References of "Willems, Luc"
     in
Bookmark and Share    
See detailReprogramming of replication origin firing and checkpoint adaptation in adult T cell leukemia
Barez, Pierre-Yves ULg; Carpentier, Alexandre ULg; Willems, Luc ULg

Conference (2012, December 14)

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that infects about twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most common are the adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). A key parameter of HTLV-1 pathogenesis is faster replication of provirus-carrying lymphocytes allowing clonal expansion of infected cell populations. The virally-encoded Tax oncoprotein plays an essential role in this process by interacting with DNA replication origins and accelerating S phase progression. By reprogramming the timing of origin firing, Tax also creates a replicative stress leading to DNA double strand breaks. This mechanism further triggers the DNA damage response (DDR) that induces cell cycle arrest and initiates either apoptosis or senescence. However, HTLV-1 infected cells have developed strategies to interfere with the DDR and are adapted to checkpoint control. These cells are thus able to proliferate despite occurrence of DNA damage. Based on these observations, we now propose a novel therapeutic approach based on the principle of synthetic lethality. [less ▲]

Detailed reference viewed: 27 (0 ULg)
Full Text
Peer Reviewed
See detailTransformation by deltaretroviruses: mechanisms and therapies
Willems, Luc ULg

in Proceedings of the Belgian Royal Academies of Medicine (2012), 1

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million subjects worldwide and causes Adult T-cell leukemia-lymphoma (ATLL) or HAM/TSP (HTLV-induced myelopathy - tropical spastic paraparesis). BLV is the etiological agent of enzootic bovine leukemia. HTLV-1 and BLV have developed strategies to subvert hosts' immune surveillance. Understanding these mechanisms has allowed development of novel therapeutic approaches. [less ▲]

Detailed reference viewed: 13 (1 ULg)
Full Text
Peer Reviewed
See detailTransformation by deltaretroviruses: mechanisms and therapies
Willems, Luc ULg

in Proceedings of the Belgian Royal Academies of Medicine (2012), 1

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million subjects worldwide and causes Adult T-cell leukemia-lymphoma (ATLL) or HAM/TSP (HTLV-induced myelopathy - tropical spastic paraparesis). BLV is the etiological agent of enzootic bovine leukemia. HTLV-1 and BLV have developed strategies to subvert hosts' immune surveillance. Understanding these mechanisms has allowed development of novel therapeutic approaches. [less ▲]

Detailed reference viewed: 5 (2 ULg)
Full Text
Peer Reviewed
See detailTransformation by deltaretroviruses: mechanisms and therapies
Willems, Luc ULg

in Proceedings of the Belgian Royal Academies of Medicine (2012), 1

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million ... [more ▼]

Human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are two closely related deltaretroviruses inducing hematological diseases in human and ruminants. HTLV-1 infects about 25 million subjects worldwide and causes Adult T-cell leukemia-lymphoma (ATLL) or HAM/TSP (HTLV-induced myelopathy - tropical spastic paraparesis). BLV is the etiological agent of enzootic bovine leukemia. HTLV-1 and BLV have developed strategies to subvert hosts' immune surveillance. Understanding these mechanisms has allowed development of novel therapeutic approaches. [less ▲]

Detailed reference viewed: 3 (0 ULg)
Full Text
See detailSynthesis and physico-chemical characterization of fatty esters
Sainvitu, Pauline ULg; Nott, Katherine ULg; Nicks, Francois ULg et al

Poster (2012, November 16)

Specific antioxidant molecules (e.g. phenolics) help to prevent oxidation reaction of the cell membrane. A fatty chain grafted on these compounds should enhance their capacity to interact with the ... [more ▼]

Specific antioxidant molecules (e.g. phenolics) help to prevent oxidation reaction of the cell membrane. A fatty chain grafted on these compounds should enhance their capacity to interact with the membrane lipids. In our study, three fatty esters comprising an aromatic part were synthesized. They differentiate the aromatic substituent and the number of carbons between the aromatic ring and the ester function. A structure-function relationships study was performed to identify the structural pattern affecting the interfacial properties and the membrane interaction properties. The behavior of their monolayer film at an air-water interface was studied. The interactions with membrane were assessed on living cells and were predicted by a computational approach. In the future, we will investigate the effect of the presence of a sugar unit on these molecules. [less ▲]

