12 research outputs found
Analyse in vitro et in vivo de l'activité anti-tumorale d'UVI5008, un nouvel inhibiteur d'enzymes modifiant la chromatine
De plus en plus de donnĂ©es indiquent que le cancer n est pas uniquement la consĂ©quence d'altĂ©rations gĂ©nĂ©tiques, mais rĂ©sulte Ă©galement en partie d'altĂ©rations Ă©pigĂ©nĂ©tiques. De façon intĂ©ressante, cette dĂ©rĂ©gulation Ă©pigĂ©nĂ©tique est rĂ©versible, faisant des enzymes responsables des cibles thĂ©rapeutiques potentielles. En effet, les enzymes de modification de la chromatine et en particulier les Histones DĂ©acĂ©tylases (HDACs) et les ADN MĂ©thyltransfĂ©rases (DNMTs), ont rĂ©cemment Ă©mergĂ© comme de nouvelles cibles prometteuses appelĂ©es drogues Ă©pigĂ©nĂ©tiques pour le traitement des cancers. Le but de ce projet a Ă©tĂ© de caractĂ©riser l'activitĂ© de UVI5008, un dĂ©rivĂ© de la psammaplin A qui a initialement Ă©tĂ© isolĂ©e de l'Ă©ponge marine Psammaplysilla. Ce composĂ© a Ă©tĂ© synthĂ©tisĂ© dans le laboratoire de l'un de nos collaborateurs, le professeur Angel R. de Lera (UniversitĂ© de Vigo, Espagne), et nous avons pu montrer que ce composĂ© cible spĂ©cifiquement plusieurs enzymes Ă©pigĂ©nĂ©tiques et prĂ©sente une activitĂ© anti-tumorale in vitro et in vivo. Nous avons Ă©valuĂ© l'activitĂ© anti-tumorale potentielle de UVI5008 in vitro sur des lignĂ©es de cellules cancĂ©reuses et ex vivo sur des blastes issus de patients leucĂ©miques. Nos rĂ©sultats indiquent que UVI5008 rĂ©duit la prolifĂ©ration cellulaire en induisant un arrĂȘt du cycle cellulaire en phase G1-M et l'apoptose dans des lignĂ©es cellulaires de leucĂ©mie myĂ©loĂŻde aiguĂ« (AML) Ă©tablies et dans des blastes issus de patients AML'en culture ex vivo. Des essais enzymatiques in vitro ont permis de mettre en Ă©vidence que UVI5008 bloque l'activitĂ© de HDAC1, 4 et 6 et augmente l'acĂ©tylation globale et spĂ©cifique des histones. Outre son activitĂ© d'inhibition des HDACs, ce nouvel inhibiteur bloque Ă©galement la mĂ©thylation des Ăźlots CpG situĂ©s sur les promoteurs des gĂšnes suppresseurs de tumeur p16/INK4 et RAR-Beta, un rĂ©cepteur de l'acide rĂ©tinoĂŻque. Enfin, nous avons observĂ© que UVI5008 possĂšde des capacitĂ©s inhibitrices des sirtuines, le niveau d'acĂ©tylation de p53 sur le rĂ©sidu lysine 382 Ă©tant augmentĂ© suite Ă un traitement avec ce composĂ©. Nous avons Ă©galement pu mettre en Ă©vidence une activitĂ© antitumorale de UVI5008 in vivo dans des xĂ©nogreffes de cellules HCT116 (issues de cancer du colon humain) et de cellules MCF7 (provenant de cancer du sein humain) dans des souris nues, de mĂȘme que dans un modĂšle murin de cancer mammaire, les souris MMTV-Myc. Dans ces diffĂ©rents modĂšles, une augmentation de l'acĂ©tylation des histones et de p53K382 a pu ĂȘtre observĂ©e in tumouri. De façon importante, l'activitĂ© de UVI5008 est spĂ©cifique des cellules cancĂ©reuses et sans toxicitĂ© importante pour les cellules normales. De plus, son activitĂ© est indĂ©pendante de p53, ce qui reprĂ©sente un avantage, la majoritĂ© des cancers ayant une mutation ou une extinction de l'expression de p53. ErbB2 joue un rĂŽle important dans de nombreuses pathologies humaines. Son niveau est augmentĂ© par amplification gĂ©nique ou surexpression dans environ 30 % des cancers mammaires humains, de mĂȘme que dans d'autres pathologies humaines, et cette marque est associĂ©e Ă un mauvais pronostique pour les patients. Nous avons donc choisi de tester l'activitĂ© anti-tumorale de UVI5008 sur un autre modĂšle de tumorigenĂšse chez la souris par la surexpression de l'oncogĂšne ErbB2 dans la glande mammaire, les souris MMTV-ErbB2, et nous avons pu montrer une efficacitĂ© similaire de UVI5008 sur ces tumeurs mammaires. Ă l'heure actuelle, il n existe pas de traitement qui cible simultanĂ©ment l'ensemble de ces 3 familles d'enzymes que sont les HDACs, les DNMTs et les SIRTs. Nos rĂ©sultats suggĂšrent fortement que ces enzymes peuvent ĂȘtre ciblĂ©es simultanĂ©ment par un composĂ© unique, ce qui pourrait reprĂ©senter un avantage pour les nouvelles thĂ©rapies contre le cancer.It is becoming increasingly clear that cancer is a consequence not only of genetic but also of epigenetic alterations. Interestingly, this epigenetic deregulation is reversible making the corresponding enzymes promising drug targets. Chromatin modifying enzymes, in particular histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), have recently emerged as new promising targets of the so-called epigenetic drugs for the treatment of cancer. The aim of this project is to characterize the activities of UVI 5008, a derivative of psammaplin A, a natural product that was originally isolated from the marine sponge Psammaplysilla sp. This compound was synthesized by one of our collaborators, Prof. Angel. R de Lera s lab (Vigo University, Spain) and we were able to show that it targets several epigenetic effector enzymes and displays anti-tumour activity in vitro and in vivo. We have assessed the tumoricidal activity of UVI5008 both in vitro in a panel of cancer cell lines as well as ex vivo in leukemia patient s blasts. Our results indicate that UVI5008 reduces cell proliferation by inducing G1-M arrest and apoptosis in established acute myeloid leukemia (AML) cells and AML patient s blasts in ex vivo culture. In vitro enzymatic assays showed that UVI5008 blocks HDAC1, 4 and 6 as well as increases the global and site-specific histone acetylation. Apart from its HDAC inhibitory activity, the novel inhibitor blocks CpG island methylation of the promoters of p16/INK4 and retinoic acid receptors (RAR)-beta tumor suppressors. Moreover, we have observed that UVI5008 has sirtuin inhibitory capacity as it increases the acetylation levels of p53 on lysine 382 residue. We could also show that UVI5008 exerts its antitumor effect in vivo in HCT-116 (human colon cancer) and MCF-7 (human breast cancer) xenografted tumours in nude mice as well as in a mouse breast cancer model MMTV-myc, which was accompanied by increased histone and p53K382 acetylation in tumouri. Importantly, UVI5008 anti-tumoral activity is selective for cancer cells, without significant toxicity to normal cells and is p53-independent which is also promising, as in the majority of cancers p53 is either silenced or mutated. It is well documented that ErbB2 gene plays an important role in human malignancies. It is amplified and /or overexpressed in approximately 30% of human breast carcinomas and in many other types of human malignancies and individuals with ErbB2-overexpressing tumours have significantly poor clinical outcome. Taking into consideration this fact, we have assessed the anti tumour activity of UVI5008 in one more mouse breast cancer model MMTV-ErbB2, which revealed that UVI5008 is equally active in ErbB2 overexpressing breast tumours. To date there is not a single drug that simultaneously targets all these three families of enzymes namely HDACs, DNMTs and SIRTs. Taken together, our data strongly suggest that targeting these enzymes simultaneously by a single drug is a feasible and an attractive paradigm for new cancer therapies
