Triphenyltin isoselenocyanate: a novel nuclear retinoid X receptor ligand with antiproliferative and cytotoxic properties in cell lines derived from human breast cancer.

Several commercially available triorganotin compounds were previously found to function as agonist ligands for nuclear retinoid X receptor (RXR) molecules. Triphenyltin isoselenocyanate (TPT-NCSe), a novel selenium atom containing a derivative of triorganotin origin, was found to represent a new cognate bioactive ligand for RXRs. TPT-NCSe displayed a concentration- and time-dependent decrease in the cell viability in both human breast carcinoma MCF-7 (estrogen receptor positive) and MDA­MB­231 (triple negative) cell lines. Reactive oxygen species levels generated in response to TPT-NCSe were significantly higher in both carcinoma cell lines treated with TPT-NCSe when compared to mock-treated samples. Treatment with 500 nM TPT-NCSe caused a decrease in SOD1 and increased SOD2 mRNA in MCF-7 cells. The levels of SOD2 mRNA were more increased following the treatment with TPT-NCSe along with 1 µM all-trans retinoic acid (AtRA) in MCF-7 cells. An increased superoxide dismutase SOD1 and SOD2 mRNA levels were also detected in combination treatment of 500 nM TPT-NCSe and 1 µM AtRA in TPT-NCSe-treated MDA-MB-231 cells. The data have also shown that TPT-NCSe induces apoptosis via a caspase cascade triggered by the mitochondrial apoptotic pathway. TPT-NCSe modulates the expression levels of apoptosis­related proteins, Annexin A5, Bcl­2 and BAX family proteins, and finally, it enhances the expression levels of its cognate nuclear receptor subtypes RXRalpha and RXRbeta.

The effect of all-trans retinoic acid on the mitochondrial function and survival of cardiomyoblasts exposed to local photodamage.

Using H9C2 cardiomyoblasts, we have shown that all-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A, affects mitochondrial dynamics and functions. The low dose (10 nM) ATRA stimulates the expression of nuclear retinoid receptors and induces mechanisms that are protective against severe local damage caused by laser irradiation at the mitochondrial level. These changes include increased density of the mitochondrial network, higher number of mitochondrial junctions, and enhanced mitochondrial velocity. Moreover, the treated cells had lower basal level of reactive oxygen species (ROS) and could maintain mitochondrial potential (ΔΨm ) after photodamage. Cells treated with 10 nM ATRA had significantly better survival rate after photodamage in comparison to control cells. Cells treated with pharmacological concentration of ATRA (1 µM) expressed higher mitochondrial connectivity without increased motility, which did not lead to better survival or decreased ROS level as was in the case of low-dose ATRA. The proteomics analysis showed changes in proteins related to cellular metabolism (glycolysis) and respiration in ATRA-treated cells. The l-lactate assay confirmed the shift to anaerobic glycolysis in cells treated with 1 µm ATRA, whereas the 10 nM ATRA decreased the level of lactate in medium. The increased levels of cytochrome c or peroxiredoxins 5 level and also lower expression of retinoid and rexinoid receptors were observed in cells treated with 1 µM ATRA. The effect of ATRA is concentration-dependent; the increased mitochondrial dynamics and slower metabolism at 10 nM ATRA contributed significantly to the chance of survival of the cells after photodamage whereas the higher concentration of ATRA overrode the protective effect and led to the unfavorable ones.

Biological functions of kojic acid and its derivatives in medicine, cosmetics, and food industry: Insights into health aspects.

This review traces the road leading to the demonstration of a variety of kojic acid chemical and biological properties. It illustrates the biological effects of several synthetic kojic acid derivatives. Besides the main capability of kojic acid to inhibit the activity of tyrosinase in melanin synthesis, the focus is also on antibacterial, antifungal, antiproliferative, anti-inflammatory, and other biological activities of kojic acid derivatives, which may be applicable in medicine. Kojic acid derivatives manifest antiparasitic effects and its metal complexes may serve as potential radioprotective agents. Several kojic acid derivatives exert antidiabetic therapeutic potential as nuclear peroxisome proliferator-activated receptor alpha/gamma dual agonists. Kojic acid derivatives show pancreatic lipase inhibitor properties and some of its derivatives are cognate ligands for the histamine H3 receptor. Recently, "KojoTacrines" were reported as novel perspective preparations for the therapy of Alzheimer's disease. Kojic acid derivatives possess insecticidal or pesticidal activity, and they are powerful chelators, able to form iron(III) containing nanocomposites, as well. Toxicology and health aspects of products containing kojic acid produced by the cosmetic, health care, or food industry are summarized. Kojic acid thus represents a highly attractive molecule containing a skeleton that allows the synthesis of new kojic acid derivatives to create a novel class of effective and specific pharmaceutical preparations.

