A free radical may be any substance, a molecule, atom or ion, which has one or more free electrons in its outer orbit. The pairing of electrons between different atoms and molecules forms a strong covalent bond. A radical is highly reactive to surrounding substances as it seeks to form a covalent bond with them. A free radical may bond to another free radical and form a stable molecule or it may bond to another stable molecule by taking away an atom of its (most often a hydrogen atom), thus converting it into a new free radical. In this way a chain reaction may be triggered that ends when all free radicals have formed covalent bonds with surrounding substances.
The most common free radicals in cells are reactive oxygen species (ROS). Examples of these are: hydroxyl radical (HO-), superoxide radical (O2-), hydrogen peroxide (H2O2-), nitric oxide (NO-), peroxynitrite (NO3-), etc. They may be formed both by endogenous cell biological processes that use oxygen (mitochondria, peroxisomes, endoplasmic reticulum, phagocytic cells, etc.) and from exogenous sources (pollution, alcohol, tobacco smoke, heavy metals, transition metals, industrial solvents, pesticides, chemotherapy, radiation therapy and radiation). Free radicals may react with various important cell structures such as DNA, membrane lipids, proteins and other biomolecules, thereby increasing oxidative stress in the cell and putting a strain on its normal function.(1)
An antioxidant is any molecule that may be an electron donor without becoming a free radical and thus it breaks the chain reaction of new free radical formation. According to where they derive from, antioxidants are classified into 2 types:
1. Endogenous antioxidants – enzymes and metabolites:
Vitamins, micronutrients and macronutrients, amino acids, carotenoids, saponins and fatty acids are most effectively absorbed in the small intestine (3)(4), while the large molecules of polyphenols (flavonoids, phenolic acids polyphenolic amides, etc.) remain most concentrated in the lumen of the gastrointestinal tract, where their metabolism by gut microbiome occurs. Their metabolites cover the gastrointestinal mucosa where they are simultaneously absorbed and exert a protective anti-inflammatory effect on it.(5)
Polyphenols (derived from the Greek word polos meaning many) are a large family of naturally occurring organic molecules characterized by multiple phenolic groups. They are found abundantly in plants and are structurally diverse (Figure 1 and 2).
Chemical structure of garlic and raspberry polyphenols:
The polyphenol family includes flavonoids, tannins, phenolic acids, polyphenolic amides, lignans, stilbenes, etc.
Increased consumption of polyphenols reduces inflammation in the gastrointestinal tract, increases the diversity of gut microbiome and is associated with a lower risk of developing cancer.(6)(7)
Green tea is made from the leaves of the Camellia sinensis plant and is one of the most popular beverages in the world, especially in Asia. Green tea is known to have beneficial health effects. Green tea contains the polyphenols epicatechin (EC), epigallocatechin (EG), epicatechin-3-gallate (ECG) and epigallocatechin-3-gallate (EGCG), etc. Of all polyphenols, EGCG has shown the strongest antioxidant properties.(7) Animal studies show that intake of green tea polyphenols during chemotherapy results in decreased liver enzyme levels and decreased hepatic steatosis, decreased gastrointestinal inflammatory infiltrate, decreased kidney nephron damage and decreased leukoneutropenia compared to chemotherapy alone.(8) Additional studies show that EGCG’s antioxidant abilities may have a cardioprotective role during antitumor treatments.(9) Data from a clinical study published in ESMO show no cross-reactions of EGCG with Tamoxifen hormone therapy in breast cancer patients.(13)
Oral intake of green tea polyphenol in humans reaches peak plasma concentration of EGCG after 1.6 hours and its half-life is 3.6 hours.(10) Intake of up to 700 mg a day is considered a safe daily dose of EGCG.(11) Side effects such as drowsiness, dizziness, gastrointestinal symptoms, hypoglycemia and hepatotoxicity have been described with intake of very high doses.(12)
Possible drug cross-reactions of EGCG:
Saffron is a spice derived from the flower of Crocus sativus, also known as saffron crocus. Crocus sativus fibers contain anthocyanin, carotenoids, the pigment zeaxanthin and the vitamins riboflavin and thiamine. The main carotenoid derivatives found in saffron are crocin, crocetin and safranal. Of all carotenoids, crocin is considered the most active ingredient of saffron. Data from a double-blind placebo-controlled study conducted show that crocin is highly effective in alleviating symptoms of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients on antitumor therapy.(16) Data from a meta-analysis demonstrate high effectiveness of saffron intake in the treatment of mild to moderate depressive symptoms compared to placebo and equivalent effectiveness compared to some synthetic antidepressants.(17) Multiple antioxidant, anti-inflammatory, hepatoprotective and gastroprotective properties have been described that may also be helpful in the recovery of the body from toxicities associated with standard antitumor therapies.(18)
Saffron intake is safe in doses of up to 100 mg a day for up to 26 weeks. Carotenoids are rapidly absorbed and detected in plasma within one hour of administration. The time to peak plasma concentration is 4.0 to 4.8 hours and their half-life is 6.1 to 7.5 hours.(19) Some common adverse reactions associated with increased saffron intake include drowsiness, gastrointestinal problems, nausea and vomiting. Allergic reactions are also possible. High doses of 5 grams or more for a prolonged period of time may cause poisoning and doses of 12 to 20 grams may be lethal.(20)