In vitro and in vivo analysis of antiâtumour activity of UVI5008, a novel chromatin enzyme inhibitor
De plus en plus de donnĂ©es indiquent que le cancer nâest pas uniquement la consĂ©quence dâaltĂ©rations gĂ©nĂ©tiques, mais rĂ©sulte Ă©galement en partie dâaltĂ©rations Ă©pigĂ©nĂ©tiques. De façon intĂ©ressante, cette dĂ©rĂ©gulation Ă©pigĂ©nĂ©tique est rĂ©versible, faisant des enzymes
responsables des cibles thérapeutiques potentielles. En effet, les enzymes de modification de la chromatine et en particulier les Histones Déacétylases (HDACs) et les ADN
Méthyltransférases (DNMTs), ont récemment émergé comme de nouvelles cibles prometteuses appelées « drogues épigénétiques » pour le traitement des cancers. Le but de ce
projet a Ă©tĂ© de caractĂ©riser lâactivitĂ© de UVI5008, un dĂ©rivĂ© de la psammaplin A qui a initialement Ă©tĂ© isolĂ©e de lâĂ©ponge marine Psammaplysilla. Ce composĂ© a Ă©tĂ© synthĂ©tisĂ© dans le laboratoire de lâun de nos collaborateurs, le professeur Angel R. de Lera (UniversitĂ© de Vigo, Espagne), et nous avons pu montrer que ce composĂ© cible spĂ©cifiquement plusieurs enzymes Ă©pigĂ©nĂ©tiques et prĂ©sente une activitĂ© anti-tumorale in vitro et in vivo. Nous avons Ă©valuĂ© lâactivitĂ© anti-tumorale potentielle de UVI5008 in vitro sur des lignĂ©es de cellules cancĂ©reuses et ex vivo sur des blastes issus de patients leucĂ©miques. Nos rĂ©sultats
indiquent que UVI5008 rĂ©duit la prolifĂ©ration cellulaire en induisant un arrĂȘt du cycle cellulaire en phase G1-M et lâapoptose dans des lignĂ©es cellulaires de leucĂ©mie myĂ©loĂŻde
aiguĂ« (AML) Ă©tablies et dans des blastes issus de patients AML en culture ex vivo. Des essais enzymatiques in vitro ont permis de mettre en Ă©vidence que UVI5008 bloque lâactivitĂ© de HDAC1, 4 et 6 et augmente lâacĂ©tylation globale et spĂ©cifique des histones. Outre son activitĂ©
dâinhibition des HDACs, ce nouvel inhibiteur bloque Ă©galement la mĂ©thylation des Ăźlots CpG situĂ©s sur les promoteurs des gĂšnes suppresseurs de tumeur p16/INK4 et RAR-Beta, un rĂ©cepteur de lâacide rĂ©tinoĂŻque. Enfin, nous avons observĂ© que UVI5008 possĂšde des capacitĂ©s inhibitrices des sirtuines, le niveau dâacĂ©tylation de p53 sur le rĂ©sidu lysine 382 Ă©tant augmentĂ© suite Ă un traitement avec ce composĂ©. Nous avons Ă©galement pu mettre en Ă©vidence une activitĂ© antitumorale de UVI5008 in vivo dans des xĂ©nogreffes de cellules HCT116 (issues de cancer du colon humain) et de cellules MCF7 (provenant de cancer du
sein humain) dans des souris nues, de mĂȘme que dans un modĂšle murin de cancer mammaire, les souris MMTV-Myc. Dans ces diffĂ©rents modĂšles, une augmentation de lâacĂ©tylation des histones et de p53K382 a pu ĂȘtre observĂ©e in tumouri. De façon importante, lâactivitĂ© de UVI5008 est spĂ©cifique des cellules cancĂ©reuses et sans toxicitĂ© importante pour les cellules normales. De plus, son activitĂ© est indĂ©pendante de p53, ce qui reprĂ©sente un avantage, la
