Selenium or No Selenium That Is the Question in Tumor Patients: A New Controversy

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1 Selenium or No Selenium That Is the Question in Tumor Patients: A New Controversy Integrative Cancer Therapies 9(2) The Author(s) 2010 Reprints and permission: sagepub.com/journalspermissions.nav DOI: / Ralph Muecke, MD 1, Lutz Schomburg, PhD 2, Jens Buentzel, MD 3, Klaus Kisters, MD 4, and Oliver Micke, MD 5, on behalf of the German Working Group Trace Elements and Electrolytes in Oncology AKTE Abstract The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more attention from both laypersons and expert groups. The interest of oncologists mainly focuses on the following clinical aspects: protection of normal tissues, sensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that it has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism, and protection against DNA damage. Recent clinical trials have shown the importance of selenium in clinical oncology. In 2009, a significant benefit of sodium selenite supplementation with no protection of tumor cells, which is often suspected by oncologists was shown in a prospective randomized trial in gynecologic cancer patients undergoing radiation therapy. More recently, concerns arose from 2 large clinical prevention trials (NPC, SELECT) that selenium may increase the risk of developing type 2 diabetes. Despite obvious flaws in both studies and good counterarguments, controversy remains on the possible advantages and risks of selenium in cancer prevention. However, in the light of the recent clinical trials the potential benefits of selenium supplementation in tumor patients are becoming obvious, even though further research is needed. Keywords selenium, tumor patients, radioprotection, cytoprotection, primary and secondary cancer prevention The essential trace element selenium (Se) is of fundamental importance to human health. As a constituent of the small group of selenocysteine-containing selenoproteins, Se elicits important structural and enzymatic functions. 1,2 Se deficiency has been linked to increased infection risk and adverse mood states. 3 It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism, and protection against DNA damage. These and other functions are mediated through a small number of approximately 50 different selenoproteins encoded by 25 separate genes, which require adequate Se availability for their regular biosynthesis and expression. Selenoproteins include several forms of the enzymes glutathione peroxidase (GPx), thioredoxin reductase, and iodothyronine deiodinase. 1,2 Plasma Se concentration is the most commonly used indicator of Se status. The normal level depends on the geographical region, the relative amount of selenomethionine consumed and on the personal genotype controlling selenoprotein expression. 4-6 Therefore, different methods and biomarkers are currently used in parallel to define the Se status of an individual person. 7 Nevertheless, in the majority of the published work a normal level of approximately 60 to 120 mg/l Se in plasma or serum (corresponding to approximately 1 Lippe Hospital, Lemgo, Germany 2 Charité Berlin, Berlin, Germany 3 Suedharz Hospital, Nordhausen, Germany 4 St Anna Hospital, Herne, Germany 5 Franziskus Hospital, Bielefeld, Germany Corresponding Author: Oliver Micke, Department of Radiotherapy and Radiation Oncology, Franziskus Hospital Bielefeld, Kiskerstrasse 26, D Bielefeld, Germany strahlenklinik@web.de

2 Muecke et al to 151 mg/l in whole blood) is given. Nutritional Se intake, plasma Se concentration, and GPx activity display a positive correlation up to a threshold plasma Se concentration (70 to 100 mg/l), beyond which the GPx activity plateaus. 8 This maximum GPx concentration is thought to represent repletion, and commensurate Se intake forms the basis for the recommended dietary requirement. Concentrations of other selenoproteins are also influenced by Se intake and may represent even better functional indicators of Se status, but assay methods and reference standards are at an early stage, and comparisons between different studies are difficult. There is a certain hierarchical expression of the selenoproteins, with relative preservation of the presumably more metabolically important members at lower intakes of Se. Moreover, male and female organisms differ in their regulation of selenoprotein expression and epidemiological and intervention studies correlating health effects with Se status highlighted some important differences between the sexes. 9 Thus, we are far from understanding the health implications of suboptimal expression of the selenoproteins in humans. 3,10,11 Various epidemiological and experimental studies have shown an association between low Se levels and increased cancer incidence. 