Thyroid hormone and thyroid hormone nuclear receptors: History and present state of art.

The present review traces the road leading to discovery of L-thyroxine, thyroid hormone (3,5,3´-triiodo-L-thyronine, T3) and its cognate nuclear receptors. Thyroid hormone is a pleio-tropic regulator of growth, differentiation, and tissue homeostasis in higher organisms. The major site of the thyroid hormone action is predominantly a cell nucleus. T3 specific binding sites in the cell nuclei have opened a new era in the field of the thyroid hormone receptors (TRs) discovery. T3 actions are mediated by high affinity nuclear TRs, TRalpha and TRbeta, which function as T3-activated transcription factors playing an essential role as transcription-modulating proteins affecting the transcriptional responses in target genes. Discovery and characterization of nuclear retinoid X receptors (RXRs), which form with TRs a heterodimer RXR/TR, positioned RXRs at the epicenter of molecular endocrinology. Transcriptional control via nuclear RXR/TR heterodimer represents a direct action of thyroid hormone. T3 plays a crucial role in the development of brain, it exerts significant effects on the cardiovascular system, skeletal muscle contractile function, bone development and growth, both female and male reproductive systems, and skin. It plays an important role in maintaining the hepatic, kidney and intestine homeostasis and in pancreas, it stimulates the beta-cell proliferation and survival. The TRs cross-talk with other signaling pathways intensifies the T3 action at cellular level. The role of thyroid hormone in human cancers, acting via its cognate nuclear receptors, has not been fully elucidated yet. This review is aimed to describe the history of T3 receptors, starting from discovery of T3 binding sites in the cell nuclei to revelation of T3 receptors as T3-inducible transcription factors in relation to T3 action at cellular level. It also focuses on milestones of investigation, comprising RXR/TR dimerization, cross-talk between T3 receptors, and other regulatory pathways within the cell and mainly on genomic action of T3. This review also focuses on novel directions of investigation on relationships between T3 receptors and cancer. Based on the update of available literature and the author's experimental experience, it is devoted to clinicians and medical students.

CD44 and vimentin, markers involved with epithelial-mesenchymal transition: A proteomic analysis of sequential proteins extraction of triple-negative breast cancer cells after treatment with all-trans retinoic acid.

This work aimed to provide, in one isolation and separation step, an overview of the content of proteins with different solubility after treatment with all-trans retinoic acid, which is considered to be an important therapeutic agent, predominantly in acute promyelocytic leukemia. Breast, ovarian, bladder, and skin cancers have been demonstrated to be suppressed by retinoic acid, as well. The bottom-up proteomic strategies were applied for the analysis of proteins extracted from triple-negative breast cancer MDA-MB-231 cells utilizing a commercially manufactured kit. The gel electrophoresis followed by MALDI-TOF MS analysis was used for protein determination. By employing PDQuest™ software, we identified several proteins affected by all-trans retinoic acid. Two proteins, vimentin and CD44, which are associated with the epithelial-mesenchymal transition, were selected for a detailed study. We have found that all-trans retinoic acid results in significantly reduced levels of vimentin and CD44 in both the cytoplasmic and membrane fractions. A significant effect was particularly evident in CD44, where protein level in the cytoplasmic fraction was almost completely suppressed.

Novel insights into the combined effect of triorganotin compounds and all-trans retinoic acid on expression of selected proteins associated with tumor progression in breast cancer cell line MDA-MB-231: Proteomic approach.