Possible drug cross-reactions of saffron extract:
Intake of saffron extract may potentiate the effect of antihypertensives, antidiabetics and sedatives.(21)
Chinese rose, Hibiscus (Hibiscus sabdariffa) is known as the Rose of the Tropics. This rose species is a herbaceous, deciduous and evergreen perennial shrub or tree and abounds in subtropical and tropical areas where it is often grown as an ornamental plant. Hibiscus extract contains multiple polyphenols, which demonstrate plenty of healing properties. Data from human prospective studies show that intake of Hibiscus extract polyphenols is associated with increased red blood cell, granulocyte and hemoglobin laboratory levels.(22) An increased serum antioxidant potential and reduced oxidative stress have been observed.(23) A double-blind placebo-controlled study showed that intake of Hibiscus extract in combination with amino acids statistically significantly reduced xerostomia (dry mouth).(24) Another double-blind placebo-controlled study demonstrated the anti-inflammatory and renoprotective properties of Hibiscus extract by reducing CRP, urea and creatinine laboratory levels and decreasing protein loss in urine in patients with chronic kidney disease.(25)
High doses of 3 g/d of dry Hibiscus leaf extract have been used for 4 weeks in various clinical studies with no evidence of unacceptable toxicity.(26) Peak plasma concentration is reached in 1.5 hours and the half-life of the anthocyanins in the extract is 2.6 hours.(27) Side effects are rare and usually associated with overdose as gastrointestinal disorders, gas and constipation have been mainly described.
Possible drug cross-reactions of Hibiscus extract:
Hibiscus extract may potentiate the effect of antihypertensives and antidiabetics.(28)
Ginger (Zingiber officinale) is one of the most widely used products consumed as a spice and drug to treat nausea, dysentery, heartburn, flatulence, diarrhea, loss of appetite, infections, cough and bronchitis.(29) Gingerols, shogaols and paradols are the three main active components in ginger. Gingerols accumulate in the gastrointestinal tract and have an effect on the gastrointestinal system through their anti-inflammatory properties by stimulating gastric emptying and reducing nausea and vomiting.(30) According to various in vitro and animal studies ginger has proven antibacterial, antiviral, antioxidant and tumor-preventive properties.(31) New evidence is continuously emerging on the role of the extract and its metabolites in the prevention of various gastrointestinal tumors.(32) Chemotherapy-induced nausea and vomiting (CINV) is one of the most common complications during the active treatment phase of cancer patients. Data from a phase 2 double-blind placebo-controlled study show high effectiveness of intake of 6-gingerol in CINV prevention and management.(33)
Intake of ginger extract is considered harmless and safe in doses of 500 mg to 3 g a day for 3 to 4 months. Peak plasma concentration of gingerol is reached in 0.45 to 1.2 hours and the half-life of the drug is 1.8 to 2 hours.(34) At higher doses (>5 g/d) and longer intake side effects such as heartburn, diarrhea, upper dyspeptic symptoms and discomfort have been described.(35)
Possible drug cross-reactions of ginger extract:
Ginger extract may potentiate the action of anticoagulants (Warfarin, Nifedipine, Phenprocoumon) and may increase the effect of Losartan.(36)
Ginseng is perhaps one of the most widely used herbs in traditional Chinese medicine. There are two main types of ginseng: Asian (Chinese or Korean) ginseng called Panax ginseng and American ginseng, Panax Quinquefolius. Ginseng is traditionally used to improve immune system function, increase attention, reduce fatigue, improve appetite, improve physical activity and endurance, correct anemia, regulate glucose levels, improve digestion and reduce stress. The effect of ginseng extract has been studied in a number of cancer-related studies. Data from a meta-analysis show that intake of ginseng is associated with a significantly lower risk of cancer incidence.(37) Cancer-related fatigue (CRF) is a common complaint in patients. Patients describe weakness, exhaustion and infirmity cumulatively caused by the toxic effects of therapies and the progression of the underlying disease. A number of publications, including a double-blind placebo-controlled study conducted at Mayo Clinic, show that intake of high doses of ginseng extract during active chemotherapy statistically significantly improves cancer-related fatigue (CRF) and quality of life (QoL), respectively.(38) Another clinical study that assessed the safety of intake of high-dose (750 to 2,000 mg/d) ginseng during CT for 8 weeks versus placebo showed equal number of adverse drug reactions reported in both arms, which demonstrated the good safety profile of taking the extract during antitumor treatment.(39) Data from other double-blind placebo-controlled studies show that ginseng intake may improve immune function and white blood cell lineage laboratory parameters (40), promote normal function and diversity of gut microbiome (41), reduce cardiac toxicity associated with chemotherapeutic infusion of Doxorubicin (42), reduce liver dysfunction (43), reduce mental strain and fatigue (44) and in combination with Omega-3 fatty acids it has been even shown to contribute to improvement in concentration in attention deficit children (45).