3,12-17 In this context, some authors have correlated the decreased levels of Se in blood, serum, or plasma with reduced Se-dependent enzymatic antioxidant capacities in patients with malignant diseases. 15,16 The issue of whether this difference is secondary to the malignancy or represents a predisposing factor leading to higher cancer incidence is at present unresolved. Furthermore, the potential of Se as a natural anticancer agent is well documented by several clinical interventional trials. 18,19 Secondary findings from the 10-year US Nutritional Prevention of Cancer (NPC) Trial demonstrated a protective effect of supplementation with 200 mg/day of organic Se (from yeast) on total cancer incidence and mortality, 18 and on prostate cancer (relative risk 0.51 and 95% confidence interval ) with the strongest effect in men with lower baseline plasma Se levels (<123 mg/l). 20 There are numerous limitations to what was intended as a prospective study to prevent nonmelanoma skin cancer, and the relatively high baseline plasma Se levels (115.1 mg/l) make it difficult to generalize the findings. Nevertheless, the results of the NPC trial remain under discussion. 18 It appears that protection from cancer may require a Se supplementation dosage beyond correction of submaximal GPx expression potentially needed for a maximal expression of other selenoproteins, which cannot easily be measured from plasma samples. Beside the antioxidative capacity in the healthy tissue via increased biosynthesis of the different GPx and thioredoxin reductase isoenzymes, a selective unusual activation of wild-type p53 in healthy cells by Se-dependent reduction of 2 critical cysteine residues by Ref 1 might be responsible for consecutive activation of DNA-repair. 21,22 In addition, Se may reduce translocation of the inflammatory transcription factor NFkB into the nucleus and thereby reduce cytokine production and release. 23,24 Radiotherapy and chemotherapy as well as the suboptimal nutrition of cancer patients in the clinic might aggravate the situation in a Se-deficient patient even further, and increase the likelihood of radiation-induced side effects during and after therapy Preliminary experimental and clinical evidence indicate that Se might function as an effective radioprotector and chemoprotector with the ability to alleviate side effects of tumor specific chemotherapy or radiotherapy treatments In 2003, an English retrospective study indicated a positive correlation between initial serum Se levels and the dose delivery of chemotherapy and outcome in patients with aggressive non-hodgkin s lymphoma. 37 In light of the results of a follow-up experimental study the authors concluded that the Se compounds methylseleninic acid (MSA) and selenodiglutathione (SDG) induce cell death in lymphoma cell lines and primary lymphoma cultures, which may be partly attributable to the generation of reactive oxygen species. 38 A randomized study in postoperative gynecological patients with supplementation of Se under radiotherapy conditions supported these findings. In particular, the patients with higher plasma and whole blood Se levels tolerated the side effects of radiotherapy significantly better, without any obvious impairment of survival data. The aim of the study was to assess whether adjuvant supplementation with Se improves the Se status and reduces the radiation-induced side effects of patients treated by pelvic radiotherapy for cervical and uterine cancer. A total of 81 patients were randomized of whom 39 were enrolled in the Se group (SG) and 42 in the control group (CG). Plasma and whole blood Se concentrations increased in the SG and the actuarial incidence of at least grade 2 diarrhea was significantly reduced compared with the CG. The 5-year overall survival rate of patients in the SG was calculated to be 92% compared with 83% in the CG (P =.34). 39 A nonlinear association between serum Se levels and allcause and cancer mortality was published by Bleys et al 40 in 2008 based on the analysis of a representative sample of the US population with 13,887 adult participants. Increased serum Se levels were associated with decreased mortality up to concentrations of 130 mg/l. Some analyses, however, raised the concern that higher serum Se levels may be associated with increased mortality. 40 In October 2008, the abrogation of the so called Selenium and Vitamin E Cancer Prevention Trial (SELECT) was announced because of a number of reasons. In the intervention group of this prostate cancer prevention trial

