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L'invention concerne l'utilisation non-thérapeutique, en tant qu'agent de déméthylation de l'ADN, d'au moins un composé organométallique comprenant un atome de fer lié à deux groupes terpyridines. L'invention porte également sur un composé organométallique comprenant un atome de fer lié à deux groupes terpyridines pour son utilisation comme médicament.

Présentation Poster; National audience; Breast cancer is one of the leading causes of cancer death in women worldwide.[1] Among the various types of breast cancer, triple-negative breast cancers (TNBCs) are characterized by a lack of expression of estrogen and progesterone receptors and human epidermal growth factor 2 (HER2). They hence do not respond to targeted therapies and present a higher chance of recurrence after conventional chemotherapy treatments. In this context, thiazolidine-2,4-dione (TZD) derivatives which were shown to exhibit several biological activities are of particular interest.[2-6] Our team previously developed [7-9] Structure-Activity Relationships (SAR) starting from the structure of troglitazone (TGZ), formerly used as an antidiabetic. The present work was based on the synthesis of new desulfured troglitazone derivatives, and their in vitro biological evaluation on both TNBC and hormone-dependent breast cancer cell lines.[1] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal, CA-Cancer J. Clin. 2018, 68, 394–424.[2] Mohd.J. Naim, Md.J. Alam, S. Ahmad, F. Nawaz, N. Shrivastava, M. Sahu, O. Alam Eur. J. Med. Chem. 2017, 129, 218–250.[3] Sucheta, S. Tahlan, P.K. Verma, Chem. Cent. J. 2017, 11, 130.[4] N. Chadha, M.S. Bahia, M. Kaur, O. Silakari, Bioorg. Med. Chem. 2015, 23, 2953–2974.[5] S. Prost, F. Relouzat, M. Spentchian, Y. Ouzegdouh, J. Saliba, G. Massonnet, J.-P. Beressi, E. Verhoeyen, V. Raggueneau, B. Maneglier, S. Castaigne, C. Chomienne, S. Chrétien, P. Rousselot, P. Leboulch, Nature 2015, 525, 380–383.[6] V. Shafiei‐Irannejad, N. Samadi, R. Salehi, B. Yousefi, N. Zarghami, Chem. Biol. Drug Des. 2017, 90, 1056–1066.[7] S. Salamone, C. Colin, I. Grillier-Vuissoz, S. Kuntz, S. Mazerbourg, S. Flament, H. Martin, L. Richert, Y. Chapleur, M. Boisbrun, Eur. J. Med. Chem. 2012, 51, 206–215.[8] A. Bordessa, C. Colin-Cassin, I. Grillier-Vuissoz, S. Kuntz, S. Mazerbourg, G. Husson, M. Vo, S. Flament, H. Martin, Y. Chapleur, M. Boisbrun, Eur. J. Med. Chem. 2014, 83, 129–140.[9] S. Mazerbourg, S. Kuntz, I. Grillier-Vuissoz, A. Berthe, M. Geoffroy, S. Flament, A. Bordessa, M. Boisbrun, Curr. Top. Med. Chem. 2016, 16, 2115–2124.

Human exposure to airborne carbon nanotubes (CNT) is increasing because of their applications in different sectors; therefore, they constitute a biological hazard. Consequently, developing studies on CNT toxicity become a necessity. CNTs can have different properties in term of length, size and charge. Here, we compared the cellular effect of multiwall (MWCNTs) and single wall CNTs (SWCNTs). MWCNTs consist of multiple layers of graphene, while SWCNTs are monolayers. The effects of MWCNTs and SWCNTs were evaluated by the water‐soluble tetrazolium salt cell proliferation assay on NR8383 cells, rat alveolar macrophage cell line (NR8383). After 24 hours of exposure, MWCNTs showed higher toxicity (50% inhibitory concentration [IC50] = 3.2 cm2/cm2) than SWCNTs (IC50 = 44 cm2/cm2). Only SWCNTs have induced NR8383 cells apoptosis as assayed by flow cytometry using the annexin V/IP staining test. The expression of genes involved in oxidative burst (Ncf1), inflammation (Nfκb, Tnf‐α, Il‐6 and Il‐1β), mitochondrial damage (Opa) and apoptotic balance (Pdcd4, Bcl‐2 and Casp‐8) was determined. We found that MWCNT exposure predominantly induce inflammation, while SWCNTs induce apoptosis and impaired mitochondrial function. Our results clearly suggest that MWCNTs are ideal candidates for acute inflammation induction. In vivo studies are required to confirm this hypothesis. However, we conclude that toxicity of CNTs is dependent on their physical and chemical characteristics., The physical and chemical properties of carbon nanotubes (CNTs) are of interest in many fields, particularly in the biomedical one. Consequently, human exposure to different CNTs is growing. Therefore, using NR8383 cells, rat alveolar macrophages, we evaluated modifications in gene expression after exposure to multiwall CNTs (NM403) and single wall CNTs (NRCWE‐055). We found different NR8383 cell responses, which confirm that CNT toxicity depends on physical and chemical characteristics of CNTs.

Présentation Poster; International audience; Introduction: Advanced breast cancers do not respond well to therapies and represent a relevant focus for studying molecular mechanisms involved in the tumour progression and drug resistance. The transcription factor NF-κB is often activated constitutively in aggressive breast cancer cells and plays a significant role by inducing many target genes involved in tumour progression and drug resistance. Mechanisms controlling constitutive NF-kB activation are not all clearly understood. Among them, repression of the gene encoding the NF-κB inhibitor, IκBα is not well known. This protein controls NF-κB activation by sequestering it in the cytoplasmic compartment. The present study reports the identification of the hnRNP K/J protein, which is initially known for its role in mRNA splicing and translation, as a repressor of the IκBα gene expression.Material and methods: Identification of hnRNP K/J protein on the IκBα promoter was carried out by DNA pull-down coupled with a mass spectrometry analysis, and chromatin immunoprecipitation (ChIP) using a specific polyclonal antibodies. The hnRNP K/J protein was overexpressed in breast cancer cell lines by transient transfection, and consequence on the IκBα expression and the proximal IκBα promoter activity was evaluated by RT-qPCR and gene reporter assay, respectively. The hnRNP K/J protein localization was visualised in cells by Western blotting using nuclear and cytoplasmic extracts.Results and discussions: The IκBα gene is expressed higher in nonaggressive compared to aggressive breast cancer cells. We used previous data showing the importance of the proximal promoter at position −495 from the transcription site for DNA pull-down with nuclear protein extract from MCF-7 cells. Mass spectrometry analysis led to identify hnRNP K/J protein, whose the binding to this region of the proximal IκBα promoter was confirmed by ChIP. The IκBα expression at mRNA level and proximal IκBα promoter activity was strongly decreased in hnRNP K/J-overexpressing breast cancer cells, in contrast to the respective parental cells, suggesting the role of hnRNP K/J protein as a gene repressor.Conclusion: The identification of hnRNP K/J as a repressor of IκBα gene expression depicts a new molecular mechanism, which may contribute to the high constitutive NF-kB activation in aggressive breast cancer cells and suggests to take it into account in the development of new therapies targeting NF-kB pathway in advanced breast cancers.

Présentation Poster; International audience