Review Selenium compounds as therapeutic agents in cancer ☆ Aristi P. Fernandes a, ⁎, Valentina Gandin b a Division of Biochemistry, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, SE-171 77 Stockholm, Sweden b Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy abstract article info Article history: Received 3 September 2014 Received in revised form 6 October 2014 Accepted 8 October 2014 Available online 16 October 2014 Keywords: Selenium Cell death Chemotherapeutics Background: With cancer cells encompassing consistently higher production of reactive oxygen species (ROS) and with an induced antioxidant defense to counteract the increased basal ROS production, tumors have a lim- ited reserve capacity resulting in an increased vulnerability of some cancer cells to ROS. Based on this, oxidative stress has been recognized as a tumor-specific target for the rational design of new anticancer agents. Among redox modulating compounds, selenium compounds have gained substantial attention due to their promising chemotherapeutic potential. Scope of review: This review aims in summarizing and providing the recent developments of our understanding of the molecular mechanisms that underlie the potential anticancer effects of selenium compounds. Major conclusions: It is well established that selenium at higher doses readily can turn into a prooxidant and thereby exert its potential anticancer properties. However, the biological activity of selenium compounds and the mechanism behind these effects are highly dependent on its speciation and the specific metabolic pathways of cells and tissues. Conversely, the chemical properties and the main molecular mechanisms of the most relevant inorganic and organic selenium compounds as well as selenium-based nanoparticles must be taken into account and are discussed herein. General significance: Elucidating and deepening our mechanistic knowledge of selenium compounds will help in designing and optimizing compounds with more specific antitumor properties for possible future application of selenium compounds in the treatment of cancer. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Selenium (Se) is an essential and unique trace element that plays a crucial role in health and disease. Se exerts many cellular physiological functions mediated by its incorporation into selenoproteins, mainly in the form of selenocysteine (Sec), the 21st amino acid. The human ge- nome harbors 25 selenoprotein genes (for more comprehensive reading on selenoproteins please see ref [1] and references therein). Some of these proteins are essential enzymes that do not only integrate Se in the form of Sec, but also requires Sec in their active site for an intact en- zymatic activity (functions of Sec in selenoproteins are discussed in de- tail in the review by Arnér E.S. [2]). The antioxidant function of Se is conferred by some of these selenoproteins that directly protects against oxidative stress. Additionally, the regeneration and activation of low molecular weight antioxidants (Q10, Vitamins C and E etc.) mediated by selenoproteins, also make Se an indirect antioxidant, when provided at low nutritional levels [3]. However, at elevated doses, Se typically turns into a pro-oxidant with well-established growth inhibiting prop- erties and with high cytotoxic activities (Fig. 1). Both efficacy and toxic- ity of Se compounds are thus strictly dependent on the concentration and chemical species as well as the redox potential [4]. Inorganic and or- ganic selenium compounds metabolize differently in vivo, activating distinct molecular mechanisms responsible for the toxicity/activity profile, where the redox active forms have been shown to be far more effective [7]. However, the literature on the properties of Se and seleni- um compounds in cancer is confusing, to say the least, since it does not properly take into consideration that the distinct effects of Se strictly depend on compound, concentration and model used [5]. The main research on Se and cancer has been focused on the chemopreventive effects of selenium. This primary theory was grounded on the direct and indirect antioxidant functions of Se in non-transformed cells, which lead to a greater cellular defense against oxidative damages. At the same time, this hypothesis lays its basis on the ability of Se to “target” preneoplastic cells early in the carcinogenic process, as a cohort of evidence indicates that Se will turn into a pro-oxidant in these cells at lower concentrations than benign cells, making the preneoplastic cells more sensitive to Se supplementation. On the contrary, when exploring Biochimica et Biophysica Acta 1850 (2015) 1642–1660 ☆ This article is part of a Special Issue entitled Redox regulation of differentiation and de- differentiation. ⁎ Corresponding author at: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Tel.: +46 8 52486990. E-mail address: aristi.fernandes@ki.se (A.P. Fernandes). http://dx.doi.org/10.1016/j.bbagen.2014.10.008 0304-4165/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen