhibits antitumor activity through at least three different mechanisms – antiproliferative, immunostimulatory and antioxidant.

In patients with metastatic tumors, daily administration of a mixture of Aloe arborescens (3×10 mL) as an adjunct to chemotherapy significantly increased both the percentage of objective tumor regressions and 3-year survival compared with patients not taking aloe *. The mixture consisted of 300 g of fresh aloe leaves with the addition of 500 g of honey and 40 mL of 40% alcohol as a preservative. However, this was the only clinical study showing such a high result; in experiments on rodents, aloe juice was only able to restrain the process of metastasis *.

Despite the centuries-old practice of aloe in traditional medicine, the FDA regards it as a possible group 2B * carcinogen in the intestines and liver, which makes it impossible to use high doses of aloe for a long time.

Cat's claw ( Uncaria tomentosa, Uncaria guianensis), aka Una de Gato.

One clinical study involved patients with stage II invasive ductal carcinoma who were receiving FAC (fluorouracil/doxorubicin/cyclophosphamide) combination therapy. Here, the experimental group received chemotherapy plus a dry hydroalcoholic extract of the plant (3×100 mg) and the control group received chemotherapy alone *. Taking the extract significantly increased the number of neutrophils, and also provided a protective effect on the DNA molecule. These effects have been confirmed in a clinical study of healthy volunteers *.

In another study, patients with advanced solid tumors who had no other further treatment options were given a dry standardized plant root bark extract (3×100 mg). The treatment improved the overall quality of life of patients and their social functioning, and in 8% of patients the disease stabilized within 8 months of taking the drug *.

Repurposing drugs.

At least 235 drugs already used to treat other diseases have been identified as cancer candidates under the ReDO (Repurposing Drugs in Oncology) project*. Three-quarters of them are generics. Many of them can be repurposed to fight breast cancer. Despite the lack of clinical trials for cancer, they all remain potentially promising.

Mebendazole *, as well as other antiparasitic agents of the benzimidazole group – fenbendazole, albendazole, flubendazole. Their therapeutic action is based mainly on the suppression of the process of cell division by preventing the polymerization of tubulin, similar to the way vinca alkaloids * do. However, other antitumor mechanisms have also been reported *. In particular, mebendazole can quench the expression of progesterone-induced blocking factor (PIBF), which greatly attenuates the damaging activity of immune killer cells *.

There are isolated reports of success with the use of mebendazole (2×100 mg) in tumor patients * *. But the results of clinical studies have not yet been published.

Dosage: for a 70-week course, 100-500 mg/day in the form of chewable tablets, after meals; with a 3-week treatment cycle, the oral daily dosage is gradually increased from 2×400 to 2×1'200 mg *.
The combination of mebendazole with cimetidine increases its plasma level *. Side effects of benzimidazoles can be similar to conventional chemotherapy.

The antitumor activity of mebendazole is expected to be improved by the following agents: metformin *, itraconazol, diclofenac * and celecoxib, chloroquines *, clarithromycin, losartan, taxanes and vinca alkaloids *, as well as albendazole and other benzimidazoles *.

Mebendazole has many of the characteristics that are desirable for a reusable drug: a good and proven toxicity profile, pharmacokinetics to achieve therapeutic concentrations at the tumor site, ease of administration, and low cost.

Cimetidine * is a drug used in diseases of the gastrointestinal tract. It reduces the acidity of the stomach by reducing the production of hydrochloric acid, and also reduces the activity of pepsin, an enzyme that breaks down proteins. The antitumor effect of cimetidine is due to four different mechanisms: anti-proliferative *, immunomodulatory * *, anti-angiogenic * and anti-adhesion *.

In colon cancer patients treated with cimetidine (2×400 mg orally) for at least 5 preoperative days and then intravenously for 2 postoperative days, there was no significant reduction in either lymphocyte proliferation or cellular immunity *. In the next 3 years, the survival of patients treated with cimetidine was significantly higher * *. The success of cimetidine monotherapy in other cancers has been much more modest; in most cases, the combination of cimetidine with other therapies has been successful.

The results of clinical studies show a significant improvement in the survival of patients with colorectal cancer treated with cimetidine (oral 800 mg/day) together with 5-fluorouracil (oral 200 mg/day). In the group treated with cimetidine for a year, the 10-year survival rate was 84.6%, and in the group treated with 5-fluorouracil alone, it was 49.8% *. However, there is evidence that long-term use of hydrochloric acid blockers impairs the functioning of the digestive system and disturbs the balance of the intestinal microflora, which ultimately increases the risk of gastrointestinal cancer. In addition, cimetidine can occasionally cause reversible leukopenia and thrombocytopenia and may not be desirable during chemotherapy *.

Cimetidine is expected to combine well with metformin, aspirin, intraconazol, diclofenac, mebendazole, chloroquine.

Itraconazol * is a common antifungal drug. It works by disrupting the integrity of fungal cell membranes, which contain ergosterol instead of the cholesterol found in human cells. Itraconazole exhibits anti-angiogenic activity * and can inhibit the Hedgehog signaling pathway * and can also induce growth arrest by autophagy *. In addition, itraconazol is able to combat multidrug resistance by inhibiting the ABC transporters P-glycoprotein (ABCB1) * and breast cancer resistance protein (BCRP) *.

In patients with TNBC, itraconazol 400 mg supplementation during a two-week cycle of docetaxel/carboplatin/gemcitabine therapy given injectables 2 days before and 2 days after chemotherapy resulted in a therapeutic response in 62% of all cases, with a complete response in 23% *. Long-term use of itraconazol is allowed at an oral dosage of 100-200 mg. The therapeutic response in patients with metastatic breast cancer was not very high: out of 13 experimental patients, only 1 had a partial response, 3 had a stabilization of the disease, and 9 had progression *.

Itraconazole is expected to work well with the following drugs: fluvastatin, mebendazole, disulfiram, methotrexate, cimetidine, celecoxib.

Propranolol * is a beta-blocker commonly used for hypertension (80-240 mg/day). It exhibits the ability to suppress the proliferation, invasion and metastasis of cancer cells. In addition, propranolol increases the sensitivity of cancer cells to certain chemotherapy drugs, including trastuzumab *.

Long-term use of propranolol by women in connection with other diseases significantly reduces their risk of developing and dying from breast cancer * *. The use of beta-blockers after diagnosis is associated with a 10% reduction in the risk of breast cancer and all-cause mortality *.

Clarithromycin * is a macrolide antibiotic with a broad antimicrobial spectrum of action that inhibits protein synthesis in bacteria.

Clarithromycin (500 mg/day) helps reduce post-operative inflammatory and infectious complications, potentially reducing metastasis and increasing patient survival *. At the same time, the use of clarithromycin during radiation or chemotherapy does not find a consensus due to its ability to suppress autophagy.

Synergy of action of clarithromycin with dexamethasone and NSAIDs (diclofenac, ketorolac) is expected.

Diclofenac * and Ketorolac, like other NSAIDs, exhibit a marked antitumor effect.

Patients treated with diclofenac (75 mg/day) or ketorolac (20-30 mg/day) before surgery showed a significant improvement in relapse-free survival (up to 43%) and overall survival compared with patients who did not receive NSAIDs *. In another case, patients who received ketorolac (but not diclofenac) before surgery had a significant (up to 41%) reduction in the frequency of distant relapses *. Diclofenac or indomethacin also helps to reverse radiation therapy-induced lymphocyte dysfunction in breast cancer patients, which may increase survival rates *.

Tranilast * is antifibrotic and antihistamine drug. Three-week injections of tranilast in mice implanted with highly metastatic 4T1 cells showed a relative reduction in primary tumor growth of up to 50% and a reduction in lung metastasis by more than 90% *. A similar effect was observed in the case of implantation of human TNBC cells (MDA-MB-231) *. In the latter case, tranilast is able to normalize the tumor microenvironment by improving immune function, as well as reducing excessive permeability of tumor vessels or repairing compressed vessels *.

Oral tranilast (300 mg/day) improved therapeutic outcomes in patients with prostate cancer * *. However, there are no reports on the results of clinical trials involving patients with breast cancer.

Nitroglycerin improves tissue oxygen supply *. Sublingual administration lasts no more than 30 minutes, therefore, for a longer effect of nitroglycerin, transdermal administration using patches (0.033 mg/h) or ointment is used.

In patients who underwent removal of the mammary gland with its simultaneous reconstruction, the application of nitroglycerin ointment (15-45 g) led to a significant reduction in skin flap necrosis * *.

