Supplements commonly used for cancer prevention and treatment

Patients with cancer commonly use antioxidants to protect the body against O₂-induced tissue damage by handling free radicals and H₂O₂. Oxidative stress occurs as part of the normal metabolism, but is also exploited as a chemotherapeutic target in, for example, treatment with anthracycline antibiotics and radiotherapy⁽Reference Labriola and Livingston¹⁰⁾. Oxidative stress may also contribute to undesirable severe side effects such as doxorubicin-induced cardiotoxicity⁽Reference Labriola and Livingston^10, Reference Pommier, Goldwasser, Strumberg, Chabner and Logo¹¹⁾. The effectiveness of antioxidants may depend on their ability universally to either prevent tissue damage or specifically to repair damage where it has occurred. It seems intuitive to assume that repairing existing tissue damage may be the harder task, requiring higher supplement doses. Also, it may be necessary to match the antioxidant properties to the oxidative mechanism that led to the particular tissue damage originally. The choice of antioxidant as well as the specific formulation of the chosen antioxidant may be important⁽Reference Drake¹²⁾. This factor may explain why the effectiveness of most antioxidants in cancer prevention has been rather limited (Table 1). Currently, Se seems to be the most promising supplement, but doubts have been raised about whether the observed anticarcinogenic effects are associated with its pro-oxidant properties rather than its antioxidant properties. Some forms of Se are able to form reactive oxygen species that may induce apoptosis⁽Reference Drake¹²⁾. For instance, Na₂SeO₄ may be a more potent reactive oxygen species donor than organic forms of Se such as selenomethionine, which seems to be more commonly used. Trials are required to compare the efficacy of both forms⁽Reference Drake¹²⁾. The concept that antioxidants can develop pro-oxidant properties under specific conditions may also potentially explain why β-carotene in combination with smoking may actually increase the mortality from lung cancer⁽Reference Virtamo, Pietinen, Huttunen, Korhonen, Malila, Virtanen, Albanes, Taylor and Albert^{13, 14)}.

Table 1. Supplements commonly used for cancer prevention and treatment

↑, Increase; ↓, decrease.

Supplements commonly used for depression

Supplements used in the treatment of depression include n-3 fatty acids, SAMe, 5-hydroxytryptophan, l-tryptophan, folic acid and Se (Table 2). As with many conventional antidepressants, the objective of using SAMe, 5-hydroxytryptophan, l-tryptophan and folic acid is to increase serotonin availability and/or activity. SAMe, n-3 fatty acids and inositol seem to influence cell-membrane composition and second-messenger systems, thereby modifying synaptic neurotransmission.

Table 2. Supplements commonly used for the treatment of depression

↑, Increase; ↓, decrease; SAMe, S-adenosylmethionine; RCT, randomised controlled trial.

l-Tryptophan is an essential amino acid that is absorbed from dietary proteins, converted to 5-hydroxytryptophan and then to 5-hydroxytryptamine, i.e. serotonin. In contrast to peripheral serotonin, both l-tryptophan and 5-hydroxytryptophan can cross the blood–brain barrier. However, only 10% of l-tryptophan is available to the serotonin pathway, whilst the rest is metabolised by an alternative pathway, so that 5-hydroxytryptophan may be more effective at increasing serotonin synthesis⁽Reference Turner and Blackwell¹⁵⁾. Clinical evidence is sparse, presumably because of the continued concerns about an association with eosinophilic myalgic syndrome (see p. 488). The available trial evidence suggests that both l-tryptophan and 5-hydroxytryptophan may be effective antidepressants⁽Reference Shaw, Turner and Del Mar¹⁶⁾.