Trialkyltins and triaryltins function as nuclear retinoid X receptors (RXR) agonists due to their affinity to the ligand-binding domain of RXR subtypes and function as transcriptional activators. We present the data on combined effects of all-trans retinoic acid (ATRA), retinoic acid receptor (RAR) ligand and tributyltin chloride or triphenyltin chloride (RXR ligands) on protein pattern in MDA-MB-231 cells. Proteomic strategies based on bottom-up method were applied in this study. The total cell proteins were extracted, separated on 2D SDS-PAGE and their characterization was achieved by MALDI-TOF/TOF MS/MS. By employing PDQuest™ software, we identified more than 30 proteins differently affected by the above compounds. For further studies, we selected specific proteins associated either with metabolic pathway (glyceraldehyde-3-phosphate dehydrogenase) or to cellular processes as apoptosis, regulation of gene transcription or epithelial-mesenchymal transition (annexin 5, nucleoside diphosphate kinase B and vimentin). We have found that treatment of MDA-MB-231 cells with triorganotins reduced the expression of studied proteins. Moreover, the treatment of MDA-MB-231 cells with triorganotin compounds together with ATRA resulted in an additional reduction of annexin 5, vimentin and nucleoside diphosphate kinase B. These results demonstrate that RXR/RAR heterodimer may act under this experimental design as permissive heterodimer allowing activation of RXR by triorganotins.

Genotoxic Effects of Tributyltin and Triphenyltin Isothiocyanates, Cognate RXR Ligands: Comparison in Human Breast Carcinoma MCF 7 and MDA-MB-231 Cells.

The cytotoxicity of two recently synthesized triorganotin isothiocyanate derivatives, nuclear retinoid X receptor ligands, was tested and compared in estrogen-receptor-positive MCF 7 and -negative MDA-MB-231 human breast carcinoma cell lines. A 48 h MTT assay indicated that tributyltin isothiocyanate (TBT-ITC) is more cytotoxic than triphenyltin isothiocyanate (TPT-ITC) in MCF 7 cells, and the same trend was observed in the MDA-MB-231 cell line. A comet assay revealed the presence of both crosslinks and increasing DNA damage levels after the 17 h treatment with both derivatives. Differences in cytotoxicity of TBT-ITC and TPT-ITC detected by FDA staining correspond to the MTT data, communicating more pronounced effects in MCF 7 than in the MDA-MB-231 cell line. Both derivatives were found to cause apoptosis, as shown by the mitochondrial membrane potential (MMP) depolarization and caspase-3/7 activation. The onset of caspase activation correlated with MMP dissipation and the total cytotoxicity more than with the amount of active caspases. In conclusion, our data suggest that the DNA damage induced by TBT-ITC and TPT-ITC treatment could underlie their cytotoxicity in the cell lines studied.

Stability studies of endocrine disrupting tributyltin and triphenyltin compounds in an artificial sea water model.

Triorganotins belong to toxic components present predominantly in antifouling paints for marine vessels. Tributyltin/triphenyltin at pico- or nanomolar concentrations in sea water are known to induce an irreversible sexual abnormality in females of over 190 marine species, an "imposex" phenomenon - the superimposition of male genitalia on a female. Moreover, trialkyltins and triaryltins function as potent nuclear retinoid X receptors (RXR) agonists. In mammals, triorganotin compounds induce immunosuppressive, metabolic, reproductive or developmental effects. Toxic effects of triorganotins warrant the need for monitoring of their long-lasting presence in the environment. This study brings novel data on the stability of two triorganotin compounds in artificial sea water model obtained by applying ultra-pressure liquid chromatography (UPLC) and gas chromatography-mass spectrometry (GC-MS) methods. Stability of tributyltin and triphenyltin chlorides was studied for 180 days and the degradation kinetic parameters were obtained. Tributyltin chloride was the less stable with the degradation kinetic parameters Kdeg = 0.00014 day-1 and t1/2 = 4950 days (13.6 years). Kdeg of the more stable triphenyltin chloride was determined to be Kdeg = 0.00006 day-1 with t1/2 = 11550 days (31.6 years). Since similar stability data of triorganotin compounds were not published previously, we report high stability for both tested compounds, which indicates a significant environmental problem when these substances enter sea water and later coastal sediments.

Effects of selected triorganotin compounds on transcriptional activity of vitamin D3 receptor and peroxisome proliferator-activated receptor gamma.

Both, the vitamin D3 receptor (VDR) and the peroxisome proliferator-activated receptor gamma (PPARγ), are ligand-inducible transcription factors that control expressions of various genes involved in essential biological processes. Structurally diverse chemical substances are capable to bind to VDR and PPARγ, consequently acting in agonistic or antagonistic mode. Ubiquitous triorganotin compounds, key components of antifouling, disinfectant and biocidal agents were found to act as cognate ligands of several nuclear receptors. Triorganotins affect endocrine systems in disruptive manner recruiting proliferative, differentiation and apoptotic pathways. In this study, we have investigated agonistic as well as antagonistic effects of selected triorganotin compounds on VDR and PPARγ in transgenic gene reporter IZ-VDRE and PAZ-PPARγ human cell lines, allowing rapid and sensitive assessment of receptor transcriptional activity. We demonstrated that most of investigated triorganotins at nanomolar concentration exerted significant agonistic effects on VDR with fold activation ranging from 2.0 to 3.0-fold as well as some significant changes ranging from 127 to 199% of the maximal 1,25-dihydroxyvitamin D3 (calcitriol) induction, in antagonistic mode. In agonistic mode, PPARγ transcriptional activity was not affected by studied triorganotins significantly, but studied tributyltin compounds in antagonistic mode, revealed significant values ranging from 147 to 171% of the maximal 15-deoxy-δ12,14-prostaglandin J2 induction.

Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression.

The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives­tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)­could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells.

Effects of natural ligands and synthetic triorganotin compounds of nuclear retinoid X receptors in human MCF-7 breast cancer cell line.

In the present study, we analyzed in vitro effects of natural and synthetic triorganotin ligands of nuclear retinoid X receptors in human MCF-7 breast cancer cells. Our data has shown that all-trans retinoic acid significantly reduced expression of RXRalpha mRNA, Bcl2 and enhanced expression of BAX proteins. Tributyltin bromide markedly decreased mRNA level of RXRalpha and RXRbeta. Significantly reduced levels of both RXRs proteins were observed after treatment with tributyltin chloride (TBT-Cl) but not after treatment with triphenyltin chloride (TPT-Cl) for RXRbeta protein. Both RXRalpha and RXRbeta protein levels decrease was found also by combination ATRA+TBT-Cl/TPT-Cl.

A comparative study of protein patterns of human estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines.

In the present study, we analyzed the cell lysates of human tumour cell lines representing two major clinically different types of breast cancer. Our main goal was to show the differences between them on proteomic level. Gel electrophoresis followed by MALDI-TOF MS analysis was used for proteins determination. Exactly 98 proteins were unequivocally identified and 60 of them were expressed differentially between MDA-MB-231 and MCF-7 cell lines. Among the proteins reported here, some well-known breast cancer markers (e.g., annexin A1, annexin A2 and vimentin) were identified in the MDA-MB-231 cell line and thus we were able to distinguish both cell lines sufficiently.

Agonistic effect of selected isoflavones on arylhydrocarbon receptor in a novel AZ-AhR transgenic gene reporter human cell line.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. Structurally diverse compounds bind to AhR and act as AhR agonists. Well characterised family of natural AhR ligands are isoflavones, which are compounds found predominantly in soy beans or red clover. In this study we have examined agonistic effect of selected isoflavones (genistein, daidzein, biochanin A, formononetin and equol) on AhR in the novel transgenic gene reporter human cell line AZ-AhR, a stably transfected AhR-responsive cell line allowing rapid and sensitive assessment of AhR transcriptional activity. We demonstrated that biochanin A, formononetin and genistein at concentration 10(-4) mol/l exerted agonistic effects on AhR with fold activation of 309- fold, 108-fold and 27-fold, which is about 84.8%, 29.6% and 7.4%, respectively, of the value attained by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Daidzein and equol did not show any significant effects on AhR.

Nuclear receptors - target molecules for isoflavones in cancer chemoprevention.

Breast cancer is the most occurring type of cancer among women. In Slovakia, there are yearly diagnosed about 1900 new cases of this disease. Breast cancer treatment is very expensive, psychic stressful and in some cases ineffective. Therefore, it is essential to search for new and/or alternative methods for breast cancer treatment, since nuclear receptors are considered to be a central goal for maximizing treatment opportunities in breast cancer. Among natural ligands for estrogen receptors (ERα and ERß), which are member of nuclear receptors superfamily, belongs also isoflavones. These natural compounds have similar structure to main female hormon-17ß estradiol. A rich source of isoflavones is soy and its products. Three aglycones form of isoflavones (genistein, daidzein, glycitein) are predominantly found in soybean and red clover. Among other important isoflavones belongs also biochanin A and formononetin.

In vitro antiproliferative and cytotoxic activities of novel triphenyltin isoselenocyanate in human breast carcinoma cell lines MCF 7 and MDA-MB-231.

Intensive investigation for novel antiproliferative and cytotoxic effective chemical compounds is currently concentrated on structurally modified agents of natural or synthetic source. The selenium derivative of triorganotin compound, triphenyltin isoselenocyanate (TPT-NCSe) caused higher cytotoxicity in hormone sensitive MCF 7 (IC 50-250 nM) in comparison with triple-negative MDA-MB-231 breast carcinoma cell line (IC 50-450 nM) as determined by MTT assay. Measurement of DNA damage showed presence of crosslinks in both cell lines treated by increasing TPT-NCSe concentrations. This compound decreased mitochondrial membrane potential shown by JC-1 staining in a concentration-dependent manner in both cell lines. Activation of caspases-3/7 was observed in MDA-MB-231 cells and was significant only by concentrations causing significant level of crosslinks. On the other hand, migration assay revealed inhibitory effect of viability keeping 100 nM concentration of TPT-NCSe on migration of MDA-MB-231 cells. Our data has shown that this selenium containing triorganotin molecule exerts DNA damage-linked antineoplastic activity in breast carcinoma cell lines studied.

Amphioxus postembryonic development reveals the homology of chordate metamorphosis.

Most studies in evolution are centered on how homologous genes, structures, and/or processes appeared and diverged. Although historical homology is well defined as a concept, in practice its establishment can be problematic, especially for some morphological traits or developmental processes. Metamorphosis in chordates is such an enigmatic character. Defined as a spectacular postembryonic larva-to-adult transition, it shows a wide morphological diversity between the different chordate lineages, suggesting that it might have appeared several times independently. In vertebrates, metamorphosis is triggered by binding of the thyroid hormones (THs) T(4) and T(3) to thyroid-hormone receptors (TRs). Here we show that a TH derivative, triiodothyroacetic acid (TRIAC), induces metamorphosis in the cephalochordate amphioxus. The amphioxus TR (amphiTR) mediates spontaneous and TRIAC-induced metamorphosis because it strongly binds to TRIAC, and a specific TR antagonist, NH3, inhibits both spontaneous and TRIAC-induced metamorphosis. Moreover, as in amphibians, amphiTR expression levels increase around metamorphosis and are enhanced by THs. Therefore, TH-regulated metamorphosis, mediated by TR, is an ancestral feature of all chordates. This conservation of a regulatory network supports the homology of metamorphosis in the chordate lineage.

Changes in retinoic acid receptor status, 5'-deiodinase activity and neuroendocrine response to voluntary wheel running.

Little information is available on the involvement of retinoic acid in processes related to physical activity. The aim of this study was to test the hypotheses that long-term voluntary wheel running (1) modifies RARs concentration as well as the expression of RAR subtypes and (2) alters Iiodothyronine deiodinase (5'-DI) activity in rat liver. To evaluate relevant mechanisms, hepatic gene expression of specific nuclear receptor coregulators and stress hormone levels in plasma have also been measured. Sprague-Dawley rats were housed either in standard cages or in cages with access to running wheel attached for 3 weeks. RAR maximal binding capacity in the liver was found to be significantly lower while gene expression of RAR beta increased in rats exposed to voluntary running compared to that in sedentary controls. Gene expression of RAR alpha, RXR alpha and RXR beta was found to be unaffected. Voluntary running led to a significant decrease of 5'-DI activity in the liver. No significant changes in the gene expression of specific nuclear receptor coregulators in the liver were observed. Significant elevation of aldosterone while no changes in ACTH and corticosterone concentrations were observed in rats exposed to wheel running compared to those in controls. In conclusion, this study provided first evidence on the reduction of liver RAR concentrations and 5'-DI activity in response to long-term voluntary wheel running. Neuroendocrine mechanisms involved in these changes may include adrenal mineralo- and glucocorticoids.