majoritĂ© des cancers ayant une mutation ou une extinction de lâexpression de p53. ErbB2 joue un rĂŽle important dans de nombreuses pathologies humaines. Son niveau est
augmentĂ© par amplification gĂ©nique ou surexpression dans environ 30 % des cancers mammaires humains, de mĂȘme que dans dâautres pathologies humaines, et cette marque est
associĂ©e Ă un mauvais pronostique pour les patients. Nous avons donc choisi de tester lâactivitĂ© anti-tumorale de UVI5008 sur un autre modĂšle de tumorigenĂšse chez la souris par la surexpression de lâoncogĂšne ErbB2 dans la glande mammaire, les souris MMTV-ErbB2, et nous avons pu montrer une efficacitĂ© similaire de UVI5008 sur ces tumeurs mammaires. Ă lâheure actuelle, il nâexiste pas de traitement qui cible simultanĂ©ment lâensemble de ces 3
familles dâenzymes que sont les HDACs, les DNMTs et les SIRTs. Nos rĂ©sultats suggĂšrent fortement que ces enzymes peuvent ĂȘtre ciblĂ©es simultanĂ©ment par un composĂ© unique, ce qui pourrait reprĂ©senter un avantage pour les nouvelles thĂ©rapies contre le cancer.It is becoming increasingly clear that cancer is a consequence not only of genetic but also of epigenetic alterations. Interestingly, this epigenetic deregulation is reversible making the corresponding enzymes promising drug targets. Chromatin modifying enzymes, in particular
histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), have recently emerged as new promising targets of the so-called âepigenetic drugsâ for the treatment of
cancer. The aim of this project is to characterize the activities of UVI 5008, a derivative of psammaplin A, a natural product that was originally isolated from the marine sponge Psammaplysilla sp. This compound was synthesized by one of our collaborators, Prof. Angel.
R de Leraâs lab (Vigo University, Spain) and we were able to show that it targets several epigenetic effector enzymes and displays anti-tumour activity in vitro and in vivo.
We have assessed the tumoricidal activity of UVI5008 both in vitro in a panel of cancer cell lines as well as ex vivo in leukemia patientâs blasts. Our results indicate that UVI5008 reduces cell proliferation by inducing G1-M arrest and apoptosis in established acute myeloid leukemia (AML) cells and AML patientâs blasts in ex vivo culture. In vitro enzymatic assays showed that UVI5008 blocks HDAC1, 4 and 6 as well as increases the global and site-specific histone acetylation. Apart from its HDAC inhibitory activity, the novel inhibitor blocks CpG island methylation of the promoters of p16/INK4 and retinoic acid receptors (RAR)-beta
tumor suppressors. Moreover, we have observed that UVI5008 has sirtuin inhibitory capacity as it increases the acetylation levels of p53 on lysine 382 residue. We could also show that UVI5008 exerts its antitumor effect in vivo in HCT-116 (human colon cancer) and MCF-7 (human breast cancer) xenografted tumours in nude mice as well as in a mouse breast cancer model MMTV-myc, which was accompanied by increased histone and p53K382 acetylation in tumouri. Importantly, UVI5008 anti-tumoral activity is selective for cancer cells, without significant toxicity to normal cells and is p53-independent which is also promising, as in the
majority of cancers p53 is either silenced or mutated.