Intake of 200 mg to 3 g/day of ginseng extract is considered safe within 12 to 16 weeks. After oral intake peak plasma concentration of the active ingredients of ginseng is reached between 0.7 and 4 h and their half-life is up to 22 h.(46)
Possible drug cross-reactions of ginseng extract:
Ginseng intake may potentiate the effect of some antidiabetics, antihypertensives and anticoagulants. When used concomitantly the extract may increase the effects and toxicities of Metronidazole (Flagyl).(47)
Vitamin D3 is a fat-soluble vitamin that is required for normal bone development. It is involved in the homeostasis of calcium, magnesium and phosphorus, is required for normal immune system function, reduces inflammation, is involved in glucose metabolism and cell proliferation, differentiation and apoptosis signaling.(48) Vitamin D3 deficiency may lead to a number of problems, most notably rickets in children and osteoporosis in adults. In Europe between 30 and 60% of the population suffers from low serum Vitamin D3 levels (49). There are many studies showing an association between Vitamin D3 deficiency and cancer (50), cardiovascular diseases, diabetes, development of autoimmune disease (51) and depression (52). A double-blind placebo-controlled study demonstrated that concomitant supplementation of protein, Vitamin D and Vitamin E in older patients with sarcopenia (muscle wasting) statistically significantly improved muscle strength, increased muscle volume and improved quality of life.(53) Another study associated concomitant intake of Vitamin D and probiotics with reduction of inflammation, oxidative stress and improvement in mental health.(54) During symptomatic and palliative care of cancer patients Vitamin D supplementation has been shown to improve symptoms of fatigue and reduce the need to increase opioid analgesic doses.(55) Data from a large prospective placebo-controlled study conducted in the United States show that Vitamin D supplementation in healthy individuals without deficiency may reduce high-risk cancer incidence.(56) Vitamin D3 has an important role in bone loss prevention and musculoskeletal pain management during hormone therapy with aromatase inhibitors as well.(57)
Chemotherapy is known to induce stress in the body, which leads to a decrease in Vitamin D levels and thus significantly increases the risk of Vitamin D deficiency, respectively.(58)
Vitamin D is fat-soluble and has a long half-life of 2 months. Most people do not experience side effects during Vitamin D3 supplementation unless taking too high doses (over 4,000 IU or 100 mcg a day). Some side effects associated with overdose include weakness, dry mouth, nausea, vomiting, hypercalcemia, cardiovascular symptoms, etc.(59)
Possible drug cross-reactions of Vitamin D
Concomitant use of Vitamin D3 with Calcipotriene, Digoxin and Verapamil is likely to increase their side effects and is also likely to decrease the effect of Diltiazem (60).
Vitamin C (ascorbic acid) is an important nutrient needed by the body for collagen synthesis and the formation of blood vessels, cartilage, muscles, bones, etc. Vitamin C with its anti-inflammatory properties is involved in all stages of tissue repair and regeneration process.
