Oxidative medicine and cellular longevity
Diphenyl ditelluride: redox-modulating and anti-proliferative properties
Cristiano Trindade1#, André Luiz Mendes Juchem2#, Temenouga N. Guecheva3, Iuri M. de Oliveira2, Priscila dos Santos Silveira2, José Eduardo Vargas4, Renato Puga5, Claudia Ó Pessoa6and João A. P. Henriques2",7
1 –Facultad de Ciências Básicas y Biomédicas, Universidad Simón Bolívar, Barranquilla, Colombia.
2 – Departamento de Biofísica/Centro de Biotecnologia, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
3 – Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia, Porto Alegre, Brazil.
4 – Instituto de Ciências Biológicas (ICB) - Universidade de Passo Fundo, Passo Fundo, Brazil.
5 –ClinicalResearch Center, Hospital Israelita Albert Einstein (HIAE), São Paulo, Brazil
6 – Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, Brazil.
7 – Laboratório de Cultura de Células, Programa de Pós-graduação em Biotecnologia, Universidade do Vale do Taquari, Lajeado, Brazil.
#Contributed equally.
*To whom correspondence should be addressed. João AntonioPêgas Henriques, Departamento de Biofísica - Prédio 43431 - Laboratório 11, Campus do Vale – Universidade Federal do Rio Grande do Sul, Avenida Bento Gonçalves 9500, Bairro Agronomia–CEP 91501–970, Porto Alegre, RS, Brazil. Tel: +55 51 33087600; Fax: +55 51 33167003;
Email: [email protected]
Abstract: Tellurium is a rare element thathas been regarded as a toxic, non-essential element, and its biological role is not clearly established. In addition, biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and pro-oxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties.In addition, DPDT may exert its effects through different pathways, includingdistinct ones to those responsible forchemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion and structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to presentrecent advances in our understanding of thebiological effects",therapeutic potential, and safety of DPDT treatment. Moreover",original results demonstratingthe cytotoxic effects of DPDT in different mammalian cell lines and system biology analysisareincluded, andemerging approaches for possible future applications are inferred.
Keywords: diphenyl ditelluride; organochalcogens; antiproliferative properties
1. Introduction
Tellurium (Te) is a stable and solid element that belongs to chalcogens (group 16 in the periodic table), which is the same group that includessulfur, selenium, and polonium. It was discovered by Franz Joseph Müller von Reichensteinin 1782, 35 years before thelighter",closelyrelated metalloid",selenium, was discovered[1].Te is classified as a metalloid because of its features between metals and non-metals[2]. In contrast to oxygen, sulfur, and selenium, Te has no essential physiological role in mammalian cell biology [3]",though anumber of studies have shown that trace amounts of Te are present in body fluids, such as blood and urine [1]. Moreover, Teis present as tellurocysteine and telluromethionine in several proteins in bacteria, yeast, and fungi; however, until now, no Te-containing proteins have been identified in animal cells [4].In a comprehensive review of the biological activities of Te compounds, it was pointed out that Te could be facing the same discrimination as selenium once did and that the natural biological functions ofTe may be revealed in the future[5].
Current industrial applications ofinorganic Teinclude its uses in the vulcanization of rubber, in metal oxidizing solutions (to blacken or tarnish metals), and in nanoparticulate semiconductors[6, 7].Moreover, the use of organic Te compounds is tending to increase owing to their importance as catalysts in inorganic and organic synthesisas stabilizers for polymers, as components of insecticides and phase-change optical magnetic disks, and as compounds used in the photography industry[6, 8].In addition, Te has been used in the composition of quantum dots in thermoelectric materials, in digital versatile disk-random access memory, and in DVD-recordable disks[9].
The risk of occupational and environmental human exposure to Te may be implied because of its increased use[10]. The presence of Te in different types of electronic materials and nanomaterials is an important health issue. Moreover, these materials usually contain numerous toxic elements",explaining whyresearch onthe environmental and occupational toxicity of thesematerialshas been widely conducted[11-14]. The mainpoint offocus on the biologicaleffects of Tehas been its toxicitybecause it is a non-essential and harmful metalloid, though few studies examining the toxicity of its ionic forms havebeen conducted[15, 16]. After its release into the environment, Te can be biomethylated to more volatile intermediates and, consequently, can be mobilized from soil or from aquatic bodies into the atmosphere [11, 17]. Consequently, the presence of Te in the environment is expected to increase in the next years or decades.
Synthetic organotellurium (OT) compounds have found limited use in the past, but they have become a promising and advantageous alternative for numerous applications, as evidenced by the increase in reports on OT chemistry in the literature [18, 19]. In the last few decades, evidence has emerged that OT molecules are promising pharmacological agents. Several reports have been published demonstrating theimmunomodulatory, antioxidant, antiproliferative, and anti-inflammatory properties of OT compounds [18-20].
In the present review, we emphasizethe biological activities of an OT compound, diphenyl ditelluride (DPDT) (Figure 1)",aiming to argue and discuss its contrasting effects as an antioxidant [21], cytotoxic [22], and antiproliferative agent [20, 23].
[image: ]
Figure 1.Chemical structure of diphenyl ditelluride
2. Antioxidant and chemopreventive effects
The antioxidant effectsof certain molecules are based on their ability to retard or inhibit oxidative damage. Their antioxidant role includesblocking oxidative reactions induced by highly reactive oxidant molecules—the so-called free radicals or reactive oxygen species (ROS)—that damage other molecules. The antioxidant properties of substances such as OT compounds can protect the cell membrane and other components of the cellular structure [24-26]. OT compounds are readily oxidized from the divalent to the tetravalent state, and this property makes them attractive as scavengers of reactive oxidizing agents such as hydrogen peroxide, hypochlorite, and peroxyl radicals, and as inhibitors of lipid peroxidation in chemical and biological systems [19].