It is well documented that ErbB2 gene plays an important role in human malignancies. It is amplified and /or overexpressed in approximately 30% of human breast carcinomas and in many other types of human malignancies and individuals with ErbB2-overexpressing tumours
have significantly poor clinical outcome. Taking into consideration this fact, we have assessed the anti tumour activity of UVI5008 in one more mouse breast cancer model MMTV-ErbB2, which revealed that UVI5008 is equally active in ErbB2 overexpressing breast tumours. To date there is not a single drug that simultaneously targets all these three families of enzymes namely HDACs, DNMTs and SIRTs. Taken together, our data strongly suggest that targeting these enzymes simultaneously by a single drug is a feasible and an attractive paradigm for new cancer therapies
Analyse in vitro et in vivo de l'activité anti-tumorale d'UVI5008, un nouvel inhibiteur d'enzymes modifiant la chromatine
De plus en plus de donnĂ©es indiquent que le cancer n est pas uniquement la consĂ©quence d altĂ©rations gĂ©nĂ©tiques, mais rĂ©sulte Ă©galement en partie d altĂ©rations Ă©pigĂ©nĂ©tiques. De façon intĂ©ressante, cette dĂ©rĂ©gulation Ă©pigĂ©nĂ©tique est rĂ©versible, faisant des enzymes responsables des cibles thĂ©rapeutiques potentielles. En effet, les enzymes de modification de la chromatine et en particulier les Histones DĂ©acĂ©tylases (HDACs) et les ADN MĂ©thyltransfĂ©rases (DNMTs), ont rĂ©cemment Ă©mergĂ© comme de nouvelles cibles prometteuses appelĂ©es drogues Ă©pigĂ©nĂ©tiques pour le traitement des cancers. Le but de ce projet a Ă©tĂ© de caractĂ©riser l activitĂ© de UVI5008, un dĂ©rivĂ© de la psammaplin A qui a initialement Ă©tĂ© isolĂ©e de l Ă©ponge marine Psammaplysilla. Ce composĂ© a Ă©tĂ© synthĂ©tisĂ© dans le laboratoire de l un de nos collaborateurs, le professeur Angel R. de Lera (UniversitĂ© de Vigo, Espagne), et nous avons pu montrer que ce composĂ© cible spĂ©cifiquement plusieurs enzymes Ă©pigĂ©nĂ©tiques et prĂ©sente une activitĂ© anti-tumorale in vitro et in vivo. Nous avons Ă©valuĂ© l activitĂ© anti-tumorale potentielle de UVI5008 in vitro sur des lignĂ©es de cellules cancĂ©reuses et ex vivo sur des blastes issus de patients leucĂ©miques. Nos rĂ©sultats indiquent que UVI5008 rĂ©duit la prolifĂ©ration cellulaire en induisant un arrĂȘt du cycle cellulaire en phase G1-M et l apoptose dans des lignĂ©es cellulaires de leucĂ©mie myĂ©loĂŻde aiguĂ« (AML) Ă©tablies et dans des blastes issus de patients AML en culture ex vivo. Des essais enzymatiques in vitro ont permis de mettre en Ă©vidence que UVI5008 bloque l activitĂ© de HDAC1, 4 et 6 et augmente l acĂ©tylation globale et spĂ©cifique des histones. Outre son activitĂ© d inhibition des HDACs, ce nouvel inhibiteur bloque Ă©galement la mĂ©thylation des Ăźlots CpG situĂ©s sur les promoteurs des gĂšnes suppresseurs de tumeur p16/INK4 et RAR-Beta, un rĂ©cepteur de l acide rĂ©tinoĂŻque. Enfin, nous avons observĂ© que UVI5008 possĂšde des capacitĂ©s inhibitrices des sirtuines, le niveau d acĂ©tylation de p53 sur le rĂ©sidu lysine 382 Ă©tant augmentĂ© suite Ă un traitement avec ce composĂ©. Nous avons Ă©galement pu mettre en Ă©vidence une activitĂ© antitumorale de UVI5008 in vivo dans des xĂ©nogreffes de cellules HCT116 (issues de cancer du colon humain) et de cellules MCF7 (provenant de cancer du sein humain) dans des souris nues, de mĂȘme que dans un modĂšle murin de cancer mammaire, les souris MMTV-Myc. Dans ces diffĂ©rents modĂšles, une augmentation de l acĂ©tylation des histones et de p53K382 a pu ĂȘtre observĂ©e in tumouri. De façon