organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment

Abstract Selenium(Se)-containing compounds have attracted a growing interest as anticancer agents over recent decades, with mounting reports demonstrating their high efficacy and selectivity against cancer cells. Typically, Se compounds exert their cytotoxic effects by acting as pro-oxidants that alter cellular redox homeostasis. However, the precise intracellular targets, signalling pathways affected and mechanisms of cell death engaged following treatment vary with the chemical properties of the selenocompound and its metabolites, as well as the cancer model that is used. Naturally occurring organic Se compounds, besides encompassing a significant antitumor activity with an apparent ability to prevent metastasis, also seem to have fewer side effects and less systemic effects as reported for many inorganic Se compounds. On this basis, many novel organoselenium compounds have also been synthesized and examined as potential chemotherapeutic agents. This review aims to summarize the most well studied natural and synthetic organoselenium compounds and provide the most recent developments in our understanding of the molecular mechanisms that underlie their potential anticancer effects

Protective effects of the thioredoxin and glutaredoxin systems in dopamine-induced cell death

Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathogenic mechanism. The thioredoxin (Trx) and glutaredoxin (Grx) systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. By examining the expression of redox proteins in human postmortem PD brains, we found the levels of Trx1 and thioredoxin reductase 1 (TrxR1) to be significantly decreased. The human neuroblastoma cell line SH-SY5Y and the nematode Caenorhabditis elegans were used as model systems to explore the potential protective effects of the redox proteins against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. 6-OHDA is highly prone to oxidation, resulting in the formation of the quinone of 6-OHDA, a highly reactive species and powerful neurotoxin. Treatment of human cells with 6-OHDA resulted in an increased expression of Trx1, TrxR1, Grx1, and Grx2, and small interfering RNA for these genes significantly increased the cytotoxic effects exerted by the 6-OHDA neurotoxin. Evaluation of the dopaminergic neurons in C. elegans revealed that nematodes lacking trxr-1 were significantly more sensitive to 6-OHDA, with significantly increased neuronal degradation. Importantly, both the Trx and the Grx systems were also found to directly mediate reduction of the 6-OHDA-quinone in vitro and thus render its cytotoxic effects. In conclusion, our results suggest that the two redox systems are important for neuronal survival in dopamine-induced cell death. © 2014 Elsevier Inc.A.P.F. was supported by Stiftelsen Lars Hiertas Minne and Karolinska Institutet research grants. Research in the Swoboda laboratory was supported by the Swedish Research Council (VR) and the NordForsk Nordic network for C. elegans research. A.M.-V. was supported by the Instituto de Salud Carlos III (Projects PI050065 and PI080557, cofinanced by the Fondo Social Europeo, FEDER) and Junta de Andalucía (Projects P07-CVI-02697 and P08-CVI-03629), Spain. Some C. elegans strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440).Peer Reviewe

Novel methylselenoesters induce programed cell death via entosis in pancreatic cancer cells

Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH3SeH) being one of the key executors. In search of novel CH3SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI50 < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH3SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds

Novel methylselenoesters as antiproliferative agents

Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH3SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with different scaffolds aiming to modulate the release of CH3SeH. The fifteen compounds follow Lipinski’s Rule of Five and with exception of compounds 1 and 14, present better drug-likeness values than the positive control methylseleninic acid. The compounds were evaluated to determine their radical scavenging activity. Compound 11 reduced both DPPH and ABTS radicals. The cytotoxicity of the compounds was evaluated in a panel of five cancer cell lines (prostate, colon and lung carcinoma, mammary adenocarcinoma and chronic myelogenous leukemia) and two non-malignant (lung and mammary epithelial) cell lines. Ten compounds had GI50 values below 10 μM at 72 h in four cancer cell lines. Compounds 5 and 15 were chosen for further characterization of their mechanism of action in the mammary adenocarcinoma cell line due to their similarity with methylseleninic acid. Both compounds induced G2/M arrest whereas cell death was partially executed by caspases. The reduction and metabolism were also investigated, and both compounds were shown to be substrates for redox active enzyme thioredoxin reductase.The authors express their gratitude to the Plan de Investigación de la Universidad de Navarra, PIUNA (Ref 2014-26), “la Caixa” and “CAN” Foundations for financial support for the project. The research leading to these results has also received funding from “la Caixa” Banking Foundation and from the Asociación de Amigos de la Universidad de Navarra, to whom Nuria Díaz-Argelich wishes to expresses her gratitude

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

Redox active selenium (Se) compounds at sub toxic doses act as pro-oxidants with cytotoxic effects on tumor cells and are promising future chemotherapeutic agents. However, little is known about how Se compounds affect immune cells in the tumor microenvironment. We demonstrate that the inorganic Se compound selenite and the organic methylseleninic acid (MSA) do not, despite their pro-oxidant function, influence the viability of immune cells, at doses that gives cytotoxic effects in ovarian cancer cell lines. Treatment of the ovarian cancer cell line A2780 with selenite and MSA increases NK cell mediated lysis, and enhances the cytolytic activity of T cells. Increased T cell function was observed after incubation of T cells in preconditioned media from tumor cells treated with MSA, an effect that was coupled to decreased levels of PDL1, HIF-1α, and VEGF. In conclusion, redox active selenium compounds do not kill or inactivate immune cells at doses required for anti-cancer treatment, and we demonstrate that MSA enhances T cell-mediated tumor cell killing via PDL1 and VEGF inhibition

Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure

<p>Abstract</p> <p>Background</p> <p>Selenite is a promising anticancer agent which has been shown to induce apoptosis in malignant mesothelioma cells in a phenotype-dependent manner, where cells of the chemoresistant sarcomatoid phenotype are more sensitive.</p> <p>Methods</p> <p>In this paper, we investigate the apoptosis signalling mechanisms in sarcomatoid and epithelioid mesothelioma cells after selenite treatment. Apoptosis was measured with the Annexin-PI assay. The mitochondrial membrane potential, the expression of Bax, Bcl-XL, and the activation of caspase-3 were assayed with flow cytometry and a cytokeratin 18 cleavage assay. Signalling through JNK, p38, p53, and cathepsins B, D, and E was investigated with chemical inhibitors. Furthermore, the expression, nuclear translocation and DNA-binding activity of p53 was investigated using ICC, EMSA and the monitoring of p21 expression as a downstream event. Levels of thioredoxin (Trx) were measured by ELISA.</p> <p>Results</p> <p>In both cell lines, 10 μM selenite caused apoptosis and a marked loss of mitochondrial membrane potential. Bax was up-regulated only in the sarcomatoid cell line, while the epithelioid cell line down-regulated Bcl-XL and showed greater caspase-3 activation. Nuclear translocation of p53 was seen in both cell lines, but very little p21 expression was induced. Chemical inhibition of p53 did not protect the cells from apoptosis. p53 lost its DNA binding ability after selenite treatment and was enriched in an inactive form. Levels of thioredoxin decreased after selenite treatment. Chemical inhibition of MAP kinases and cathepsins showed that p38 and cathepsin B had some mediatory effect while JNK had an anti-apoptotic role.</p> <p>Conclusion</p> <p>We delineate pathways of apoptosis signalling in response to selenite, showing differences between epithelioid and sarcomatoid mesothelioma cells. These differences may partly explain why sarcomatoid cells are more sensitive to selenite.</p

Metal- and semimetal-containing inhibitors of thioredoxin reductase as anticancer agents

The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide disulfide oxidoreductases playing a central role in cellular redox homeostasis and signaling pathways. Recently, these selenoproteins have emerged as promising therapeutic targets for anticancer drug development, often being overexpressed in tumor cells and contributing to drug resistance. Herein, we summarize the current knowledge on metal- and semimetal-containing molecules capable of hampering mammalian TrxRs, with an emphasis on compounds reported in the last decade

Redox proteins in the defense against dopamine induced cell death

Póster presentado en la Nordforsk C. elegans Network Meeting (Nordic Symposium), celebrada en Holte (Dinamarca) del 8 al 10 de marzo de 2013.[Background] Although the etiology of sporadic Parkinson disease (PD) is unknown, it is well established that oxidative stress plays an important role in the pathophysiology. The thioredoxin and glutaredoxin systems are two central systems upholding the sulfhydryl homeostasis by reducing disulfides and mixed disulfides within the cell and thereby protecting against oxidative stress. In the present study we used the dopamine metabolite 6-hydroxydopamine (6-OHDA) to model PD and to explore the protective effects of these two systems. The powerful neurotoxin 6-OHDA is highly prone to oxidation, resulting in the formation of the 6-OHDA-quinone, a highly reactive species.[Results] In human post-mortem PD brains the levels of thioredoxin 1 and thioredoxin reductase 1 were found to be significantly decreased. The neuroblastoma cellline SH-SYSY and the nematode C. elegans were used as model systems to evaluate the toxic effects of 6-0HDA. Selenite supplementation protected neuroblastoma cells against 6-0HDA, possibly by upregulating the selenoprotein thioredoxin reductase. A knock-down of thioredoxin and thioredoxin reductase by siRNA resulted in increased cell death in SH -SYSY. Furthermore, both the thioredoxin and the glutaredoxin systems were able to reduce 6-0HDA-quinone. The reduction required the dithiol mechanism as glutaredoxin with a mutation in the C-terminal cysteine ofthe active s i te was found to be ineffective at reducing 6-0HDA-quinone. To further investigate the protective role of proteins belonging to the thioredoxin system, experiments were conducted in C. elegans with 6-0HDA treatment ofnull mutants for trxr-1, trx4 or trx5 followed by evaluation of their neuronal integrity.[Conclusions] Our results suggest that the glutaredoxin and the thioredoxin systems appear to be important for neuro nal survival in dopamine induced cell death.Peer Reviewe