Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

Scalcon, Valeria; Top, Siden; Lee, Hui Zhi Shirley; Citta, Anna; Folda, Alessandra; Bindoli, Alberto; Leong, Weng Kee; Salmain, Michèle; Vessières, Anne; Jaouen, Gérard; Rigobello, Maria Pia

doi:10.1016/j.jinorgbio.2016.04.005

Cited by 21 publications

(19 citation statements)

References 39 publications

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“…Therefore, their inhibition of the isolated and purified cytosolic isoform of thioredoxin reductase (TrxR1) was measured. In accordance with previous results, we tested the action of 1 and 2 alone, and the compounds obtained by enzymatic oxidation by the HRP/H 2 O 2 mixture of 1 and 2 , that is, 8 A and 10 , respectively. Compounds 1 and 2 only moderately inhibited cytosolic TrxR1 (IC 50 =19.36 μ m and 32.2 μ m , respectively), whereas 8 A and 10 were strong TrxR1 inhibitors (IC 50 =27 n m and 31 n m , respectively; Figure ).…”

Section: Resultsmentioning

confidence: 67%

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects

et al. 2019

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The ferrocenyl diphenol complexes 1,1‐bis(4′‐hydroxyphenyl)‐2‐ferrocenyl‐but‐1‐ene (1) and 1,2‐bis(4′‐hydroxyphenyl)‐1‐ferrocenyl‐but‐1‐ene [(Z)‐2], which differ by the relative position of the two phenolic substituents, display dramatically different antiproliferative activities on cancer cells (1 is far more cytotoxic than 2). In this study, our goal was to discover the origin of this difference by comparing their reactivity and biological behaviour. In terms of common behaviour, we found that 1 and 2 are both efficient inhibitors of thioredoxin reductase (TrxR) in vitro after oxidation by a horseradish peroxidase/H2O2 system. However, as 1 is only a moderate inhibitor of TrxR in MDA‐MB‐231 cells, TrxR is probably not the major target responsible for the cytotoxicity of 1. In terms of differences, we noted that 1 induced a significant redox imbalance characterised by lipid peroxidation and thiol oxidation, and a moderate decrease of the mitochondrial membrane potential in breast cancer cells, whereas 2 has almost no effect. These results underline the importance of the trans configuration in the ferrocenyl–double bond–phenol motif, which is present in 1 but is cis in (Z)‐2.

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Section: Resultsmentioning

confidence: 67%

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects

et al. 2019

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“…However, this inhibition was larger than that obtained with the corresponding quinine methides (IC 50 = 5.40 μM for 202 and 3.60 μM for 203 ). They found that the cytotoxicity of osmocifens depends on their oxidation within the cell and that inhibition of TrxR by oxidized species is a key factor in rationalizing the cytotoxic effects of these complexes on Jurkat cells . The authors also reported the inhibition of TrxR1 in vitro by the ansa‐ferrocifen derivative ( 204 , Figure ).…”

Section: Thioredoxin Reductase Inhibitorsmentioning

confidence: 99%

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Zhang

et al. 2018

Medicinal Research Reviews

127

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Mammalian thioredoxin reductase (TrxR) enzymes are homodimeric flavin proteins sharing a unique yet essential selenocysteine residue at their C-terminus. TrxRs, together with their endogenous substrate thioredoxins, play a crucial role in regulating diverse cellular redox events. A wealth of evidence from both clinic observations and bench studies supports that overactivation/dysfunction of TrxRs has a close link to the onset and development of various diseases, such as cancer and neurodegeneration. Thus, an increasing interest has been attracted to find small molecule modulators of TrxRs during the past years. Herein, we briefly discussed the relevance of targeting TrxRs inhibition for cancer treatment, and presented the small molecule inhibitors of mammalian TrxRs published in the nonpatent literatures from 2011 to 2016. The mechanisms of inhibition by different classes of molecules were summarized, and some inhibitors with promising anticancer activity were further discussed. We expect this work would be a comprehensive reference in the medicinal chemistry, and have a broad audience across multiple disciplines.

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“…At the end of the incubation time, the culture medium was removed and adherent cells were detached, collected by centrifugation, then digested in HNO3. 36 . 37,38 This resolution is significantly better than that of classic FTIR spectromicroscopy, which is limited by the criterion of light diffraction (Abbe criterion) establishing the resolution limit at a level of /2.…”

Section: Quantification Of Metals In Cancer Cells By Icp-oesmentioning

confidence: 99%

Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells

et al. 2018

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Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = η5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4-6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32-2.5 μM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 °C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 °C for 1 hour with 10 μM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm-1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus.

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Osmocenyl-tamoxifen derivatives target the thioredoxin system leading to a redox imbalance in Jurkat cells

Cited by 21 publications

References 39 publications

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects

Small Structural Differences between Two Ferrocenyl Diphenols Determine Large Discrepancies of Reactivity and Biological Effects

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells

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