PDE5 selective inhibitors * such as sildenafil (Viagra™), tadalafil and vardenafil are used in the treatment of erectile dysfunction. In oncology, they can be useful due to their ability to increase blood flow, as well as due to powerful immunomodulatory properties. SEFs alter the tumor microenvironment by inhibiting the function of suppressor cells derived from myeloid cells *.

The combination of sildenafil (60 mg/day) with celecoxib kills cancer cells of various tumor types, including CSC, through activation of the CD95 death receptor pathway, reactive oxygen species generation, and mitochondrial dysfunction *. Tadalafil (20 mg/day) for 10 days enhances the immune response, increasing the number of T cells by an average of 2.2 times compared with control patients *.

Verapamil is an antihypertensive agent that blocks calcium channels in the cell membrane.

In patients with metastatic breast cancer, verapamil (1'200 mg/day) enhances the chemotherapy effect of paclitaxel * and epirubicin *.

Defeat of tumorigenic cells.

The mass of cancer cells contains only a small part of the cells that provide initiation and maintain the malignancy of the tumor. These tumor-inducing cells have the properties of stem cells and are commonly referred to as cancer stem cells (CSCs).

The phenotypically weak point of CSCs is their strong dependence on mitochondrial mass, which ensures their survival and expansion. There are several classes of FDA-approved antibiotics that have the side effect of suppressing mitochondrial production, which can be used as a primary effect *. These are, for example, erythromycins, tetracyclines, glycycyclines, some antiparasitic drugs and chloramphenicol. Many of these drugs are non-toxic to normal cells, which is unlikely to cause severe negative side effects.

An explanation for how antibiotics can be effective against cancer stem cells may be that mitochondria are essentially intracellular bacteria with their own genetic makeup, similar to other bacteria. Thus, some antibiotics actually target mitochondrial damage, resulting in the death of cells with poorly functioning mitochondria, such as cancer cells.

Salinomycin is an ionophore antibiotic isolated from the bacteria Streptomyces albus, effective against gram-positive bacteria. Ionophores disrupt ion transport across the cell membrane, causing an excess of calcium and a deficiency of potassium inside the cell, which leads to the cell death of parasites *. Due to its high toxicity, salinomycin was not allowed into clinical practice, but it is widely used in agriculture to combat coccidosis in birds. Another promising ionophore antibiotic is monensin.

Salinomycin exhibits a wide spectrum of therapeutic action against cancer * *. It is effective against conventional cancer cells *, highly multidrug-resistant *, apoptosis-resistant cancer cells *, and CSCs *. Salinomycin destroys malignant cells through various mechanisms, including apoptosis, autophagy, and necrosis. There is growing evidence for the ability of salinomycin to inhibit cell proliferation, invasion, and migration, as well as to reverse the immunoinhibitory microenvironment *.

Salinomycin in vitro suppressed the expression of genes that contribute to the formation of tumor spheres * and activated genes involved in the differentiation of the mammary gland epithelium *. It also suppressed the expression of genes that are inversely correlated with the overall survival of breast cancer patients * *. Salinomycin induces apoptosis in cancer cells regardless of p53, Bcl2, or multidrug resistance protein status, and regardless of cell cycle arrest and caspase activation *.

Some studies have shown that salinomycin inhibits CSC proliferation through the Wnt/β-catenin signaling pathway *, induces apoptosis through the accumulation of reactive oxygen species * *, activates autophagy *, promotes the leakage of calcium ions from the endoplasmic reticulum * and potassium ions from cells and mitochondria *, and also inhibits oxidative phosphorylation. Salinomycin is a potent inhibitor of the multidrug-resistant ABC transporter in various types of cancer cells * *. By inhibiting ligand-independent ERα activation, salinomycin induces additional cytotoxicity in tamoxifen-responsive cells as well as resistant A-luminal breast cancer cell lines *.

The salinomycin molecule is lipophilic and has low bioavailability: up to 80% of orally administered salinomycin is excreted in the faeces. Taking an antibiotic inside will certainly cause a violation of the existing balance of intestinal microflora. Therefore, injections will be more effective in the fight against tumors. Intraperitoneal injections of salinomycin (10 mg/kg for 3 weeks; 8 mg/kg for 6 weeks and 7.5 mg/kg for 6 weeks) significantly retarded the growth of mice inoculated prostate tumor (PC-3) *, hepatocellular carcinoma (HepG2) * and HER2-positive breast tumor (BT-474) *, respectively. Even small doses of salinomycin (equiv. to 40 mg/day) significantly reduced the metastatic capacity of grafted breast cancer cells in mice *.

Mammary tumor-grafted mice treated with salinomycin (5 mg/kg intraperitoneally for 27 days) had similar tumor suppression efficacy as mice treated with paclitaxel, but with fewer signs of metastasis *. In mice grafted with hepatocellular carcinoma, salinomycin (8 mg/kg intraperitoneally for 35 days) retarded tumor volume growth 30-fold compared to controls *.

Intravenous administration of salinomycin (200-250 μg/kg every second day for three weeks) resulted in partial regression of tumor metastases in patients with metastatic breast, ovarian, and head and neck cancer *. Minor acute side effects were tachycardia and mild tremor within 30-60 minutes after administration. This was the only clinical study of its kind.

Combinations of salinomycin with other chemicals may enhance the effects of salinomycin, allowing for a reduction in dosage. In vitro studies have shown synergy with metformin *, resveratrol * *, temozolomide *, valproate *, dichloroacetate *, chloroquine *. Salinomycin also enhances the effects of chemotherapy drugs such as 5-fluorouracil *, gemcitabine *, doxorubicin *, etoposide *, cisplatin *, paclitaxel *, tamoxifen * and trastuzumab *. While these chemotherapy drugs killed cancer cells in the tumor volume, salinomycin selectively killed cancer stem cells, drastically reducing the tumor's chances of revenge.

The European Food Safety Authority (EFSA) considers an acceptable daily intake (ADI) of salinomycin up to 5 µg/kg. Higher doses (1 mg/kg) taken systemically are extremely dangerous and cause severe acute and chronic general toxicity *.

Salinomycin appears to be one of the most promising destroyers of breast cancer stem cells, although its mechanism of action remains unclear. Despite successful animal studies, large-scale clinical trials of salinomycin against tumors have not yet been carried out, and there is no interest in doing them.

Doxycycline is a broad-spectrum tetracycline antibiotic. Unlike salinomycin, it has been successfully used in the clinic for more than 50 years. At a standard dose of 200 mg/day, doxycycline exhibits minimal side effects. It has excellent pharmacokinetics, a long serum half-life (18-22 hours), and almost complete oral absorption.

Doxycycline effectively suppresses mitochondrial respiration. It prevents the formation of new mitochondria, which significantly weakens the viability of cancer cells *. The combination of an aerobic respiration inhibitor (doxycycline) with anaerobic respiration inhibitors (high-dose vitamin C) works synergistically to successfully target breast CSCs in vitro *. The triple combination of doxycycline (1 μM), azithromycin (1 μM), and vitamin C (250 μM) is even more toxic to CSC, reducing the possibility of mammosphere formation in vitro by 10 times compared to the control. While doxycycline affects the small mitochondrial ribosome, azithromycin affects the large ribosome *. Unfortunately, there are no reports of clinical studies of this therapy yet.

Preliminary 14-day therapy with doxycycline (2×100 mg/day) before surgery to remove early malignant breast tumors (ER–, ER+ and HER2+) resulted in a significant reduction in the number of CSCs in 90% of the participants in the clinical study. The decrease in the tumor marker CD44 averaged about 40% (18-67%). Patients with the HER2+ subtype more than halved another stem cell marker, ALDH1 *.

Although patients with triple negative breast cancer were not taken in this clinical study, preclinical results show that doxycycline reduces the ALDH1 marker also in CSC and this type of cancer *, which looks very encouraging. In addition, doxycycline has been reported to halve in vitro expression levels of other stem markers (Oct4, Sox2, Nanog and CD44) *.

Disulfiram, also known as Antabuse, is a drug that has been used for more than half a century to avert alcohol. Disulfiram inhibits the ability of the intracellular enzyme aldehyde dehydrogenase (ALDH) to detoxify, which reduces the drug resistance of cancer cells. The addition of copper to disulfiram significantly increases its antitumor efficacy.

High-throughput screening has identified disulfiram as a potential therapeutic agent for all TNBC cell lines *. Lung tumor-grafted mice treated with disulfiram (equiv. to 17 mg/kg orally for 2 months) slowed the growth of lung cancer by a third *. Breast cancer patients treated with chemotherapy concomitantly with the metabolite of disulfiram (sodium dithiocarb) improved survival compared to placebo *.