It is well established that oxidative stress plays an important role incancer development",andis also associated with the pathogenesis of several diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune disorders, diabetes, and cancer [27]. Using mammalian models, researchers have studied the molecular basis of ROS generation andits cellular effects, as well as the efficacy of various antioxidants in attenuatingROS-induced cellular damage [28]. The potential for OT compounds to offer efficient treatment for diseases associated with oxidative stress has been of interest to several research groups [19, 29, 30]. The ROS scavenging activities and glutathione peroxidase mimetic properties of the organochalcogens likely accounts for their efficacy in attenuating oxidative stress in both in vitro studies and in vivo rodent models [25, 31, 32].
In vitro studies comparing the antioxidant properties of organochalcogenide compounds (such as diphenyldiselenide (PhSe)2, diphenylditelluride (PhTe)2, diphenyl disulfide (PhS)2, p-Cl-diphenyldiselenide (pCl-PhSe)2, bis-[S-4-isopropyl 2-phenyl oxazoline] diselenide (AA-Se)2, bis-[S-4-isopropyl 2-phenyl oxazoline] ditelluride (AA-Te)2, and bis-[S-4-isopropyl 2-phenyl oxazoline] disulfide (AA-S)2) have demonstrated that their protective effectsagainst lipid peroxidation reactionsaremediated by free radical-scavenging activities (Table 1) [24, 26, 33]. In fact, DPDT (1.63 M) inhibited lipid peroxidation (50%) in rat brain homogenates induced by quinolinic acid (QA) and sodium nitroprusside (SNP) with higher efficacy than selenides, and with similar efficacy to ebselen (a classic antioxidant) [34]. Indeed, Brito et al. (2009) showed that DPDT provided protection against 4-aminopyridine-induced neurotoxicity and oxidative stressin adult mice[35]. Moreover, it has been reported that DPDT at low concentrations (1–4 μM) significantly increased Na+/K+-ATPase activity in rat brains, suggesting that DPDT could be an antioxidant agent (Table 1) [36].
Table 1. The chemopreventive effects of diphenyl ditelluride
Model
DPDT (µM)
Effects
Inducing Agent
Ref.
Rat brain
1.63
Inhibition of thiobarbituric
reactive species (TBARS) formation by 50%
Quinolic acid (QA)
and sodium
nitroprusside (SNP)
[24]
Rat brain
150 (µmol/kg)
Neuroprotective activity
4-aminopyridine
[35]
Rat brain
1–4
Increased Na+/K+-ATPase
-
[36]
V79 cell line
0.01–0.1
Reduced cytotoxicity;reducedDNA damage, micronucleus and ROS formation
Hydrogen peroxide (H2O2), t-butyl hydroperoxide
(t-BOOH), methyl methanesulphonate (MMS) and UV-C.
[21]
V79, MRC5",
XPD cell lines
0.01–0.1
Reduced DNA damage and ROS formation
Doxorubicin (DOX)
Fig. 2–4
The above results show that pretreatmentwith non-cytotoxic concentrationsof DPDT (0.01, 0.05 and 0.1 μM) for 2 hincreased cell survival in Chinese hamster fibroblast cells (V79) after exposure to hydrogen peroxide (H2O2), t-butyl hydroperoxide (t-BOOH), methyl methanesulphonate (MMS), or ultraviolet (UV)C radiation[21].Thispretreatment with DPDT decreased the oxidative DNA damage detected by formamidopyrimidine DNA-glycosylase (Fpg, specific for oxidized purines) and endonuclease III (endo III, recognizing mainly oxidized pyrimidines)-sensitive sites. Therefore",DPDT pre-exposure decreased ROS induction by oxidative agents, and thisprotective behavior could be attributed to the antioxidant capacity of DPDT at these particular concentrations in V79 cells (Table 1)[21].
Some chemotherapeutic approaches have proposed the use of antioxidants to minimize cytotoxicity and DNA damage induced by free radical-inducing antitumor agents in normal tissues. Doxorubicin (DOX) is one of the commonly used chemotherapeutic agents in the treatment of hematological malignancies [37].However, it is thoughtthat DOX inducescardiotoxicity viathe generation of ROS by at least two mechanisms: enzymatic reduction of quinone with subsequent redox cycling and/or formation of an iron-anthracycline complex capable of intramolecular reduction and redox cycling [37]. In view oftheantioxidant effect of DPDT, we evaluated the effect of low DPDT concentrations on DOX-induced toxicity and genotoxicity in Chinese hamster fibroblasts (V79)",in human fibroblasts(MRC5) proficient innucleotide excision repair (NER)",andinNER deficient XPD cells. For this purpose, the cell lines MRC5 and V79 were treated with DOX in the presence or absence of DPDT pretreatment, and cell viability was evaluated using MTT assays. The pretreatment with DPDT (10 and 50nM) in V79, MRC5, and XPD cell lines increased cell survival after challenge with 0.6 µg/mL DOX (Figure 2).
Figure 2. Protective effect of 2h DPDTpretreatment in serum-free medium on doxorubicin-induced cytotoxicity in Chinese hamster fibroblasts (V79) as well as in human fibroblasts proficient (MRC5) and deficient (XPD) in NER evaluated by MTT assay 72 h after pretreatment
Data are reported as means ± SD of threeindependent experiments. *Significantly different at p