Neutrophils are immune cells preferentially targeted by retinoic acid in elderly subjects.

BACKGROUND: The immune system gradually deteriorates with age and nutritional status is a major factor in immunosenescence. Of the many nutritional factors implicated in age-related immune dysfunction, vitamin A may be a good candidate, since vitamin A concentrations classically decrease during aging whereas it may possess important immunomodulatory properties via its active metabolites, the retinoic acids. This prompted us to investigate the immune response induced by retinoids in adults and elderly healthy subjects. Before and after oral supplementation with 13cis retinoic acid (0.5 mg/kg/day during 28 days), whole blood cells were phenotyped, and functions of peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were investigated by flow cytometry and ELISA tests. RESULTS: In both young adults (n = 20, 25 ± 4 years) and older subjects (n = 20, 65 ± 4 years), retinoic acid supplementation had no effect on the distribution of leukocyte subpopulations or on the functions of PBMC (Il-2 and sIl-2R production, membrane expression of CD25). Concerning PMN, retinoic acid induced an increase in both spontaneous migration and cell surface expression of CD11b in the two different age populations, whereas bactericidal activity and phagocytosis remained unchanged. CONCLUSIONS: We demonstrated that retinoic acid induces the same intensity of immune response between adult and older subjects, and more specifically affects PMN functions, i.e. adhesion and migration, than PBMC functions.

Natural and synthetic retinoid X receptor ligands and their role in selected nuclear receptor action.

Important key players in the regulatory machinery within the cells are nuclear retinoid X receptors (RXRs), which compose heterodimers in company with several diverse nuclear receptors, playing a role as ligand inducible transcription factors. In general, nuclear receptors are ligand-activated, transcription-modulating proteins affecting transcriptional responses in target genes. RXR molecules forming permissive heterodimers with disparate nuclear receptors comprise peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstan receptor (CAR). Retinoid receptors (RARs) and thyroid hormone receptors (TRs) may form conditional heterodimers, and dihydroxyvitamin D3 receptor (VDR) is believed to form nonpermissive heterodimer. Thus, RXRs are the important molecules that are involved in control of many cellular functions in biological processes and diseases, including cancer or diabetes. This article summarizes both naturally occurring and synthetic ligands for nuclear retinoid X receptors and describes, predominantly in mammals, their role in molecular mechanisms within the cells. A focus is also on triorganotin compounds, which are high affinity RXR ligands, and finally, we present an outlook on human microbiota as a potential source of RXR activators. Nevertheless, new synthetic rexinoids with better retinoid X receptor activity and lesser side effects are highly required.

Down-regulation of vimentin by triorganotin isothiocyanates-nuclear retinoid X receptor agonists: A proteomic approach.

An attempt has been made to delineate the role of natural and synthetic retinoid receptor ligands on vimentin expression in the human triple-negative breast cancer cells. The effects of currently synthesized triorganotin derivatives of the general formula R3SnX (R is butyl or phenyl, X is isothiocyanate), which are considered RXR ligands, were investigated in the human MDA-MB-231 breast cancer cell line. Studies were evaluated in the presence and absence of all-trans retinoic acid (ATRA), a natural RAR ligand. Vimentin represents the major protein associated with epithelial-mesenchymal transition (EMT), an essential process when the primary tumour transforms into a malignant one. mRNA and proteomic data obtained in this study, based on the PDQuest software protein evaluation and further quantification of proteins by iTRAQ analysis, suggest that vimentin was significantly reduced in the combination of RAR ligand and RXR ligand treatment. Both tested triorganotin compounds showed similarly reduced expression of vimentin, but tributyltin isothiocyanate (TBT-ITC) proved to be more effective than triphenyltin isothiocyanate (TPT-ITC). Furthermore, the effect of natural (9cRA) and synthetic RXR ligands, both chloride and isothiocyanate derivatives, on vimentin expression was compared.