Tretinoin (alpha retinoic acid, ATRA) affects multiple signaling pathways associated with stem cell maintenance, cell differentiation, and organ development. Expressive analysis of microarrays revealed about 350 genes that were changed under the influence of ATRA. The Notch signaling pathway was the most prominent of these pathways *. Neurosphere-implanted mice treated with ATRA (1.5 μg/kg, intraperitoneally 12 days) reduced tumor growth rates by three-quarters and increased median survival by half compared to control mice.

In experiments on mice inoculated with head and neck tumors, ATRA (0.2 mg/day intraperitoneally for 21 days) reduced tumor volume growth by 4 times compared to control *. The equivalent human dosage would be 65 mg/day.

Daily administration of tretionin (150 mg/m2 orally every other week for 7 weeks) concomitantly with tamoxifen resulted in stabilization of the disease over the next 6 months in 7 of 18 patients tested with advanced ER+ breast cancer *. Of the 15 patients assessed as having tamoxifen resistance, disease stabilization occurred in five.

In metastatic breast cancer, ATRA administered orally at a dose of 50 mg/m2 three times a day for 14 consecutive days of a 21-day cycle stabilized the disease in 2 people *. Meanwhile, ATRA monotherapy can induce resistance in cancer cells against it. Physiologically acceptable dose: 300 mg/day *, however, ATRA should not be taken for a long time to avoid chronic toxicity.

Artemisinin and its derivatives look like a promising direction in complementary medicine. In vitro experiments show the high antitumor efficacy of artemisin compounds, which act by producing high concentrations of free radicals within cells.

However, clinical reports of artemisin use are limited and their results show modest results.

Patients with advanced cervical cancer received 28 days of treatment with artenimol (up to 200 mg/day) with improved clinical symptoms and doubled expected survival rates *.

Artesunate, an artemisin malaria drug given before colon surgery (200 mg/day for 14 days), reduced cancer recurrence rates and increased rates of cancer cell apoptosis by 7% *.

Intravenous injections of artesunate (120 mg/day for 8 days) in addition to the combination of vinorelbine/cisplatin in advanced non-small cell lung cancer slightly (15%) improved short-term survival *.

The safe oral dose of artesunate for advanced breast cancer, as an adjunct to chemotherapy, is 200 mg/day for 4 weeks *. The maximum tolerated intravenous dose is 18 mg per kg of body weight, and stabilization of the disease has been observed in some patients with advanced tumors *.

Artemisinin works synergistically with high dose vitamin C, vitamin D *, curcumin *, allicin *, resveratrol *. One can expect a synergistic oxidative effect of artemisinin with sulfasalazine, mefloquine, chloroquine, parthenolide. Unfortunately, the experience of treatment with artemisin derivatives shows that cancer cells are able to develop resistance against this therapy.

Metformin, a dimethyl biguanide from Goat's rue (Galega officinalis) *, is a cheap and widely used blood glucose lowering agent for diabetics. Remarkably, metformin causes a marked decrease in glucose levels when it is in excess, which is observed in type II diabetes, but this effect is very small at normal glucose levels.

In fact, metformin is a mitochondrial toxin. It reduces mitondrial energy production, which is already reduced in cancer cells. Thus, cells with poorly functioning mitochondria, including CSCs, are weakened *. Metformin also acts as an anti-inflammatory agent, chemosensitizer * * * *, autophagy and apoptosis stimulator, antioxidant and anti-angiogenic agent in cancer chemotherapy *.

Metformin can act against the tumor directly by activating the metabolic regulator of cellular energy utilization and conservation (AMPK) *, and indirectly by suppressing the expression of pro-tumor genes *. AMPK is a cellular energy level sensor; it is activated in situations of intracellular energy depletion, such as hypoxia and hypoglycemia, or in situations of increased demand for ATP, such as muscle exertion or hunger. Thus, AMPK activation stimulates energy (food) consumption and reduces its expenditure (thermogenesis). Metformin activates AMPK through suppression of the mitochondrial respiratory chain *.

In skeletal muscle, AMPK activation results in increased glucose uptake, increased insulin sensitivity, and fatty acid oxidation. In the liver, AMPK activation results in increased fatty acid oxidation and decreased production of glucose, cholesterol, and triglycerides *. Metformin-induced energy restriction of cells causes physiological effects similar to food starvation *. Activation of AMPK forces cells to produce energy at the expense of their growth and motility, which helps to reduce the proliferation and metastasis of tumor cells. In addition, activated AMPK inhibits aromatase, which reduces the estrogen load on breast tissue *.

Metformin also increases immune T cell activity, reducing chronic inflammation, hypoxia, and PD-L1 levels, which inhibit T cell activity, and promotes memory T cell differentiation.

In HER2-dependent tumors, metformin helps to solve two problems: chemotherapy damage to the heart muscle and counteracting drug resistance *. At low concentrations of metformin (in the micromol range), only HER2 tyrosine kinase activity is blocked *, while at high concentrations (in the millimol range), HER2 protein expression is downregulated *. Metformin has a different effect on gene expression in HER2-positive and HER2-negative cell lines *. In HER2-positive breast cancer lines, metformin reduces the expression of genes associated with mitosis. And in HER2-positive lines, it overexpresses genes involved in apoptosis. Metformin has also been reported to act synergistically with an anti-HER2 monoclonal antibody (trastuzumab) to inhibit self-renewal and proliferation of trastuzumab-resistant breast cancer stem cells *.

Metformin causes significantly greater inhibition of proliferation and clonogenicity in trastuzumab-resistant sublines (BT-474-HR20, SKBr3-R20) than in trastuzumab-sensitive sublines (BT-474 and SKBr-3) *. In addition, metformin may also be involved in the regulation of tumor-initiating breast cells * * *, including trastuzumab-resistant HER2+ tumors *. Metformin is able to reduce the viability and migration of the ER+ cell line (MCF-7) at lower concentrations than aspirin *. Tumors with loss of p53 function are especially sensitive to metformin *.

Diabetics taking standard doses of metformin (1'500-2'250 mg/day) have significantly reduced cancer risk * * * * and all-cause mortality * * compared to non-diabetics. This effect is clearly manifested only with long-term use of metformin *. A meta-analysis of studies regarding metformin use and breast cancer risk showed an overall risk reduction of 17% with regular use of metformin, and 25-32% with longer use *.

Mice with inoculated mammary tumors (BT-474 and MDA-MB-231) treated with metformin (100 mg human equivalent) concomitantly with doxorubicin showed tumor regression *.

The combination of doxorubicin, which attacks conventional cancer cells, with metformin, which attacks stem cancer cells, in vitro reduces the ability to form mammospheres of all tumor subtypes, although with less success for TNBC. While doxorubicin alone caused only a 2-fold reduction in tumor volume growth, and metformin alone had little effect on tumor growth, the combination of both substances virtually stopped the growth of the grafted tumor in mice. Animals remained in remission for at least 60 days after the end of combined treatment, which in human terms would be about 6 years. At the same time, after therapy with doxorubicin alone, tumor growth resumed after 3 weeks at the same rate as before treatment *.

The combination of metformin with doxorubicin allows a 4-fold reduction in the dose of the latter with an equivalent effect of tumor regression and relapse-free survival in experimental animals. Selective destruction of CSC occurred at the level of consumption of metformin, which is prescribed for the treatment of type II diabetes (approximately 1'500 mg/day) *. Oral administration was as effective as intraperitoneal injections. However, clinical studies on the same topic have not been successful *.

Approximately 24% of diabetics who took metformin before surgical removal of the tumor had a complete pathological response compared to 8% of diabetics who did not take it *.

Although metformin has a beneficial effect on markers of tumor proliferation, it has not yet been clinically proven to improve the survival of patients with breast cancer. However, in ovarian cancer, metformin supplementation (500-2'000 mg/day) before surgery and together with postoperative chemotherapy was associated with an 18-month median progression-free survival, and nearly a 5-year median overall survival. In addition, there was an increase in the sensitivity of cancer cells to cisplatin *.

Metformin reduces circulating levels of androgen and estrogen in women with breast cancer. Women treated with 1'500 mg/day metformin showed a significant decrease in free testosterone (-29%) and, respectively, estradiol (-38%) *. The decrease in estradiol levels in women taking metformin was independent of their body mass index *.

Dosage: 500-1'000 mg/day orally, but not more than 1'500 mg/day without a doctor's prescription *. Metformin is not metabolized and is excreted unchanged in the urine *. Since metformin depletes vitamin B12, supplementation with this vitamin is recommended at high metformin doses (1'500-2'000 mg/day) *.