SAMe is produced from methionine and ATP. Folic acid is a cofactor in the methylation of homocysteine to methionine⁽Reference Bottiglieri^17, Reference Morris, Fava and Jaques¹⁸⁾ and may exert its antidepressant action through the increase in SAMe. However, the exact mechanism of the antidepressant action is not clear. SAMe is a methyl donor required for the synthesis of many neurotransmitters. SAMe increases serotonin activity in human subjects and has also been shown to increase cerebral concentrations of serotonin and noradrenaline in animal experiments⁽Reference Bottiglieri¹⁷⁾. Methylation is also involved in maintaining the integrity of cell membranes, rendering them more fluid. This process may change the configuration of membrane-bound receptors and ion-channels and alter neurotransmission patterns. G protein–receptor coupling–uncoupling dysfunction, which has been implicated in the genesis of mood disorders, may be counteracted⁽Reference Bottiglieri^17, Reference Schreiber and Avissar¹⁹⁾. Interestingly, stabilisation of neuronal membranes and modulation of second messengers are also purported mechanisms of action for mood stabilisers such as Li and valproate⁽Reference Hahn, Umapathy, Wang, Koneru, Levinson and Friedman²⁰⁾. SAMe has been shown to be superior to placebo and equivalent to tricyclic antidepressants⁽Reference Bressa^21, Reference Delle Chiaie, Pancheri and Scapicchio²²⁾ and folic acid⁽Reference Taylor, Carney, Geddes and Goodwin²³⁾ as an adjunctive treatment for depression.

EPA and DHA are two n-3 fatty acids that are integral components of neuronal membranes such as synaptic, dendritic, mitochondrial and vesicle membranes⁽Reference Hallahan and Garland²⁴⁾. Thus, if there is a lack of these fatty acids the integrity of neuronal membranes and the corresponding neurotransmitter activity may be disturbed. EPA and DHA may have several mechanisms of action operating at different levels. They seem to exert their effectiveness through modification of the cell-membrane structures and influence serotonergic and dopaminergic neurotransmission, regulate corticotrophin-releasing factor and suppress phosphatidylinositol second-messenger activity⁽Reference Freeman, Hibbeln and Wisner²⁵⁾. Additionally, n-3 fatty acids have blood-thinning effects that may improve cerebral perfusion⁽Reference Freeman, Hibbeln and Wisner²⁵⁾. Current evidence suggests that EPA alone or in combination with DHA is effective as adjunctive treatment for depressive episodes, in the context of either a unipolar depression or a bipolar disorder⁽Reference Freeman, Hibbeln and Wisner²⁵⁾.

Inositol is yet another substance that has a mechanism of action that is linked to cell-membrane composition. Inositol is a component of cell-membrane phospholipids and a constituent of the intracellular phosphatidylinositol second-messenger system that is linked to serotonin, noradrenaline and cholinergic receptors⁽²⁶⁾. Disturbance of this second-messenger system has been implicated in the genesis of depression⁽Reference Dursun, Blackburn and Kutcher^27, Reference Cheng, Lumb, Polgar and Mudge²⁸⁾. It has been suggested that decreased phosphoinosite signalling may lead to depression, whereas increased signalling may lead to mania⁽Reference Taylor, Wilder, Bhagwagar and Geddes²⁹⁾. The clinical evidence supporting the use of inositol, however, remains limited⁽Reference Levine^30–Reference Eden Evins, Demopulos, Yovel, Culhane, Ogutha, Grandin, Nierenberg and Sachs³²⁾.

Se has also been implicated in the treatment of depression, but no trial has been conducted. Its antioxidant qualities may reduce nerve-cell damage. Additionally, Se is an important cofactor in the conversion of thyroxin to liothyronine. Notably, the brain receives a priority supply in the presence of Se-deprived states⁽Reference Rayman³³⁾. In animal experiments increased dopamine and serotonin turnover has been shown to be associated with low Se intake⁽Reference Castano, Ayala, Rodriguez-Gomez, Herrera, Cano and Machado³⁴⁾. Also, mood states seem to correlate with Se plasma levels⁽Reference Hawkes and Hornbostel^35, Reference Benton and Cook³⁶⁾. Whether Se supplementation is an effective treatment of depression remains unclear; a recent trial in healthy volunteers has not found any improvement of mood⁽Reference Rayman, Thompson, Warren-Perry, Galassini, Catterick, Hall, Lawrence and Bliss³⁷⁾.

