Implication des modifications épigénétiques dans les cancers : développement de nouvelles approches thérapeutiques

Involvement of epigenetic modifications in cancers: development of new therapeutic approaches. Since cancer is the second cause of death after cardiovascular diseases in industrialized countries, it is urgent to elaborate new therapeutic approaches. Besides DNA mutations of essential genes, expansion of a cancer cell is frequently associated with epigenetic modifications i.e. not directly coded by the DNA sequence. Amongst epigenetic modifications, histones acetylation and DNA methylation are known to play important roles. In this context, a very promising anticancer therapy would be to correct epigenetic errors using compounds modulating histone acetylation and DNA methylation alone or in combination with other chemotherapeutic agents

Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human

In 1871, the observation of yellowish nodules in the enlarged spleen of a cow was considered to be the first reported case of bovine leukemia. The etiological agent of this lymphoproliferative disease, bovine leukemia virus (BLV), belongs to the deltaretrovirus genus which also includes the related human T-lymphotropic virus type 1 (HTLV-1). This review summarizes current knowledge of this viral system, which is important as a model for leukemogenesis. Recently, the BLV model has also cast light onto novel prospects for therapies of HTLV induced diseases, for which no satisfactory treatment exists so far

The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer

Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activityin - volved in cancer cell growth and survival pathways. We examined the efficacyof the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC50 and LD50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD50 values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantlyde creased tumor growth byan average of 62% when compared with vehicle control. Panobinostat was equallye ffective in immunocompetent and severe combined immunodeficiencymic e, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects.Panobinostat was, however, particularlyeffective in SCLC xenografts, and the addition of the chemotherapyag ent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-XL. These studies together suggest that panobinostat maybe a useful adjunct in the treatment of thoracic malignancies, especiallySCLC

Contribution of lysine deacetylases to the therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare cancer arising from mesothelial cells from the pleura. The first line chemotherapy of the epithelioid subtype of MPM is based on a combined regimen of cisplatin and an antifolate (pemetrexed). Recently, immunotherapy with two checkpoint inhibitors (PD-1, nivolumab and CTLA-4, ipilimumab) showed promising results for the sarcomatoid subtype. Despite this major breakthrough, the median overall survival of patients only reached 18.1 months, compared to 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. Therefore, options for second line treatment are still mandatory. We previously proposed a therapy based on the combination of a topoisomerase inhibitor (doxorubicin) and a lysine deacetylase inhibitor (valproate, VPA) (Scherpereel et al, European Respiratory Journal 37:129-135). We identified one of the key determinants that modulates the chemoresistance (Staumont et al, Cancers 12:1484). In this study, we aimed to further investigate the mechanisms involved by analyzing the effect of VPA on the tumor microenvironment and more particularly on the interactions between monocytes and tumor cells. We showed that VPA affects the viability of doxorubicin-treated mesothelioma cells and promotes their apoptosis. The use of caspase and calpeptin inhibitors demonstrated that apoptosis occurs through a caspase-dependent mechanism involving both intrinsic and extrinsic pathway. Western blot analysis revealed that the combination of VPA and doxorubicin increases the expression of clived-Bid, Bax and cytochrome c while decreasing the expression of Bcl-2 and Bcl-XL. Transcriptomic analysis unveiled that epithelioid mesothelioma cells express more p21, Fas, Bbc3 and TP53INP1 upon treatment compared to the sarcomatoid subtype. To investigate the role of the microenvironment, we designed two models to study the influence of tumor-associated monocytes. Mesothelioma cells were co-cultured with THP-1 monocytes differentiated in presence of PMA. Flow cytometry, confocal microscopy and live imaging demonstrated that THP-1-derived monocytes are able to interact and kill tumor cells. Furthermore, VPA promotes the interaction between monocytes and tumor cells and fosters the cytotoxic activity of monocytes. In contrast to PMA, VPA does not affect the motility of THP-1 monocytes. These observations were validated and extended to primary monocytes isolated from peripheral blood. Increased cytotoxicity of primary monocytes is correlated with a reduced frequency of CD16+ cells. In this model, VPA augments the average speed of primary monocytes. Finally, RNA sequencing highlighted the key mechanisms involved in monocyte antitumor activity. In conclusion, we demonstrate that VPA directly affects the survival of tumor cells and indirectly modulates the cytotoxic activity of monocytes in the microenvironment

Le turnover de la lipase du pancréas exocrine du rat est plus lent que celui de quatre autres hydrolases du même tissu

info:eu-repo/semantics/publishe

La calmoduline, un médiateur essentiel du calcium intracellulaire

SCOPUS: NotDefined.jinfo:eu-repo/semantics/publishe

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Etude de l'activité anticancéreuse des inhibiteurs de désacétylases chez des cellules isolées de patients atteints de mésothéliome pleural

Le mésothéliome pleural est un cancer de la plèvre provoqué par l’inhalation de fibres d’amiante. Bien que cette maladie soit encore assez rare, une augmentation de sa fréquence est attendue vers 2010-2020. Dans le développement de cette maladie incurable, la dérégulation de l’expression de certains gènes semble jouer un rôle essentiel. Les histones désacétylases (HDACs), en modifiant la conformation de la chromatine, jouent le rôle de répresseur transcriptionnel. L’utilisation d’inhibiteurs d’ HDACs serait donc une façon de lutter contre ce type de cancer. Notre travail a tout d’abord consisté à étudier l’effet de deux de ces molécules (valproate et SAHA) sur l’apoptose, sur le cycle cellulaire et sur l’acétylation des histones. Ensuite, des combinaisons de molécules (inhibiteurs d’HDACs et composés de chimiothérapie) ont été testées de manière à rechercher un effet de synergie. Nos résultats mettent en évidence que les inhibiteurs d’HDACs provoquent l’augmentation des niveaux d’apoptose et l’arrêt du cycle cellulaire en phase G1. Différentes combinaisons de molécules permettent d’obtenir un effet additif voire une synergie. Parmi ces combinaisons, l’utilisation de l’adriamycine, de l’etoposide, du taxotère ou du TRAIL donne les meilleurs résultats