Unfortunately, like other therapeutic substances, chronic exposure to metformin eventually leads to drug resistance in cancer cells, which is associated with an increase in the level of PGC-1α * – a key regulator of cell energy metabolism. Metformin-resistant cells are able to switch from oxidative metabolism to glycolysis and glutamine metabolism for energy generation. The combination of metformin with glycolysis inhibitors seems to be a better strategy * * since depriving metformin-treated breast cancer cells of glucose can lead to their almost complete death even in the presence of a reserve energy source – glutamine *.

Statins block an enzyme that the liver uses to make cholesterol, which lowers blood cholesterol levels. Since cholesterol is involved in many biochemical processes, long-term use of statins is unhealthy. At the same time, some tumor cells require increased activity of the same enzyme pathways involved in cholesterol production, and statins block the production of these molecular elements, delaying tumor development *. In addition, cancerous tumors consume large amounts of cholesterol, and its reduction itself can reduce the rate of disease progression.

In breast cancer, long-term use of statins can reduce mortality from 16% * to 30%, and the likelihood of recurrence by up to 36% *. Thus, in tumors, short-term use of statins may be justified in cases where their positive effects can outweigh the negative ones. The negative ones include, for example, suppression of the synthesis of the coenzyme CoQ10.

Fat-soluble statins (atorvastatin, lovastatin, simvastatin) perform better than water-soluble ones (pravastatin, rosuvastatin, fluvastatin) * *. So far, there are no specific guidelines for dosage and duration of statin use as add-on treatment; however, atorvastatin appears to be appropriate at doses of 20-80 mg/day.

Dietary CSC inhibitors are incomparably weaker than those discussed above, but their presence in the diet may provide some additional assistance in the defeat of cancer stem cells.

Piperine, which is found in black pepper, blocks the pumping of chemotherapeutic agents from cancer cells through the ABCB1 membrane transporter. It acts as an effective natural bioenhancer of chemotherapeutic agents *, and is able to increase the bioavailability of various (but not all) drugs by 30% to 200% *. Piperine exacerbates the sensitivity of HER2+ cancer cells to paclitaxel * and is also the most successful enhancer of TNF-ligand proapoptotic therapy in TNBC cells *. Injected orally into TNBC tumors every other day (0.2 mg/kg), piperine halved its growth rate in mice *. In addition, piperine inhibits the proliferation of breast tumors through the mitochondrial pathway. During radiation therapy, piperine enhances the cytotoxicity of cells caused by γ-radiation.

Curcumin, which is found in the tuberous root of turmeric; genistein, which is found mainly in soybeans; resveratrol, which is found in the skin of red grapes, plums, berries; EGCG (epigallocatechin gallate), which is found in green tea leaves; sulforaphane, which is found in cruciferous vegetables have been shown notable advances in defeating CSC in numerous reports, but these were only preclinical studies.

Immunomodulators.

Beta-glucan (β-1,3/1,6-D-glucan) is a class of polysaccharides that is considered one of the strongest natural modulators of both innate immunity and, to a lesser extent, adaptive immunity. Pathogenic agents (bacteria, fungi and protozoa) have specific polysaccharides on their surface, which are a kind of label for pathogens. Once in the blood, beta-glucan polysaccharides mimic invading fungi, which activates the production and activity of immune cells such as monocytes/macrophages in patients *.

Beta-glucan markedly reduces the number of post-operative infections, greatly enhances the effect of chemotherapy * * and antibiotics, and helps to better cope with the effects of radiation therapy * by accelerating the recovery of platelets and white cells of the immune system. By themselves, beta-glucans do not show a significant antitumor effect, and can only be recommended as an additional treatment. At the same time, they are able to significantly enhance the effect of other immunomodulators, as well as monoclonal antibodies such as trastuzumab.

In addition to immunomodulation, beta-glucan inhibits the activity of the aromatase enzyme *. Aromatase may play a significant role in the proliferation of hormone-responsive cells by increasing estrogen and decreasing androgen. In breast carcinoma, beta-glucan may have an antiestrogenic effect comparable to 4 weeks of treatment with an estrogen inhibitor such as tamoxifen *.

Although beta-glucans are rapidly absorbed into the blood after ingestion (especially when taken sublingually), the rate of their metabolism remains unclear. Therefore, it is better to take them at least 3 times a day. The dosage of beta-glucan used in clinical studies is 7.5-1'500 mg/day *. In addition to brewer's yeast, the following sources can be used to obtain beta-glucan:

Selenium (L-selenomethionine). Although in breast cancer, compared with other types of cancer, the antitumor effect of selenium was less pronounced, it remains quite significant. Sodium selenite tunes the immune system to search for and destroy tumor cells and alleviates the side effects of chemotherapy. Dosages of sodium selenite in clinical studies ranged from 200 μg/day * to 15 mg/day *.

Dietary selenium intake prior to breast cancer diagnosis was inversely associated with breast cancer mortality and overall mortality. This association was especially strong in women who had ever smoked *.

In primary invasive breast cancer, women with high blood selenium levels (> 81.0 µg/L) at diagnosis, compared with women with low selenium levels (< 64.4 µg/L), had 2, 5 times lower risk of death over a five-year follow-up period *.

Selenium is especially important for carriers of the mutated BRCA1 gene. Supplementation of selenium 276 µg/day in the form of sodium selenite for 1-3 months reduces the frequency of chromosome breaks in such people to almost the level of people without mutations of this gene *.

The combination of sodium selenite (300 µg/day), bromelain (400 mg/day), papain (400 mg/day) and lectin (20 mg/day) for 4 weeks significantly reduced mucosal dryness during adjuvant hormone therapy *.

Cordyceps  (Cordyceps militaris) is a specific mushroom traditionally used in Chinese medicine. Cordyceps mycelium extract in capsules (1.7 g/day), after an 8-week intake, provides an improvement in the cytotoxic activity of NK cells by 39% compared with placebo *. Cordyceps taken for 4 weeks at a dosage of 1.5 g/day significantly improved natural killer activity, IL-2 levels, and lymphocyte proliferation compared to baseline, which was not observed in the control group *. The latest study was conducted with the participation of exclusively healthy men in order to minimize the effect of female sex hormones on immunity.
Recommended dosage of cordyceps liquid extract: from 1.5 g/day (from 10 mL/day). It is recommended that the liquid form, which is easy to take sublingually.

It is worth recalling that an increased immune response in an inadequate immune system can increase the level of general inflammation, which will have the opposite effect of what is expected.

Proteolytic enzymes.

Proteolytic enzymes purify blood and blood cells from protein debris, and cancer cells from a biofilm that hides antigens on their surface, thereby making them invisible to the immune system; and which provides them with «stickiness», thereby facilitating metastasis. In addition, proteolytic enzymes are able to attenuate inflammatory signaling.

Animal experiments show a high anti-metastatic effect of proteolytic enzymes * *. And clinical studies of cancer patients taking proteolytic enzymes on a long-term basis (at least six months) show an increase in their survival by 2-4 times * *.

Animal-derived enzymes such as trypsin and chemotrypsin are considered the most effective, while plant-derived enzymes such as papain and bromelain are less effective. However, a complex of different enzymes will be more effective than any of them alone, even at the maximum dosage.

Trypsin and chymotrypsin as part of the WobeMugos® Enzyme Complex effectively attenuated the acute toxicity associated with cisplatin and etoposide chemotherapy in a clinical study. Compared with the control group, there was a decrease in the incidence of leukopenia (from 39% to 17%), nausea (from 33% to 8%), vomiting (from 50% to 22%), sensory neuropathy (from 30% to 8%), depression (from 42% to 16%) and weight loss (from 53% to 44%) *. Here, during the entire course of chemotherapy, 2 tablets per day were used half an hour before meals with plenty of water. Each WobeMugos® tablet contains 100 mg papain, 40 mg trypsin and 40 mg chymotrypsin.
In surgical therapy, WobeMugos® enzyme therapy reduces the number of purulent-septic complications *.

A double-blind clinical study of WobeMugos® Enzyme Therapy at all stages of the standard cancer treatment protocol showed an improvement in patient survival *. An extensive multicenter study in patients with non-metastatic breast cancer showed that taking WobeMugos® for 10 months as an adjunct to primary therapy halved the severity of side effects such as nausea, loss of appetite, gastrointestinal complaints, headache, fatigue and anxiety. In addition, the intake of enzymes significantly increases the remission time *. In patients with breast cancer, the dosage of 2 tablets of WobeMugos® three times a day is well tolerated *.

