Bobigny, France
Bobigny, France

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Thepot S.,French Institute of Health and Medical Research | Thepot S.,University Paris XIII | Lainey E.,French Institute of Health and Medical Research | Lainey E.,University Paris - Sud | And 27 more authors.
Cell Cycle | Year: 2011

The deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agents - notably azacitidine - constitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine - and to a lesser degree azacitidine - induced the activation of checkpoint kinases Chk-1 and Chk-2, and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box O3, best known as FOXO3A, whose phosphorylation has been related to poor prognosis in AML. The dephosphorylation of FOXO3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FOXO3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FOXO3A and the pro-apoptotic FOXO3A targets BIM and PUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the re-activation of FOXO3A may contribute to the effects of hypomethylating agents in malignant blasts. © 2011 Landes Bioscience.

Tailler M.,French Institute of Health and Medical Research | Tailler M.,Institute Gustave Roussy | Tailler M.,University Paris - Sud | Senovilla L.,French Institute of Health and Medical Research | And 35 more authors.
Oncogene | Year: 2012

Despite recent progress in the treatment of acute myeloid leukemia (AML), the prognosis of this rather heterogeneous disease remains poor and novel chemotherapeutics that specifically target leukemic cells must be developed. To address this need at the preclinical level, we implemented a high content imaging-based screen for the identification of small agents that induce AML cell death in vitro. Among a panel of 1040 Food and Drug Administration-approved agents, we identified pyrithione zinc (PZ) and ouabain (OUA) as potential antileukemic compounds. Both PZ and OUA efficiently induced cell death associated with apoptotic chromatin condensation and inhibition of nuclear factor-κB survival signaling, leading to reduced expression of antiapoptotic proteins, in several AML cell lines. PZ-and OUA-induced cell death was associated with the permeabilization of the outer mitochondrial membrane and led to the release of cytochrome c followed by caspase activation. Both PZ and OUA exerted significant anticancer effects in vivo, on human AML cells xenografts as well as ex vivo, on CD34 + (but not CD34 - ) malignant myeloblasts from AML patients. Altogether, our results suggest that PZ and OUA may exhibit antileukemic effects by inducing the apoptotic demise of AML cells. © 2012 Macmillan Publishers Limited.

Boehrer S.,University Paris XIII | Schroeder P.,EUFETS GmbH | Mueller T.,Fresenius Biotech GmbH | Atz J.,Fresenius Biotech GmbH
Anti-Cancer Drugs | Year: 2011

Monoclonal antibodies such as rituximab and alemtuzumab show considerable therapeutic efficacy in chronic lymphocytic leukaemia (CLL). Aiming to further improve antineoplastic efficacy, the trifunctional bispecific antibody FBTA05 was developed. FBTA05 is thought to function by simultaneously binding B cells and T cells by its variable regions and by recruiting FcγR-positive accessory immune cells by its intact Fc region. As it was previously shown that this antibody shows considerable cytotoxicity towards a spectrum of B-cell lymphoma cell lines, we here tested its potential efficacy ex vivo against malignant B-CLL cells. Therefore, we assessed the capacity of increasing concentrations of FBTA05 to bind to neoplastic cells, to induce cytotoxicity (comparing it with rituximab and alemtuzumab) and cytokine release. We evaluated the results with respect to the extent of CD20 expression, the effector:target cell ratio as well as with the patients' overall effector cell status. Thus, we show that, although FBTA05-elicited cytotoxicity was comparable with that induced by alemtuzumab, it considerably exceeded the antineoplastic effects of rituximab. Noteworthy, FBTA05 shows effective elimination of malignant B cells even if CD20 surface expression is low. Importantly, a high grade of cytotoxicity was associated with the induction of T-cell proliferation and the concomittant release of interferon-γ and interleukin-6, thus overcoming the detrimental effects of an unfavourable effector:target cell ratio. In conclusion, we here present novel evidence for the therapeutic efficacy of the trifunctional, bispecific antibody FBTA05 in CLL and provide evidence for the importance of immune-mediated mechanisms conveying the cytotoxic effects against malignant B lymphocytes. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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