Detailed reference viewed: 22 (7 ULg)
Full Text
Peer Reviewed
See detailChemoresistance to Valproate Treatment of Bovine Leukemia Virus-Infected Sheep; Identification of Improved HDAC Inhibitors
Gillet, Nicolas ULg; Vandermeers, Fabian ULg; De Brogniez, Alix ULg et al

in Pathogens (2012), (2012-1), 65-82

We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms ... [more ▼]

We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA-induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1. [less ▲]

Detailed reference viewed: 25 (6 ULg)
Full Text
See detailUnderstanding angiogenesis through novel epigenetic modulators
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice; Blacher, Silvia ULg et al

Scientific conference (2012, June 22)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present work is focused on exploring the exact role of these genes on angiogenesis using RNA silencing and vectors cloned with genes of interest. We are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer. [less ▲]

Detailed reference viewed: 69 (13 ULg)
Full Text
See detailInteraction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program
Barez, Pierre-Yves ULg; Willems, Luc ULg

Poster (2012, June 22)

First human retrovirus discovered, HTLV-1 infects approximately twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most important are the adult T ... [more ▼]

First human retrovirus discovered, HTLV-1 infects approximately twenty million individuals worldwide. HTLV-1 is the causative agent of different diseases among which the most important are the adult T-cell leukemia (ATL) and a neurodegenerative disorder called HAM/TSP (Human associated myelopathy/ Tropical spastic paraparesis). We are interested in the mechanisms of transformation by the viral Tax oncoprotein. Recently, we showed that Tax interacts with the minichromosome maintenance MCM2-7 helicase and binds to origins of DNA replication (Boxus et al, 2012 Blood 119:151). Thereby, Tax modulates the spatiotemporal program of origin activation during the S phase of cell cycle. In fact, Tax accelerates S phase progression by inducing early firing of late replication origins. Concomitantly, Tax-MCM2-7 interplay also modulates viral transcription. Together, our data demonstrates that interaction between Tax and MCM2-7 is involved in replication reprogramming and viral transcription. [less ▲]

Detailed reference viewed: 23 (12 ULg)
Full Text
Peer Reviewed
See detailInteraction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program
Boxus, Mathieu ULg; Twizere, Jean-Claude ULg; Legros, Sébastien et al

in Blood (2012), 119

The Tax oncoprotein encoded by the Human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in viral persistence and pathogenesis. HTLV-1 infected cells proliferate faster than normal lymphocytes ... [more ▼]

The Tax oncoprotein encoded by the Human T-cell leukemia virus type 1 (HTLV-1) plays a pivotal role in viral persistence and pathogenesis. HTLV-1 infected cells proliferate faster than normal lymphocytes, expand through mitotic division and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax modulates the spatiotemporal program of origin activation and fires supplementary origins at the onset of S phase. Thereby, Tax increases the DNA replication rate, accelerates S phase progression but also generates a replicative stress characterized by the presence of genomic lesions. Mechanistically, Tax favors p300 recruitment and histone hyperacetylation at late replication domains advancing their replication timing in early S phase. [less ▲]

Detailed reference viewed: 20 (8 ULg)
Full Text
Peer Reviewed
See detailHow the DNA damage response determines the fate of HTLV-1 Tax-expressing cells
Boxus, Mathieu ULg; Willems, Luc ULg

in Retrovirology (2012), 9(2),

How the Human T lymphotropic virus type 1 (HTLV-1) Tax protein stimulates proliferation while triggering cell cycle arrest and senescence remains puzzling. There is also a debate about the ability of Tax ... [more ▼]

How the Human T lymphotropic virus type 1 (HTLV-1) Tax protein stimulates proliferation while triggering cell cycle arrest and senescence remains puzzling. There is also a debate about the ability of Tax to activate or inhibit the DNA damage response. Here, we comment on these different activities and propose a conceptual rationale for the apparently conflicting observations. [less ▲]