Serrapeptase (serratiopeptidase) is a proteolytic enzyme (metaloprotease) produced by enterobactria Serratia marcescens in the intestines of the silkworm. Serrapeptase is used in sports medicine for trauma, improving the delivery of antibiotics to the area of inflammation, as well as reducing the level of inflammation and post-traumatic edema *. In a placebo-controlled study of 70 patients, serrapeptase was shown to be highly effective in the treatment of fibrocystic breast disease *. The recommended dose is 30 mg/day.

Nattokinase, a serine proteinase produced by the bacterium  Bacillus subtilis, is another proteolytic enzyme. Already 2'000 fibrinolytic units of nattokinase, taken orally, exhibit anticoagulant and antithrombotic effects * *.

An important advantage of these proteolytic enzymes taken at normal doses is the absence of negative side effects. However, caution should be exercised when taking them simultaneously with other drugs that thin the blood.

Mitochondrial support.

Coenzyme Q10 (ubiquinone, CoQ10) is a critical co-factor for the electrochemical bioreactions that take place in mitochondria, allowing them to produce cellular energy. CoQ10 improves blood circulation, stimulates the immune system, increases tissue oxygenation, and serves as a powerful antioxidant in mitochondria and cell membranes, slowing down their degradation and the aging process.

When mitochondria are overstressed, which usually occurs with an excess of glucose, the production of reactive oxygen species increases, which leads to mitochondrial dysfunction *. Reactive oxygen species damage the mitochondrial membrane, leading to leakage of mitochondrial components into the cytosol, thereby producing an inflammatory effect. CoQ10 helps neutralize free radicals in the mitochondria and reduce mitochondrial damaging oxidative stress.

Vitamin B6 (pyridoxal phosphate) increases the production and concentration in the blood of CoQ10 *, while statins and NSAIDs, on the contrary, decrease, since the biochemical pathway for the synthesis of CoQ10 is the same as that of cholesterol *.

A direct correlation has been found between the degree of plasma CoQ10 deficiency (below 0.6 mg/ml) and the incidence of breast cancer *, as well as poor therapeutic prognosis *. Conversely, clinical CoQ10 supplementation stabilized the condition and increased patient survival *.

Three clinical cases have been described of patients in whom high-dose (300-400 mg/day for 3-5 years) ubiquinone supplements in combination with other antioxidants demonstrated tumor regression, including metastasizing *.

One clinical study studied patients at high risk (due to spread of the tumor to the lymph nodes in the armpit). The daily intake of antioxidants here was: 90 mg of ubiquinone, 1.2 g of linoleic acid, 3.5 g of β-3 fatty acids and a multivitamin complex (58 mg of β-carotene, 2'800 mg of vitamin C, 2'500 IU of vitamin E, up to 385 micrograms of selenium, etc.). With the expected 4 deaths, no patients died, no signs of further distant metastases were found, but quality of life was improved (no weight loss, reduced use of painkillers). Over 2 years of follow-up, 6 of 32 patients (18%) had an apparent partial remission. And in 2 patients who increased their ubiquinone intake to 300-400 mg/day, a complete remission was observed *.

This clinical study was not placebo-controlled, and the effect of ubiquinone was obscured by the effect of other elements of the mixture, which weakens the evidential strength of the benefit of ubiquinone. However, the median 5-year survival rate for patients at high risk of breast cancer (with metastases) with this therapy was as high as 50%, while for patients at low risk of breast cancer (without axillary metastases at the start of treatment), the median 10-year survival rate was 90% *.

The addition of CoQ10 (100 mg/day), riboflavin (10 mg/day) and niacin (50 mg/day) to tamoxifen reduced tumor and inflammatory markers, enhancing the effect of tamoxifen *. At the same time, the American Cancer Society is of the opinion that CoQ10 may reduce the effectiveness of radiation therapy, and recommends avoiding it during this period of treatment *.

Coenzyme Q10 can also be effectively used in combination with magnesium, succinic acid (element of the second complex of the mitochondrial respiratory chain) and L-carnitine (fatty acid carrier). It is an endogenous substance, and does not have negative side effects. Since ubiquinone is fat-soluble, it is taken with fats (such as olive oil) for better absorption.
Doses up to 600 mg/day of CoQ10 for up to 30 months are considered safe *. The usual dose is 50-200 mg taken in the morning. More than 12 million people in Japan have been reported to take it on the advice of doctors.

Pyrroloquinoline quinone (PQQ), also known as methoxanthin, increases the number of mitochondria in cells * *. In preclinical studies, methoxanthin increased the apoptosis of cancer cells without any effect on normal cells *. Methoxanthin exhibits an antioxidant effect and reduces muscle loss in cachexia *. In addition, methoxanthin lowers blood levels of low-density lipoprotein *, raises hemoglobin levels, and lowers plasma concentrations of IL-6 and CRP *. Clinical studies, however, are still insufficient to determine the benefit of methoxanthin in cancer. The usual dose is 20 mg/day, in the morning.

Vitamins and minerals.

Whole foods provide the body with almost all the vitamins and minerals it needs. However, due to inadequate nutrition, deficiencies or deficiencies of the following substances or elements are very widespread throughout the world.

Vitamin D3 (cholecalciferol). Vitamin D is one of the key components of the normal functioning of the endocrine, cardiovascular, nervous, immune and other systems and organs *. Vitamin D also regulates cell proliferation.

Although the optimal concentration of 25(OH)D in the serum is considered to be no lower than 75 nM/L (30 ng/mL), this value seems to be too low, and in fact should reach * 125-140 nM/L (50-55 ng/mL), but should not exceed * 125 nM/L.

Vitamin D inefficiency is common even in countries with sufficient solar activity, and has acquired the character of a global pandemic. Low vitamin D levels are commonly seen in patients at diagnosis and may be further reduced during breast cancer therapy *. A decrease in the level of vitamin D in the blood serum can cause many common pathological conditions in the human body, such as diabetes mellitus, hypertension, atherosclerosis, obesity, as well as autoimmune thyroiditis and other autoimmune diseases *.

A single dose of 50'000 IU of vitamin D3 every two weeks significantly reduces glucose, insulin, and C-reactive protein levels, and increases plasma antioxidant capacity in women with uterine hyperplasia *.

Women with levels around 52 ng/mL have a 50% lower risk of breast cancer than women with levels below 13 ng/mL *.

Four-year supplementation of vitamin D (1'100 IU/day) with calcium (1'500 mg/day) in postmenopausal women showed a 77% reduction in the incidence of invasive cancer, including breast cancer, compared with the no-supplementation group *. However, a repeat study by the same research group using 2'000 IU/day of vitamin D did not show a noticeable effect *. In the latter case, the mean baseline vitamin D level in the patients was 33 ng/ml versus 28 ng/ml in the first case. In a clinical study by another research group, a small reduction in breast cancer risk was found with vitamin D (800 IU/day) and calcium (1'000 mg/day), but here vitamin D supplementation was too low *.

Low blood levels of 25(OH)D may be associated with an increased risk of death from breast cancer * *, while high levels prolong survival by more than 40% * * and also reduce the risk of recurrence of PR+ tumors *. Other studies have linked higher serum 25(OH)D levels with lower breast cancer mortality * *.

Postmenopausal patients with the highest blood levels of vitamin D treated for breast cancer, compared with those with the lowest levels, improved 8-year survival by 28%. In a similar comparison of premenopausal patients, this relationship was twice as pronounced *. Each 4 ng/mL increase in serum vitamin D reduces the risk of death from breast cancer by 6% *.

Patients with HER2+ breast cancer treated with trastuzumab with vitamin D supplementation (up to 1'500 IU/day) experienced a 64% improvement in disease-free survival compared with patients treated with the same therapy but without vitamin D supplementation *.

Vitamin D supplementation (50'000 IU/week) may reduce the negative effects of aromatase inhibitors on bone * *.

Long-term intake of 600-2'000 IU/day of vitamin D is acceptable, however, serum levels of 25-hydroxyvitamin D3 should be checked periodicallyl. Administration of supplemental vitamin D3 through the skin in the form of a cream appears to be preferable to oral supplementation. In this case, it will pass through its natural metabolic pathways.

Iodine. Iodine deficiency is very common in the world. For example, the median urinary iodine concentration of Belgian women is 93.6 μg/L * *, while the range of 95-150 μg/L * is considered to be an adequate level, and a noticeable decrease in the incidence of breast cancer occurs only at a level of 300 μg/day. One or two drops of 5% Lugol's solution per day, apparently, will be enough to eliminate the existing lack of iodine, however, the dosage of the supplement can be more accurately determined only by the result of analyzing the concentration of iodine in the urine.