Vitamin C is a strong antioxidant that protects cells against oxidative stress induced by external factors such as tobacco smoke, solar radiation, X-rays and, in the context of cancer patients, systemic antitumor therapies and radiation therapy. Vitamin C also helps the body absorb and store iron in iron storage pools. Since the body does not produce Vitamin C itself, it is obtained only through diet. Citrus fruits, berries, potatoes, tomatoes, peppers, cabbage, Brussels sprouts, broccoli, spinach, etc. are high in ascorbic acid.(61)
Vitamin C supplementation has been shown to improve immune system function (62), stimulate T lymphocyte and B lymphocyte proliferation and reduce hypersensitivity reactions (63).
It has been shown that chronic oxidative stress may cause neuropsychological disorders such as anxiety, stress, depression, fatigue and mood changes in humans.(64) Data from double-blind placebo-controlled studies show that Vitamin C deficiency is associated with increased mental fatigue and its supplementation is associated with a significant reduction in the sense of anxiety (65), the sense of fatigue (66), improved work motivation, improved attention focus and better completion of cognitive tasks requiring continuous concentration (67). Short-term antioxidant supplementation with Vitamin E and Vitamin C has been shown to reduce xerostomia (dry mouth) in head and neck cancer patients after radiation therapy administered.(68) A large double-blind placebo-controlled study showed an association between antioxidant deficiency and increased cancer incidence and mortality in healthy people.(69)
Vitamin C is a water-soluble compound that is readily absorbable in the gastrointestinal tract but is also rapidly eliminated from the body through the kidneys. The average half-life of ascorbic acid in an adult individual is about 10 to 20 days. An average person maintains 1.2 to 2.0 grams of Vitamin C in the body, the supply of which has to be supplemented continuously through diet or supplementation. Intake of 140 mg/d of Vitamin C is sufficient to replenish the body’s stores in healthy people.(70)
Intake of more than 2,000 mg for a prolonged period of time may cause kidney stones, diarrhea, stomach cramps, nausea, heartburn and headache.
Possible drug cross-reactions of Vitamin С
Vitamin C supplementation beyond physiological doses may reduce the effectiveness of Fluphenazine, Warfarin, Indinavir, Levothyroxine, Aspirin, etc.(71)
Vitamin A (retinol, retinoic acid) is a fat-soluble vitamin and micronutrient important for vision, cell growth and division and immune function. Vitamin A has antioxidant properties, helps form and maintain healthy dental status, skeleton and soft tissues, gastrointestinal and respiratory mucosa and skin. Foods high in Vitamin A are spinach, potatoes, carrots, pumpkin, corn, mango, papaya, liver, eggs and milk.(79)
Retinol is the main circulating form of Vitamin A in the blood. Retinol is secreted into blood plasma from the storage pools of the liver, which homeostatically controls its levels according to the body’s demands.
Vitamin A deficiency may be caused by malnutrition or continued intake of foods poor in Vitamin A.(80) Chemotherapy has also been shown to induce deficiencies of multiple vitamins such as Vitamin A, Vitamin C, Vitamin D, etc.(81)
Vitamin A supplementation in double-blind studies has been associated with reduction and treatment of oral mucositis (82), reduction of high-risk precancerous conditions such as oral leukoplakia (83) and prolongation of recurrence intervals in patients with repeatedly recurrent noninvasive bladder cancer (84).
The recommended daily intake of Vitamin A is 700 to 900 mcg/d. Intake of high doses of 3 to 10 mg/d of Vitamin A (Retinol) for a prolonged period of time has been associated with side effects such as bone thinning, liver impairment, headaches, diarrhea, nausea, itching, joint and bone pain, etc.(85)
Possible drug cross-reactions of Vitamin А
Concomitant intake of high doses of Vitamin A with Tetracycline antibiotics may increase intracranial pressure and concomitant intake with Warfarin may increase the risk of bleeding.(86)
Zinc is a micronutrient essential for normal immune system function, wound healing, blood clotting, thyroid function, senses of taste and smell, etc. Necessary for over 100 enzyme systems, zinc plays an important role in cell biosynthesis for DNA formation, the growth and division process, protein production, etc. Zinc stores are obtained in the body through diet as red meat, seafood, legumes, seeds, nuts, dairy products, etc. are good sources of this element (87).
Malnutrition, intake of foods poor in this element, the presence of cancer and administration of antitumor therapy are known to be associated with multiple deficiencies, one of which is zinc deficiency.(88)
Double-blind placebo-controlled studies demonstrate that zinc supplementation is associated with reduction in oxidative stress and inflammatory marker laboratory levels, increase in plasma antioxidant capacity (89), improvement in sleep quality (90), support in overcoming infections (91), reduction in liver enzyme laboratory levels (92), improvement in quality of life and sense of fatigue during chemotherapy in colorectal cancer patients (93) and in combination with Vitamin A, C, B6 and E demonstrates preventive properties for reduction of recurrence in patients with non-muscle invasive bladder cancer after tumor resection performed and intravesical BCG therapy administered (94).