Detailed reference viewed: 14 (3 ULg)
Full Text
Peer Reviewed
See detailViral expression directs the fate of B cells in BLV-infected sheep.
Florins, Arnaud-Francois ULg; De Brogniez, Alix ULg; Elemans, M. et al

in Journal of Virology (2012), 86(1), 621-624

The host immune response is believed to tightly control viral replication of deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). However, this assumption ... [more ▼]

The host immune response is believed to tightly control viral replication of deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV). However, this assumption has not been definitely proven in vivo. In order to further evaluate the importance of immune response in the BLV model, we studied the fate of cells in which viral expression was transiently induced. Using a dual fluorochrome labeling approach, we show that ex vivo induction of viral expression induces higher death rates of B cells in vivo. Furthermore, cyclosporine treatment of these animals indicated that an efficient immune response is required to control virus expressing cells. [less ▲]

Detailed reference viewed: 24 (9 ULg)
Full Text
Peer Reviewed
See detailSafety of long-term treatment of HAM/TSP patients with valproic acid
Olindo, Stéphane; Belrose, Gildas; Gillet, Nicolas ULg et al

in Blood (2011), 118(24), 6306-6309

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential ... [more ▼]

HTLV-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is a neurodegenerative disease of the central nervous system induced by Human T lymphotropic virus type 1 (HTLV-1). As a potential therapeutic approach, we previously suggested reducing the proviral load (PVL) by modulating lysine deacetylase activity using valproic acid (VPA) and exposing virus-positive cells to the host immune response. We conducted a single-center, two-year open-label trial, with 19 HAM/TSP volunteers treated with oral VPA. PVL, CD38/HLA-DR expression and CD8+ lysis efficiency were not significantly affected by VPA. Mean scores of HAM/TSP disability did not differ between baseline and final visit. Walking Time Test (WTT) increased significantly (>20%) in 3 patients and was in keeping with minor VPA side effects (drowsiness and tremor). WTT improved rapidly after VPA discontinuation. We conclude that long term treatment with VPA is safe in HAM/TSP. [less ▲]

Detailed reference viewed: 15 (8 ULg)
Full Text
See detailThérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie
Costa, Chrisostome ULg; Vandermeers, Fabian ULg; Reddy, NS Sathyanarayana ULg et al

Diverse speeche and writing (2011)

Thérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie. Chrisostome Costa 1, Fabian Vandermeers 2, Sathyanarayana Reddy 2, Céline Mascaux 3, Pascale Hubert 2 ... [more ▼]