The combination of iodine with doxorubixin suppresses the expression of genes involved in invasion and chemoresistance, enhancing the effectiveness of breast cancer treatment. Supplementation of 5 mg/day I2 for 7-35 days before surgery and 170 days after surgery (during chemotherapy) shows a significant reduction in the side effects of treatment, as well as an increase in the body's immune response and a significant increase in 5-year disease-free survival *.

The absorption of iodine is highly dependent on the level of selenium (the recommended dose of selenium is 200 μg/day).

Anti-inflammatory drugs.

The results of numerous clinical studies show that the combination of NSAIDs with standard treatments often significantly improves outcomes, even in advanced metastatic cancer.

Acetylsalicylic acid (aspirin) is a good old NSAID that has the ability to inhibit pro-inflammatory signals (COX-2) * that favor tumor growth. In addition, aspirin prevents platelets from sticking together, preventing the formation of blood clots and metastasis of an already formed tumor * *.

Long-term (3-5 years) regular use of aspirin (500 mg/week) is associated with some reduction in the risk of various types of cancer *, including a 10-18% reduction in the relative risk of breast cancer * *.

The effect of reducing the risk of invasive breast cancer due to regular use of NSAIDs is not completely clear. In some cases, it was reported that it does not depend on the ER status of the tumor *. In other cases, regular aspirin use has been reported to be ineffective for ER-positive tumors, but may reduce the relative risk of ER-negative and TNBC tumors by 9% and 30%, respectively *. The benefit of low long-term doses of aspirin in the prevention of HER2 tumors has also been reported *.

Postmenopausal women who took NSAIDs at least twice a week for at least 5 years had a 21% lower risk of breast cancer, and women who took NSAIDs for at least 10 years had a 28% lower risk. compared with women not taking NSAIDs *. At the same time, low doses of aspirin (≤100 mg/day) did not cause a noticeable effect *. Regular long-term use of ibuprofen reduced the risk by 49%, while aspirin caused a 21% reduction *, however, ibuprofen is considered to be more dangerous for heart health than aspirin, and also has a number of other unwanted side effects.

In another study, comparing aspirin with other NSAIDs showed its undeniable superiority, providing a 16% reduction in cancer risk and a 13% reduction in cancer mortality *.

For pre-existing cancer, aspirin (100 mg/day) may reduce the number of circulating cancer cells, thereby reducing the risk of metastasis *. In addition, aspirin may reduce mammographic breast density *.

Unfortunately, acetylsalicylic acid has negative side effects. As an acid, it damages the epithelial layer, threatening bleeding in the gastrointestinal tract, and also increases the permeability of the intestinal wall, which can cause «leaky gut» syndrome. In one clinical study, 19% of patients reported upper gastrointestinal symptoms as early as the first day of taking aspirin at a dosage of 75-325 mg/day. And by the end of the first week of admission, this figure rose to 46% *.

In addition to the observational studies mentioned above, there is a five-year randomized control trial in which apparently healthy older participants took 100 mg/day. Compared to those taking placebo, those taking aspirin showed higher all-cause mortality, and this was mostly due to cancer. Cancer death occurred in 3.1% of participants in the aspirin group and 2.3% of participants in the placebo group (hazard ratio for breast cancer was 2.1) *.

In another controlled study of breast cancer patients taking tamoxifen, low-dose aspirin also significantly increased all-cause mortality, presumably due to higher pre-existing cardiovascular risk *.

A 2022 review of clinical studies* found prophylactic benefits for breast cancer of NSAIDs such as celecoxib and benefits of post-cancer diagnosis of NSAIDs such as aspirin and sulindac *. Given such mixed data, it remains to be assumed that the effect of aspirin may depend on many factors that are not fully understood.

Inositol (vitamin B8). Inositol (1 g/day for 12 weeks) is able to reduce the level of C-reactive protein by several times *. The inositol metabolite, inositol hexaphosphate (IP6), is more effective than inositol; and their combination works synergistically. The inositol+4Ca/2Mg/IP6 formula works even more strongly, but it is too expensive.

Myo-inositol (18 g/day for 6 months) in smokers with bronchial dysplasia significantly blocked the transformation of a benign tumor into a malignant one *.

A complex containing boswellia (50 mg), myo-inositol (200 mg), betaine (175 mg), N-acetylcysteine (100 mg) and vitamins В2, В6, В9 and В12, taken for 6 months, reduces young women the size of fibroadenomas without causing any side effects *.

In clinical trials, inositol supplementation with inositol hexaphosphate (2×6 g starting from the first postoperative day, for 6 months) avoided the drop in blood levels of leukocytes and platelets caused by chemotherapy, significantly improving the quality of life of patients *.

Patients who used phytic acid 4% topical on the breast starting at 6 weeks post-op significantly improved their quality of life with fewer side effects compared to hyaluronic acid controls; and besides, they had significantly better indicators of the number of leukocytes and platelets *.

In a pilot clinical trial in patients with non-small cell lung cancer stage III-IV, a dietary supplement containing IP6, genistein, dadzein and cumestrol caused a significant slowdown in tumor growth and stabilization of the condition, and in 10% of cases – a complete regression of brain metastases after application. radiation therapy *.

In another pilot clinical trial in 6 patients with advanced colorectal cancer with multiple liver and lung metastases, IP6 plus inositol (2×3 g/day mixture, for 6 months from the first postoperative day) was given a decrease in growth rate. the tumor as a whole, and in some cases even its regression *.

A case of 3-year remission of metastatic melanoma has also been reported after a course of treatment with IP6+inositol *.

Omega-3 fatty acids (PUFAs). These include alpha-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids.

Fatty acids ω-3 * * are a good prophylactic * – every additional 0.1 g/day of ω-3 reduces the risk of developing breast cancer by 5% *. This applies specifically to PUFAs and not to all fats: dietary intake of polyunsaturated fatty acids (EPA and DHA), but not saturated fatty acids (SFAs) *, shows a negative association with risk.

Fatty acids ω-3 exacerbate the sensitivity of tumor cells to chemotherapy * *. Patients with metastatic breast cancer treated with anthracycline-based chemotherapy supplemented with 1.8 g/day of DHA had an increased survival time that was directly correlated with DHA levels in cell membranes *.

Increasing your daily intake of EPA and DHA from fish oil (at least 150 mg/day) can significantly reduce your chance of breast cancer recurrence * and lower your risk of death * *. In addition, consumption of 4 g/day of ω-3 fatty acids reduces bone loss caused by aromatase inhibitors *.

The content of EPA and DHA depends on the type of fish and its growth conditions; the largest quantities are found in oceanic cold water fish such as salmon, herring, mackerel and tuna *. In order to notice the anti-inflammatory effects of EPA and DHA, a dosage of at least 2 g/day is required *. This amount is enough to be able to observe an increase in their concentration in the adipose tissue of the breast *.

EPA and DHA can be synthesized from other dietary fats by the enzyme δ-6-desaturase, which requires adequate levels of zinc, magnesium, and pyridoxine to function properly. As we age, δ-6-desaturase activity tends to decrease, so taking EPA and DHA in a pre-packaged form (from fish oil) is preferable to taking their precursor (such as from linseed oil).

Boswellia (Boswellia carterii). The resin of the plant (incense) has a strong anti-inflammatory effect * *.

Taking Boswellia together with betaine and myo-inositol for six months reduces mammographic density of the breast, suppresses inflammation, soothes pain and reduces the volume of an existing benign breast tumor * *. Boswellia normalized extract (500 mg) is taken as an emulsion with lecithin (1:1 ratio) to improve its bioavailability *.

Curcumin is the main active component of Turmeric (Curcuma longa) root *, which has a pronounced anti-inflammatory effect. As little as 150 mg of curcumin (0.5 tablespoon of turmeric) can reduce a person's serum levels of pro-inflammatory cytokines *.

The lecithin form of curcumin (Meriva™) at 500 mg/day alleviates symptoms caused by radiation and chemotherapy without compromising therapeutic outcomes *.

Curcumin supplementation (6 g/day) for 7 weeks markedly attenuated the severity of radiotherapy-induced dermatitis in patients with non-inflammatory breast cancer *.

Pure curcumin can be replaced with table turmeric: 1 tsp. in a day; but not more than 1 tbsp. 3 times a day for a daily dose of 1'000 mg of pure curcumin. The maximum safe clinically determined dosage of curcumin is 6 g/day *. Curcumin supplementation up to 8 g/day for 3 months was well tolerated by patients with precancerous lesions or non-invasive cancer *.