3 138 Integrative Cancer Therapies 9(2) with selenomethionine supplementation, no positive effect on prostate cancer incidence was detected. 41 Moreover, a small and nonsignificant rise in the incidence of type 2 diabetes mellitus was observed. Some potential issues need to be mentioned with respect to these surprising null results when supplementation attempts in the context of oncology are discussed. First, the supplementation during the SELECT study was based on organic selenomethionine in contrast to Se-enriched yeast as used before in the aforementioned and positive NPC trial. Here, a number of yeast-specific Se-dependent compounds might have been missing, which might have contributed to the lack of chemopreventive activity observed. Moreover, selenomethionine-based supplementation trials are always very difficult to interpret, because the supplement is incorporated nonspecifically into non-selenoenzymes because of its similarity to normal sulfur-methionine. The effect of selenomethionine on the expression of selenoenzymes cannot be predicted or measured from patients blood samples. Therefore, it appears as if choosing sodium selenite as a supplement might represent a better alternative, because the effects of the supplementation can be verified by increased serum Se or circulating selenoprotein concentrations. Second, the dosage management of an adjuvant longterm Se therapy should always be done according to the measured whole blood or serum Se or selenoprotein values. The study population in the SELECT trial initially showed a baseline serum Se level of about 135 mg/l (corresponding to approximately 170 mg/l in whole blood and in accordance with published values 7 ) and after supplementation reached abnormally high serum values of approximately 250 mg/l. 41 There is currently no convincing rationale to administer Se to already well-supplied individuals. Third, it must be taken into account that diabetes risk was not a primary study endpoint, and therefore, the trial was not stratified according to the common risk factors for type 2 diabetes, for example, body mass index. Furthermore, the trial was criticized for its 2 2 factorial design, which is not optimally suited for the central study question, because there is only one arm using Se alone. Moreover, scientific data to estimate the potential interactions of the vitamin E and Se supplementation in the particular doses were largely missing. The interaction between 2 agents might be synergistic or additive, also with respect to any potential negative (ie, pro-oxidant) effects. 42 In particular, most adverse effects were observed in the study arms with vitamin E, which had only rarely been tested in human supplementation trials before, and which is not known to exhibit particular chemopreventive properties on prostate. It is thus presently being criticized for possible side effects or interactions. This lack of knowledge on vitamin E supplementation effects in prospective prostate cancer prevention studies and the potential risks of vitamin E and Se combinations were not adequately addressed before the trial and appear to be insufficiently discussed on ending it. In addition, the adverse findings on the vitamin E arms were oversimplified and extended to the Se arms without sufficiently differentiating between the 2 supplements. Similarly, it was not acknowledged that the SELECT study actually constituted 3 individual trials in parallel, in which only the control group was identical for the different study arms. Therefore, failure of the trial needs to be more intensively and cautiously specified with respect to the individual study arms, supplements and effects. Overall, the scientific evidence on which the study conceptual design for tumor prevention and the chosen study medication and dosages was based, was relatively low especially with respect to the vitamin E arms. Notably, the incidence or rate of occurrence of prostate cancer was not the primary focus or endpoint in any of the few randomized controlled trials on which the SELECT trial was based. In fact, an overall reduction of prostate cancer by 25% by a single agent appears much too optimistic. This assumption was based on the results of the lowest tertile in the NPC trial, 18 but Se levels this low were a minority in the SELECT population. So far, there is only one medication known that is able to reduce prostate cancer incidence by about one fourth, the 5-a-reductase inhibitor finasteride, which is generally used to treat benign prostate hyperplasia and androgenetic alopecia. On the other hand, this drug may cause several side effects, such as impotence and gynecomastia, and is suspected of creating an increased rate of high Gleason grade tumors. 