Thérapie du mésothéliome pleural : compréhension des mécanismes de résistance à la chimiothérapie. Chrisostome Costa 1, Fabian Vandermeers 2, Sathyanarayana Reddy 2, Céline Mascaux 3, Pascale Hubert 2, Philippe Delvenne 2, Luc Willems 1,2 1 Laboratoire de biologie cellulaire et moléculaire, ULg, Gemboux Agro Bio-Tech, 13 av. Maréchal Juin, 5030 Gembloux ; Tél. : 32-(0)-81-622157 ; Fax : 32-(0)-81-6138 88 ; Courriel: ccosta@doct.ulg.ac.be 2 GIGA, ULg, Liège 3 Institut Bordet, ULB, Bruxelles - Introduction : Le mésothéliome pleural malin (MPM) est un cancer de la plèvre causé principalement par l’inhalation de fibres d’amiante. Nous avons montré précédemment que les inhibiteurs d’histones deacetylases (tel que le valproate, VPA) augmentent significativement l’efficacité des composés utilisés en chimiothérapie (pemetrexed et cisplatin) et prolonge la survie des patients atteints de MPM. Malheureusement, une proportion importante des patients développe une résistance au traitement de seconde ligne avec la doxorubicine et le VPA. - But du projet : L’objectif du travail est de disséquer les mécanismes qui régissent la réponse au traitement de seconde ligne du MPM. - Méthodes et résultats : Nous avons tout d’abord comparé deux types de lignées cellulaires présentant soit une sensibilité (cellules M14K) soit une résistance (cellules H28) au traitement combiné VPA+doxorubicine. En utilisant des microdamiers (Agilent), nous avons analysé le profil d’expression génique de cellules M14K et H28 traitées avec le VPA et la doxorubicine. Après quantification des fluorescences, une analyse statistique (Genespring GX) et une modélisation bioinformatique (Ingenuity) ont permis d’identifier les gènes candidats les plus relevants. En fonction de la p-value et du fold change, un nombre limité de gènes ont été sélectionnés et validés par la technique de qRT-PCR. Parmi ceux-ci, nous avons identifié le gène TGFA dont l’expression corrèle avec la résistance au traitement. En effet, nous avons observé que le niveau d’expression basale du gène TGFA est beaucoup plus important dans la lignée résistante H28 que dans la lignée sensible M14K. Dans le but de valider son implication dans la réponse à la thérapie, nous avons diminué (par interférence ARN) ou augmenté (par transfection d’un vecteur d’expression) l’expression de TGFA respectivement dans les lignées H28 ou M14K. Nous avons ensuite déterminé les taux d’apoptose en évaluant la fragmentation de l’ADN en présence de doxorubicine et de VPA. Les résultats montrent que la diminution de l’expression de TGFA permet une augmentation sensible de l’apoptose induite par le traitement combiné doxorubicine et VPA dans la lignée résistante H28 (de 9% à 36%). A l’inverse, la surexpression de TGFA est associée avec une diminution d’apoptose dans la lignée sensible M14K (de 28% à 18%). Ces observations ont été confirmées par une analyse de l’activité des caspases 3 et 7. En accord avec la propriété de la protéine TGFAd’induire la prolifération cellulaire via le récepteur à l’EGF, des inhibiteurs de l’activité tyrosine kinase (l’Iressa et le Tarceva) augmentent l’apoptose induite par la doxorubicine et le VPA dans la lignée résistante H28 (de 16% à 40%). L’efficacité du traitement combiné VPA+doxorubicine+Iressa/Tarceva est actuellement évaluée en modèle murin (souris SCID). - Conclusions : Nous avons identifié un gène, le TGFA, dont l’expression corrèle avec la résistance à l’apoptose induite par la doxorubicine et le VPA. L’utilisation d’inhibiteurs du récepteur EGF pourrait donc améliorer le traitement de seconde ligne du MPM. [less ▲]

Detailed reference viewed: 55 (10 ULg)
Full Text
Peer Reviewed
See detailOpposite effects of valproate on Tax and HBZ expressions in T-lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients.
Belrose, Gildas; Gross, Antoine; Olindo, Stéphane et al

in Blood (2011), 118(9), 2483-2491

A determinant of human T-lymphotropic virus-1 (HTLV-1)–associated myelopathy/ tropical spastic paraparesis (HAM/TSP) development is the HTLV-1–infected cell burden. Viral proteins Tax and HBZ, encoded by ... [more ▼]

A determinant of human T-lymphotropic virus-1 (HTLV-1)–associated myelopathy/ tropical spastic paraparesis (HAM/TSP) development is the HTLV-1–infected cell burden. Viral proteins Tax and HBZ, encoded by the sense and antisense strands of th pX region, respectively, play key roles in HTLV-1 persistence. Tax drives CD4 - cel clonal expansion and is the immunodominant viral antigen recognized by the immune response. Valproate (2-n-propylpentanoic acid, VPA), a histone deacetylase inhibitor, was thought to trigger Tax expression, thereby exposing the latent HTLV-1 reservoir to immune destruction. We evaluated the impact of VPA on Tax, Gag, and HBZ expressions in cultured lymphocytes from HTLV-1 asymptomatic carriers and HAM/TSP patients. Approximately one-fifth of proviruspositive CD4 T cells spontaneously became Tax-positive, but this fraction rose to two-thirds of Tax positive–infected cells when cultured with VPA. Valproate enhanced Gag-p19 release. Tax- and GagmRNA levels peaked spontaneously, before declining concomitantly to HBZmRNA increase. VPA enhanced and prolonged Tax-mRNA expression, whereas it blocked HBZ expression. Our findings suggest that, in addition to modulating Tax expression, another mechanism involving HBZ repression might determine the outcome ofVPAtreatment on HTLV-1–infected– cell proliferation and survival. [less ▲]