Toxic effects

The therapeutic index of a supplement, i.e. the relationship between therapeutic dose and toxic dose, depends on many individual factors, including supplement formulation, water solubility, organ function and other medications taken concomitantly. This margin of safety may be particularly problematic if patients take supplements at higher than the recommended dose⁽Reference Werneke, Earl, Seydel, Horn, Crichton and Fannon⁴⁴⁾. For instance, Se has a narrow therapeutic index. The upper level of safety as recommended by the UK Food Standards Agency⁽⁴⁵⁾ is 0·45 mg total Se/d. Se supplements are usually used in strengths between 0·025 and 0·2 mg daily, leaving a narrow margin for patients who chose to take a higher than recommended dose. Calculations can be confusing for those supplements measured in more than one unit, e.g. IU, milligrams or substance equivalents. For some supplements, such as vitamin A, the Food Standards Agency has not issued a safe upper level; thus, defined adverse events such as increased risk of hip fracture and teratogenecity are used as surrogate indicators (Table 3). Usually supplements are offered in various preparations, combinations and in a wide dose range, e.g. for vitamin A from 400 μg retinol equivalents to 60 000 μg retinol equivalents (1333–200 000 IU). Furthermore, patients may combine different preparations without realising the potential of accumulation and associated risks when exceeding safety margins. It may be necessary to highlight to patients how many tablets of a chosen supplement are likely to lead to adverse events (Table 3).

Table 3. Safety margins for selected supplements

↑, Increase; RE, retinol equivalent.

* Substance equivalents.

† Heterozygous for haemochromatosis and thalassaemia or predisposition to urinary or renal stones.

A particular problem arises when high-dose vitamin C is combined with methotrexate (a chemotherapy drug). This combination may increase methotrexate toxicity and could lead to kidney damage as result of increased plasma methotrexate levels and thus methotrexate toxicity. Vitamin C acidifies urine and leads to the precipitation of methotrexate and its less-water-soluble metabolites⁽Reference Sketris, Farmer and Fraser⁴⁶⁾.

Contamination

Supplement contamination can also lead to potential health hazards. Fish oil containing n-3 fatty acids and 5-hydroxytryptophan are commonly cited examples. Some cod-liver-oil products have been reported to be contaminated with toxins and pesticides such as polychlorinated biphenyls, hexachlorobenzene, hexachlorocyclohexane isomers and chlorinated pesticides (dichlorodiphenyltrichloroethanes)⁽Reference Bays⁴⁷⁾. Even if acceptable safety levels are not exceeded, these substances may accumulate over time. Contamination with heavy metals, in particular Hg, may be a further concern if fish oils are produced from fish caught in contaminated waters. Nevertheless, the overall benefits of n-3 fatty acid supplementation are judged to exceed the potential risks⁽Reference Bays⁴⁷⁾.

l-Tryptophan and, to a lesser extent, 5-hydroxytryptophan have been associated with eosinophilic myalgic syndrome. In 1989 1500 cases of l-tryptophan-associated eosinophilic myalgic syndrome were reported, most of which could be traced back to one single manufacturer. The incidence dropped dramatically after l-tryptophan products were limited⁽⁴⁸⁾. However, the association has not been fully clarified and five potential contaminants have been identified⁽Reference Simat, Kleeberg, Muller and Sierts⁴⁹⁾.

Carcinogenesis

The finding that β-carotene, traditionally used as an antioxidant, was associated with an increased incidence of and mortality from lung cancer in smokers, ex-smokers and asbestos workers^(14, Reference Omenn, Goodman and Thornquist⁵⁰⁾ was unexpected. The mechanism of this adverse effect remains unclear, but may be related to either the pro-oxidative properties of some β-carotene cleavage products or a direct mutagenic effect⁽Reference Alija, Bresgen, Sommerburg, Siems and Eckl⁵¹⁾.

Folic acid is a basic component of cell metabolism and DNA synthesis and repair. Rapidly-dividing cancer cells have an increased requirement for folate to maintain DNA synthesis⁽Reference Kelemen⁵²⁾. Thus, supplementation with folic acid, possibly from a dose of folic acid of 800 μg/d, may potentially induce tumour-cell proliferation⁽⁵³⁾.

Obviously, any supplement contaminated with a carcinogenic substance such as some fertilizers and heavy metals may promote cancer, and patients should be advised to acquire their supplements from a reliable source at all times.