43 Hence, it appears a bit too optimistic to expect such huge effects (25% less prostate cancers) just by taking 1 or 2 dietary supplements, given the thoughts summarized above. Of course, lowering the expected effect size to 20% or 15% would surely have increased the number of participants to be enrolled into an unaffordable magnitude. Concerning the supposed diabetic risk of Se, one must take into account that the absolute increase of diabetes is just 0.7% in the Se only group (10% diabetes in the verum group vs 9.3%, in the placebo group) and did not reach statistical significance (P =.16). In addition, the data were not adjusted to the general increase of diabetes in the United States (between 2001 and 2007 about 16%). Therefore, in our opinion this criterion is not appropriate to justify the discontinuation of the study. All in all, the SELECT trial is not adequate to prove either the ineffectiveness of Se to prevent prostate cancer, to estimate the hazard of Se to trigger diabetes, or to discredit Se for both. Whether surplus Se intake in already well-supplied individuals confers any health benefit or rather leads to an increased risk for developing type 2 diabetes mellitus is currently an issue of concern and intense discussion. 44

4 Muecke et al. 139 Finally, Se supplementation in the context of patients during radiotherapy and chemotherapy represents a shortterm focused intervention and not a chronic condition, in contrast to the SELECT trial. Therefore, especially with respect to the marginally supplied patients whose personal Se deficiency might be further aggravated during the course of the illness, Se supplementation effort with the aim to increase the Se status to optimal selenoprotein expression, that is, into the range of 100 mg/l Se in plasma or serum or above, appears advisable. This notion is in agreement with the large number of clinical studies correlating a reduced disease risk and a better recovery from disease with Se status at the beginning or during the course of illness. Thus, we strongly suggest measuring the Se status in tumor patients prior to and during therapy, and in the aftercare situation to avoid side effects and optimize the odds for a positive Se supplementation effect in the clinic. The most important lesson we learn from SELECT is that we must know many more details on the molecular and physiological mechanisms of Se action in the human body. With great interest, we have read the report by Chan et al 45 on the relationship between circulating Se levels at diagnosis and prognostic risk of prostate cancer as modified by the SOD2 genotype. They showed that SOD2 genotypes (AA, VA, and VV) alone were not and higher plasma Se levels alone were only slightly associated with increased risk of having aggressive prostate cancer at diagnosis. Among men with the SOD2 genotypes VA and VV, those with high versus low plasma Se levels had an increased risk of presenting with aggressive prostate cancer. 45 Some potential issues need to be mentioned with respect to these surprising new results when supplementation attempts in the context of oncology are discussed: Disregarding the patients with the VV variant of SOD2 (n = 107, 21.9%) with the highest risk of having aggressive prostate cancer at diagnosis with high versus low plasma Se levels, there is, with respect to the data of Chan et al, 45 for the other patients (n = 382, 78.1%) an increased risk only in the quintile groups IV and V with plasma Se levels higher than and mg/l, respectively. The results concerning the patients group with the VV variant of SOD2 indicate the existence of high-risk subgroups. These new findings require further confirmation. Both the results of the SELECT trial and the data of Chan et al 45 give us important information and thus confirm the results of Bleys et al. 40 Although first indications of additional factors are known, that is, different genotypes of enzymes, it seems most important to achieve and maintain a certain range of Se in the plasma. This range is most likely between 110 and 130 mg/l. For humans who are supplemented with Se sufficiently through their nutrition and thus are within the required range additional Se supplementation is not necessary; it might even be dangerous. There is currently no convincing rationale to administer Se to already well-supplied individuals. Even though there is no general recommendation in favor of or against Se supplementation in cancer patients, 46 the attempts to correct a proven suboptimal Se status prior to treatment appear justified. Therefore, we strongly advocate that physicians first determine the Se status of their patients and then take the necessary measures to improve the Se status of tumor patients under oncological therapy and in aftercare situations when Se status appears suboptimal. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article. Funding The author(s) received no financial support for the research and/or authorship of this article. References 1. Papp LV, Lu J, Holmgren A, Khanna KK. From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid Redox Signal. 2007;9: Schomburg L, Koehrle J. Selenium: benefits and risks. MMW Fortschr Med. 2007;149: Rayman MP. The importance of selenium to human health. Lancet. 2000;356: Johnson CC, Fordyce FM, Rayman MP. 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