The recommended daily intake of zinc is between 8 and 11 mg. Intake of doses higher than 40 mg/d may cause side effects such as flatulence, diarrhea, headache, nausea and vomiting, etc.
Possible drug cross-reactions of Zinc
Intake of high doses of zinc together with Tetracycline antibiotics and Penicillamine may reduce their effectiveness. Thiazide diuretics may increase zinc loss in urine.(95)
Vitamin E is a fat-soluble vitamin that has several different forms with alpha-tocopherol being its main form that is important to the human body. Alpha-tocopherol is required for normal immune system function (96), helps fight infections, reduces inflammation and blood clot formation. Vitamin E is readily available from a variety of foods and supplements, therefore, deficiency is rare. People with gastrointestinal disorders that do not properly absorb fats (e.g. pancreatitis, cystic fibrosis, gluten intolerance) may develop Vitamin E deficiency.(97) Similar conditions may develop during treatment with chemotherapy drugs.(98) Data from clinical studies published in Annals of Oncology show that intake of Vitamin E is associated with protective effects against Cisplatin-induced peripheral neuropathy, ototoxicity, hepatotoxicity and nephrotoxicity.(99) Data from in vitro experiments demonstrate that the antioxidant activity of Vitamin E does not reduce the effectiveness of chemotherapeutics.(100) A large double-blind placebo-controlled study demonstrated potential preventive qualities of Vitamin E for reduction of colorectal cancer incidence.(101) Data from analyses performed demonstrate a potential synergistic effect between Vitamin E and antitumor immunotherapies used in the treatment of cancer patients.(102)
Vitamin E (alpha-tocopherol) supplementation is considered safe in most people when used in doses lower than 1,000 mg a day or 1,100 IU. The risk of side effects increases with intake of higher doses. These may include nausea, fatigue, headache and bleeding.(103) Peak plasma concentration of tocopherol is reached by the 4th hour after oral intake and the half-life of this vitamin is 20 hours.(104)
Possible drug cross-reactions of Vitamin Е
Intake of high doses of Vitamin E may potentiate the effects of anticoagulants and antiaggregants, statins and Cyclosporine. The recommended daily intake of Vitamin E in adults is 15 mg. Higher dose supplementation may be used to treat deficiencies (105).
Selenium is an important micronutrient that is required for the function of glutathione peroxidase, a cellular antioxidant enzyme that catalyzes the conversion of hydrogen peroxide to water and oxygen and peroxide radicals to alcohol and oxygen.(106) Selenium plays an important role in thyroid function, immune system function, antioxidant activity and detoxification of the body.(107) It is obtained through consumption of whole grains, meat, seafood, poultry and nuts. Selenium level in the body may be decreased due to cancer and/or antitumor therapy (108).
Selenium demonstrates unique in vitro qualities to synergistically promote the effect of antitumor drugs on cancer cells while having a protective effect on normal tissue.(109) Double-blind placebo-controlled studies show contribution of selenium supplementation to reduction of hair loss, abdominal pain and loss of appetite in ovarian cancer patients during chemotherapy (110) and significantly lower hematological toxicity in cervical cancer women during combination radiation chemotherapy (111). Data from a clinical study show that this micronutrient may reduce postradiation lymphedema in head and neck cancer patients.(112) Another study associated selenium supplementation in combination with zinc and proteins with improvement in malnutrition and immune function in cancer patients during chemotherapy.(113)
The recommended daily intake of selenium is 50 to 100 micrograms. Selenium supplementation at doses exceeding 300 micrograms a day for 5 years has shown an increase in 10-year mortality versus placebo and should, therefore, be avoided. Supplementation at lower doses (100 to 200 mcg/d) for 5 years has NOT shown an increase in long-term mortality versus placebo, therefore, supplementation at these doses for a prolonged period of time is considered safe (114).
Selenium supplementation at doses exceeding 400 mcg/d may cause gastric discomfort, headache and rash. High selenium doses may cause hair loss, fatigue, nausea, vomiting and weight loss. Extremely high doses (overdose) may lead to organ failure and death.
Possible drug cross-reactions of selenium
Intake of high doses of selenium may potentiate the effect of anticoagulants, antiaggregants and sedatives. It may reduce the effect of immunosuppressants.(115)
