دانلود رایگان ترجمه مقاله ترکیبات سلنیوم به عنوان عوامل دارویی در سرطان (نشریه الزویر 2014)

ترکیبات سلنیوم به عنوان عوامل دارویی در سرطان

Selenium compounds as therapeutic agents in cancer

Abstract

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 limited 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.

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 genome 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 enzymatic activity (functions of Sec in selenoproteins are discussed in detail 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 the chemotherapeutic effects of Se, the rational differs and is based on the assumption that progressed malignant cells have been found to be more sensitive to Se cytotoxicity than normal cells. Despite the fact that higher doses are required to encounter the pro-oxidative effects of Se, with the generation of oxidative stress being a requirement for a favorable outcome, the cytotoxic effects seem to appear at lower doses in malignant cells compared to benign cells. Consequently, selenium compounds have been highlighted in recent studies to have great potential as anticancer agents, particularly for the treatment of aggressive late stage neoplasias [6,7]. As tumor cells generally are more susceptible to the cytotoxic effects exhibited by selenium compounds, [7–9] at pharmacologically achievable doses, there seems to be a narrow therapeutic window for the use of selenium compounds as anticancer agents. This review aims at describing the proposed mechanisms and targets of selenium compounds and their effect in the treatment of established tumors. It will not, however, cover the largely debated chemopreventive properties of Se. This overview hopes to be a useful tool for the research community actively involved in the field of Se-based drug development and intends to shed light into their activity as chemotherapeutic agents.