Unfortunately, curcumin is very slightly water soluble, has poor oral bioavailability, and is rapidly metabolized *. And the main metabolites of turmeric (glucuronides) show poor cell membrane permeability and lack of anti-inflammatory, anti-proliferative and antioxidant activity *. Therefore, to enhance the action of curcumin, it is mixed with piperine (found in black pepper) in a ratio of 100:1 and whipped in vegetable oil. The bioavailability of curcumin is also multiplied when combined with lecithin (eg Meriva®)* as well as fenugreek seed powder (CurQfen®) * *.

At the same time, curcumin increases the contraction of the gallbladder, which is undesirable for people with gallstone disease *; it may contribute to oxalate kidney stone formation; increase the risk of bleeding in those taking anticoagulant drugs due to suppression of platelet aggregation *; and reduce stomach acid production *. In addition, too high doses of curcumin (3×1'200 mg) can significantly reduce the effect of tamoxifen *.

Serrapeptase (serratiopeptidase) is a proteolytic enzyme. In clinical studies, serrapeptase reduced breast pain, swelling, and breast hardening * *. Serrapeptase also improves the delivery of antibiotics through fibrinolytic and vasodilating effects, and enhances their effectiveness by dissolving the protective biofilm that protects bacteria *.

Proanthocyanidins grape seed extract prevents the formation of advanced glycation end products, helping to reduce chronic systemic inflammation *.

In a clinical study, 30% of patients with moderate to severe breast induration after radiation therapy who received 3×100 mg orally of proanthocyanidins daily for 6 months reduced the area of breast induration by more than half *.

Hormonal remedies.

Healthy women under 40 do not need any hormonal supplements. However, age, menopausal status, and certain hormonal disorders may require supplementation.

Depending on the results of the analysis and prescriptions of a specialist, the following bioidentical hormones can be used.

Steroid hormones.

Estradiol: transdermally in the form of a gel 1.5 mg/day. Usually prescribed with a clear deficiency of this hormone. However, it seems more reasonable to take the precursor of estradiol – progesterone. Estradiol is formed from progesterone by an enzyme called aromatase, which increases in activity over the years.

Progesterone: transdermally to the breast in the form of a gel 6-7 mg/day, of which about a third will be absorbed. An alternative is 200 mg of micronized natural progesterone. Take the last 14 days of each ovulation cycle; and postmenopausal women – two weeks in a row, then 2 weeks off.

Dehydroepiandrosterone (DHEA): 25 mg/day orally in the morning for at least 6 months for postmenopausal women *. DHEA has been shown to increase postmenopausal estrogen levels without supplementation of estrogen itself, and is used to prolong and improve the quality of life of the elderly. Dosage in the range of 1.25-12.5 mg, but not higher, causes an increase in telomeres in normal cells and a decrease in telomeres in cancer cells. It has been observed that extremely low levels of DHEA in various parts of the body are associated with cancer *.

Testosterone: testosterone enanthate mixed with oil, sublingually or transdermally, in the morning, 4 mg/day. Although testosterone is considered an estradiol antagonist, it is metabolized to estradiol by aromatase. Thus, if exogenous testosterone without aromatase inhibitors is added, it can increase estradiol levels.

Nonsteroidal hormones.

Melatonin plays a central role in the regulation of the body's sleep and wake cycle, and helps to maintain the circadian rhythm (daily schedule of biological processes of all organs and systems). In addition, melatonin is an excellent preventive agent that reduces the risk of cancer. It is a very powerful antioxidant and neuroprotective agent that protects cells from oxidative and toxic damage.

Melatonin exhibits an antiestrogenic effect and also inhibits aromatase activity, thus reducing the local production of estrogen from androgen *. Melatonin levels and its receptor expression tend to decrease with aging, as well as in some disease states.

The melatonin molecule is easily destroyed in the retina by sunlight, especially the blue spectrum waves. In addition, an association has been seen between cell phone use for more than 30 minutes a day and decreased nighttime melatonin production * * as well as the negative impact on melatonin levels of low frequency electromagnetic fields emanating from the industrial power grid *.

Rolling shift workers compared to day shift workers have lower melatonin levels and an associated increase of 36-79% relative risk of breast cancer and 43% relative risk of endometrial cancer. At the same time, high levels of nighttime melatonin show a significant reduction in the risk of breast cancer *. Elevated morning urine concentrations of the metabolite melatonin are associated with a markedly lower risk of breast cancer, independent of tumor ER status, age, smoking, and body mass index *.

Long-term use of melatonin is associated with an increase in life expectancy and a decrease in the risk of cancer in rodents *. A systematic review of clinical trials of melatonin shows that melatonin 20 mg/day reduces the 1-year risk of death in patients with solid tumors by one-third *.

Clinical studies confirm the therapeutic abilities of melatonin. In a series of clinical trials, 20 mg of melatonin at night as an adjunct to radiation or chemotherapy doubled partial response and 1-year survival compared to controls, and provided a multiple reduction in treatment-related side effects such as thrombocytopenia, neurotoxicity, and fatigue *. Cancer patients taking melatonin (20 mg in the evening) had significantly lower weight loss (3 kg vs 16 kg) and risk of disease progression (53% vs 90%) than those receiving only maintenance therapy *.

Melatonin (20 mg in the evening) enhanced the efficacy of tamoxifen (20 mg/day) even in patients with ER-negative breast cancer and increased partial response in postmenopausal women *. At the same time, there was a decrease in anxiety and relief of depression. The combination of melatonin (20 mg in the evening) with aloe extract (2×1 mL during the day) doubled its therapeutic effect in patients with advanced tumors *.

However, healthy people with flexible work schedules or jet lag should not take more than 3 mg of melatonin, especially under 40 years of age. Even with just 3 mg of melatonin, bloodstream levels are 50 times higher than normal nighttime levels *. And it is still unknown how safe exogenous melatonin supplements are in the absence of its deficiency.

Lignans, which are particularly abundant in flaxseeds, exert antitumor activity, presumably through mechanisms such as decreased cell proliferation and angiogenesis, and increased apoptosis by controlling estrogen metabolism and estrogen receptor and growth factor receptor signaling pathways *. Several clinical studies support the benefits of dietary intake of flaxseed and its lignans in ER/PR-positive * and HER2-positive breast cancer *.

The highest serum concentrations of the lignan metabolite (enterolactone) versus the lowest are associated with a ~ 40% relative risk reduction in overall mortality and a 42% reduction in long-term disease *. This is especially noticeable in ER-negative tumors, where the risk reduction was 73%.

These results are supported by another review where an increase in enterolactone concentration is associated with a significant reduction in the relative risk of breast cancer in postmenopausal women *. The difference in risk between the group with the highest and lowest concentration of enterolactone was 34% here.

Premenopausal women with the highest lignan intake had a 44% lower risk of developing breast cancer compared to women with the lowest lignan intake *. Consuming flaxseed or flax bread at least weekly is associated with a reduced risk of breast cancer by 18% and 23%, respectively *.

In premenopausal women at high risk of breast cancer who consumed 50 mg of flaxseed lignan daily (~ 25 g/day of flaxseed), the cancer cell proliferation rate (Ki-67 expression) decreased by an average of 2-fold after 12 months of the experiment *. At the same time, favorable changes in histological parameters were observed.

Postmenopausal women consuming 2 tablespoons (15 g) of ground flaxseed daily for 7 weeks increased serum 2-hydroxyestrone (2-OH-E1) levels and 2:16α-hydroxyestrone ratio by 1.5 times *, significantly reducing the risk of cancer.

In a classic clinical study, a 25 gram flaxseed bakery taken for a month showed a significant reduction in tumor growth and a change in tumor biological markers in patients with newly diagnosed postmenopausal breast cancer *. Compared with the placebo group, cancer cell death increased by 30%, their malignancy index (Ki-67) decreased by 34%, and HER2 expression by 71%.

Postmenopausal women with breast cancer who consumed the most lignans (≥ 318 μg/day) were twice as likely to survive as women who consumed the least (≤ 155 μg/day) *.

Follow-ups of 6-10 years of breast cancer patients have shown a significant reduction in mortality rates associated with the intake of flax lignans, independent of ER status. In groups with the highest concentration of lignan metabolites in the blood, against groups with their lowest concentration, there was a decrease in all-cause mortality by 40-53%, and mortality from breast cancer by 33-70% * * * * *.

One observation found no negative effect of flaxseed on the effectiveness of aromatase inhibitors *. Another found no negative effect of lignans on the effectiveness of tamoxifen *; on the contrary, in experiments on rodents, flaxseed aggravated the sensitivity of cells to tamoxifen *. Flaxseed flour (25 g/day), like tamoxifen, significantly raises the level of endostatin in breast tissues, which suppresses angiogenesis in the tumor *. No negative effects or interactions were noted in all studies conducted.

In men, consumption of flaxseed (30 g/day) while limiting dietary fat (less than 20% of total calories) also improves biological performance in prostate neoplasia *.

The upper limit of the dosage of flaxseed will probably be 30 g/day dry weight, but not more than 50 g/day (3-4 tablespoons). With a further increase in its consumption, the risk of contamination of the body with cyanides, cadmium and other anti-nutrients increases without additional acquisition of noticeable benefits. Excessive consumption of flax can also impair intestinal permeability and disrupt blood clotting *.

Correctors of estrogen metabolism promote the transformation of estrogen into less carcinogenic metabolites.
Melatonin and celecoxib bind estrogen and convert it to sulfates. Lignans present in flaxseed, licorice, and green tea make it difficult for estrogen to be converted to the more carcinogenic 16α-OH. Black cohosh, indole-3-carbinol and ginkgo biloba contribute to the transformation of estrogen into less carcinogenic 2-OH-E2 and 4-OH-E2, and magnesium, selenium, ginger and DADS promote their further metabolism into safe conjugates. All the same flax, sulforaphane, indole-3-carbinol and DADS contribute to estrogen glucoronization. Melatonin, licorice, pomegranate, ginkgo biloba and hops inhibit the conversion of testosterone and androstenedione to estrogen.

Interactions and contraindications.

Complementary therapy is quite widely used, especially in developing countries * * * *. Current results show that complementary therapy can improve the well-being and quality of life of cancer patients * *.

Approximately half of cancer patients worldwide self-refer to complementary therapies * *, and about a third of breast cancer patients use a variety of herbal supplements and vitamins *. Approximately a third of them do not tell their physicians about their use *. However, interactions between co-administered drugs, herbs, and supplements can lead to significant effects on their activity, metabolism, or toxicity. An intervention in the therapeutic process that is not taken into account by the treatment protocol may not increase, but, on the contrary, reduce its effectiveness, especially due to the narrow therapeutic index of many anticancer drugs.

Patients taking complementary medicines in addition to chemotherapy are at least 27% at risk of developing clinically significant interactions between them *. Just like the main remedies, supplements have their own contraindications and side effects that must always be considered. To check the possible therapeutic interaction between various herbs and medicines, there are special reference books *  *.

If there are safe, proven and cheap ways to reduce inflammation, normalize hormonal balance, strengthen immunity, increase the effectiveness of other therapeutic agents, that is, to achieve all that determines the success of treatment, then it would simply be unwise not to use them.

However, one should be careful so that their use does not worsen the result of the main treatment, but, on the contrary, improves it.

During surgery.

Anticoagulants. Many herbal remedies promote blood thinning and may theoretically pose a risk of increased bleeding, especially when combined with one another and/or with other anticoagulants. This:

Approximately 1-2 weeks before the scheduled date of surgery, it would be wise to stop taking the above plants in order to reduce the risk of postoperative bleeding. The resumption of their reception is possible 1-2 weeks after the operation, if there are no contraindications.

During radiation and chemotherapy.

Antioxidants. Some chemotherapeutic agents (anthracyclines, platinum compounds, and alkylating agents) exert their cytotoxic effects through the production of free radicals. Antioxidants, on the contrary, neutralize free radicals, and theoretically should dampen the therapeutic effect of these drugs. However, reviews of studies show mixed results that suggest the possibility of reducing drug toxicity but do not affect patient survival rates *.

Many studies that have used low doses of antioxidants after chemotherapy show that they can reduce toxicity and prolong survival *. At the same time, in extremely high doses, some antioxidants act in conjunction with free radicals, which can be used during the course of therapy.

The complex role of antioxidants in cancer and possible reasons for the conflicting research results have been discussed earlier in «Corrective Supplements» †.

Enzyme activity modulators. Cytochrome P450 (CYP) enzymes metabolize almost half of all therapeutic and biologically active substances used. An increase in CYP activity can accelerate the elimination of drugs from the body and, as a result, reduce the effectiveness of antitumor chemotherapy *. Conversely, CYP suppression may increase their concentration and, as a result, increase the risk of toxicity of chemotherapeutic agents such as etoposide, paclitaxel, vinblastine and vincristine.

On the other hand, some drugs, such as tamoxifen, are metabolized to their active form by CYP2D6 and CYP3A4 isoenzymes *. Their inhibition will inevitably reduce the effectiveness of chemotherapy.

The two best-known examples of negative combinations with chemotherapy drugs are St. John's wort (Hypericum perforatum) and Grapefruit (Citrus spp.). The first of them is a strong activator, and the second is a strong inhibitor of the CYP3A4 enzyme. Thus, St. John's wort is able to significantly reduce the level of administered chemotherapy drugs, bringing their concentration beyond the therapeutic range. Conversely, grapefruit is able to hold excessively high concentrations of them, creating a high overall toxicity. Other herbal supplements have been reported to be able to suppress P450 activity or expression with varying degrees of strength *:

Reports of herbal supplements able to increase the expression of P450 enzymes with varying degrees of strength:

Although, with a few exceptions, the impact of these supplements remains weak *, it makes sense to limit or eliminate their use during chemotherapy. The following are examples of the involvement of metabolizing enzymes in the metabolism of chemotherapy drugs *:
CYP1A1, CYP1A2 – dacarbazine,
CYP2A6 – cyclophosphamide, ifosfamide, tegafur,
CYP2B6, CYP2C9 – cyclophosphamide, ifosfamide,
CYP2C8 – cyclophosphamide, ifosfamide, paclitaxel,
CYP2C19 – teniposide,
CYP2D6 – tamoxifen, doxorubicin, vinblastine,
CYP2E1 – dacarbazine,
CYP3A4 – teniposide, etoposide, epipodophyllotoxin, cyclophosphamide, ifosfamide, vindesine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, irinotecan, tamoxifen, tipifarnib, gefitinib, imatinib,
CYP3A5 is etoposide, tipifarnib.

Modulators of the activity of membrane transporters. Supplements and food components can not only influence the activity of enzymes that metabolize drugs, but also affect the activity of cellular pumps that actively pump out toxic substances from the cell * *.

Of particular importance is the MDR1 transporter (Multidrug-resistant transporter 1), also known as P-glycoprotein, which removes more than half of all toxins and drugs. But others are equally important, such as MRP1,2 (multiple drug resistance proteins), MXR (breast cancer resistance protein) and others. Suppression of these cellular pumps will increase the toxicity of the drugs used. And their activation, on the contrary, weakens the damage to cancer cells.

Cell transporter inhibitors:

Metformin reduces the production of ATP, and at the same time the activity of MDR1, since the operation of this membrane pump requires energy expenditure. Resveratrol enhances the cytotoxicity of docetaxel and doxorubicin by blocking their efflux through ABCB1 and reducing its gene expression *. Ginkgo may inhibit the metabolism of paclitaxel (in vitro) *. Curcumin, at a non-toxic concentration, sensitizes MXR-expressing cells to mitoxantrone, topotecan, and doxorubicin *.

Hepatotoxic effects in patients receiving imatinib may be caused by: Oleander (Nerium oleander) * and Ginseng (Panax ginseng) *.

Potential hepatoxicity in humans has also been reported for:

An increase in the antitumor effect in the form of an increase in cell death was observed with a combination of:
- Flaxseed (Linum usitatissimum) with trastuzumab in HER2 breast cancer cell line * *;
- Ginseng (Panax ginseng) with paclitaxel for multidrug-resistant breast cancer cells *;
- Milk thistle (Silybum marianum) with doxorubicin, in an ER+ breast cancer cell line *, and with cisplatin and carboplatin in an ER+ and TNBC breast cancer cell line *;
- red beet (Beta vulgaris) extract with doxorubicin in ER+ breast cancer cell line *;
- grape seed extract and doxorubicin, regardless of breast cancer subtype *.

An weakening of the antitumor effect was observed with a combination of:
- curcumin and etoposide in the ER+ breast cancer cell line *;
- echinacea and etoposide in lung cancer *.

Despite possible therapeutic conflicts between natural substances, they have a significant effect in no more than 10% of all cases, while in two-thirds of all casestheir combination is positive summative or synergistic *.

Next chapter