Detailed reference viewed: 18 (1 ULg)
Full Text
Peer Reviewed
See detailPreventive and Therapeutic Strategies for Bovine Leukemia Virus: Lessons for HTLV
Rodriguez, Sabrina ULg; Florins, Arnaud-Francois ULg; Gillet, Nicolas ULg et al

in Viruses (2011), 3(7), 1210-1248

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of ... [more ▼]

Bovine leukemia virus (BLV) is a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1). BLV is a major animal health problem worldwide causing important economic losses. A series of attempts were developed to reduce prevalence, chiefly by eradication of infected cattle, segregation of BLV-free animals and vaccination. Although having been instrumental in regions such as the EU, these strategies were unsuccessful elsewhere mainly due to economic costs, management restrictions and lack of an efficient vaccine. This review, which summarizes the different attempts previously developed to decrease seroprevalence of BLV, may be informative for management of HTLV-1 infection. We also propose a new approach based on competitive infection with virus deletants aiming at reducing proviral loads. [less ▲]

Detailed reference viewed: 84 (9 ULg)
Full Text
See detailEpigenetic regulation of angiogenesis
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice ULg; Willems, Luc ULg

Speech (2011)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We designed a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities and tested in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound (EPI) affecting global histone acetylation and having quantifiable anti-angiogenic action without cytotoxic and apoptotic effect. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with EPI and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by EPI but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway Analysis software revealing potential involvement of a subset of genes in angiogenesis. Our present aim is to validate the expression levels of a series of genes with respect to epigenetic mechanisms (histone modifications and DNA methylation). Finally, the biological relevance of the target genes will be explored by RNA silencing. Hence, we are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer. [less ▲]

Detailed reference viewed: 97 (14 ULg)
Full Text
See detailNovel HDAC/DNMT Twin inhibitors interfere with angiogenesis
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice ULg; Blacher, Silvia ULg et al

Poster (2011, January 31)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present aim is to validate the expression levels of a series of genes with respect to epigenetic mechanisms (histone modifications and DNA methylation). Finally, the biological relevance of the target genes will be explored by RNA silencing. Hence, we are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer. [less ▲]

Detailed reference viewed: 73 (17 ULg)
Full Text
Peer Reviewed
See detailValproate–doxorubicin: promising therapy for progressing mesothelioma. A phase II study
Scherpereel, a; Berghmans, t; Lafitte, j.j et al

in European Respiratory Journal (2011), 37

No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone deacetylase inhibitor ... [more ▼]

No treatment is recommended for patients with malignant mesothelioma (MM) failing after first-line cisplatin-based chemotherapy. In vitro data suggested that valproic acid, a histone deacetylase inhibitor (HDACi), had a proapoptotic effect and synergised with doxorubicin to induce apoptosis in MM cells. Our primary end-point was to determine response rate of combined valproic acid and doxorubicin in patients with unresectable MM failing after platinum based chemotherapy. Treatment consisted of doxorubicin (60 mg?m-2) plus valproic acid. An interim analysis for response rate was planned after the first 16 registered patients. All the cases were centrally reviewed. From July 2006 to March 2009, 45 eligible patients with pleural MM were registered. The majority of the patients were male (73%), had a performance status (PS) o80 (76%) and an epithelioid subtype (80%). There were seven partial responses (response rate 16%; 95% CI 3– 25%), all in patients with PS 80–100. The best disease control rate was 36% (95% CI 22–51%). Two toxic deaths were observed (febrile neutropenia and cerebral thrombotic event), both in patients with poor PS (60–70). Valproic acid, an HDACi, plus doxorubicin appeared an effective chemotherapy regimen in good PS (80–100) patients with refractory or recurrent MM, for which no standard therapy was available. [less ▲]

Detailed reference viewed: 41 (7 ULg)