Potential reversal of efficacy of chemotherapies

Chemotherapeutic agents relying on oxidative stress include alkylating agents (e.g. cyclophosphamide, anthracycline) antibiotics (e.g. doxorubicin) and epipodophyllotoxins (e.g. etoposide). Essentially, these agents produce reactive oxygen species to target DNA, thereby arresting cell cycles and inducing apoptosis. Antioxidants may suppress free radical formation and thus compromise the ability of chemotherapeutic agents to destroy micrometastases. This outcome could translate into higher risk of recurrence⁽Reference Labriola and Livingston^10, Reference Pommier, Goldwasser, Strumberg, Chabner and Logo¹¹⁾. Antioxidants may also promote multi-drug resistance mediated through membrane transporter proteins. Equally, radiotherapy depends on irradiation-induced free radical formation. As a result, antioxidants may at least theoretically compromise radiotherapy results⁽Reference Agostinelli and Seiler^54, Reference D'Andrea⁵⁵⁾.

Folic acid, because of its crucial role in DNA metabolism, is an obvious therapeutic target for anti-tumour agents. Theoretically, folic acid supplementation may decrease the efficacy of anti-folate chemotherapies. However, folic acid may also reduce the likelihood of anti-folate-associated serious adverse effects⁽Reference Calvert⁵⁶⁾. As long as the evidence remains conflicting caution is required.

Anticoagulation leading to serious bleeding

n-3 Fatty acids have been shown to inhibit platelet function. Thus, the logical question is whether n-3 fatty acids could carry a serious bleeding risk. The available clinical evidence has not upheld such concerns, even for combinations with anticoagulants such as warfarin or aspirin⁽Reference Stoll, Severus, Freeman, Rueter, Zboyan, Diamond, Cress and Marangell^57, Reference Harris⁵⁸⁾. Thus, n-3 fatty acids are rated as generally safe. Even if the risk is low, however, it does not mean that severe bleeding events can ever be excluded in individual patients. Recently, a case of subdural haematoma in an elderly patient taking high-dose n-3 fatty acids in combination with warfarin and aspirin was reported⁽Reference McClaskey and Michalets⁵⁹⁾.

Vitamin E may antagonise vitamin K-dependent clotting factors, which could translate into an increased risk of haemorrhagic stroke⁽Reference Booth, Golly, Sacheck, Roubenoff, Dallal, Hamada and Blumberg⁶⁰⁾. Such an increased risk was reported for male smokers in the original Alpha-Tocopherol, Beta-Carotene Prevention Study⁽¹⁴⁾, although subsequently the risk has only been confirmed in the presence of hypertension⁽Reference Booth, Golly, Sacheck, Roubenoff, Dallal, Hamada and Blumberg⁶⁰⁾. A 6-year follow-up study has found that the risk of cerebral infarction is increased by 13%, but the investigators suggest that this finding could be a result of chance because no other trial has highlighted an association between vitamin E and stroke⁽Reference Tornwall, Virtamo, Korhonen, Virtanen, Albanes and Huttunen⁶¹⁾.

Serotonin syndrome and induction of mania

Serotonin syndrome is caused by an excess of serotonin in the brain. It is rare but can be potentially life-threatening in its severe form; the extent of severity seems to be dose related. The features of severe serotonin syndrome include autonomic instability, hyperthermia, agitation, hyperreflexia and seizures. Serotonin syndrome can occur when serotonergic drugs or supplements are combined with each other or with substances that facilitate a serotonergic response such as opiates and Li⁽Reference Nieuwstraten, Labiris and Holbrook⁶²⁾. All serotonergic supplements reviewed here can increase the risk of serotonin syndrome, and a case of serotonin syndrome after the ingestion of tryptophan, St John's wort (Hypericum perforatum) and another unknown substance has been reported⁽Reference Bryant and Kolodchak⁶³⁾. All serotonergic supplements may increase the risk of manic episodes in predisposed patients through increased serotonergic neurotransmission, either on their own or more likely in combination with other serotonergic drugs⁽Reference Friedel, Goa and Benfield^64–Reference Goff⁶⁹⁾.