importante, l activitĂ© de UVI5008 est spĂ©cifique des cellules cancĂ©reuses et sans toxicitĂ© importante pour les cellules normales. De plus, son activitĂ© est indĂ©pendante de p53, ce qui reprĂ©sente un avantage, la majoritĂ© des cancers ayant une mutation ou une extinction de l expression de p53. ErbB2 joue un rĂŽle important dans de nombreuses pathologies humaines. Son niveau est augmentĂ© par amplification gĂ©nique ou surexpression dans environ 30 % des cancers mammaires humains, de mĂȘme que dans d autres pathologies humaines, et cette marque est associĂ©e Ă un mauvais pronostique pour les patients. Nous avons donc choisi de tester l activitĂ© anti-tumorale de UVI5008 sur un autre modĂšle de tumorigenĂšse chez la souris par la surexpression de l oncogĂšne ErbB2 dans la glande mammaire, les souris MMTV-ErbB2, et nous avons pu montrer une efficacitĂ© similaire de UVI5008 sur ces tumeurs mammaires. Ă l heure actuelle, il n existe pas de traitement qui cible simultanĂ©ment l ensemble de ces 3 familles d enzymes que sont les HDACs, les DNMTs et les SIRTs. Nos rĂ©sultats suggĂšrent fortement que ces enzymes peuvent ĂȘtre ciblĂ©es simultanĂ©ment par un composĂ© unique, ce qui pourrait reprĂ©senter un avantage pour les nouvelles thĂ©rapies contre le cancer.It is becoming increasingly clear that cancer is a consequence not only of genetic but also of epigenetic alterations. Interestingly, this epigenetic deregulation is reversible making the corresponding enzymes promising drug targets. Chromatin modifying enzymes, in particular histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), have recently emerged as new promising targets of the so-called epigenetic drugs for the treatment of cancer. The aim of this project is to characterize the activities of UVI 5008, a derivative of psammaplin A, a natural product that was originally isolated from the marine sponge Psammaplysilla sp. This compound was synthesized by one of our collaborators, Prof. Angel. R de Lera s lab (Vigo University, Spain) and we were able to show that it targets several epigenetic effector enzymes and displays anti-tumour activity in vitro and in vivo. We have assessed the tumoricidal activity of UVI5008 both in vitro in a panel of cancer cell lines as well as ex vivo in leukemia patient s blasts. Our results indicate that UVI5008 reduces cell proliferation by inducing G1-M arrest and apoptosis in established acute myeloid leukemia (AML) cells and AML patient s blasts in ex vivo culture. In vitro enzymatic assays showed that UVI5008 blocks HDAC1, 4 and 6 as well as increases the global and site-specific histone acetylation. Apart from its HDAC inhibitory activity, the novel inhibitor blocks CpG island methylation of the promoters of p16/INK4 and retinoic acid receptors (RAR)-beta tumor suppressors. Moreover, we have observed that UVI5008 has sirtuin inhibitory capacity as it increases the acetylation levels of p53 on lysine 382 residue. We could also show that UVI5008 exerts its antitumor effect in vivo in HCT-116 (human colon cancer) and MCF-7 (human breast cancer) xenografted tumours in nude mice as well as in a mouse breast cancer model MMTV-myc, which was accompanied by increased histone and p53K382 acetylation in tumouri. Importantly, UVI5008 anti-tumoral activity is selective for cancer cells, without significant toxicity to normal cells and is p53-independent which is also promising, as in the majority of cancers p53 is either silenced or mutated. It is well documented that ErbB2 gene plays an important role in human malignancies. It is amplified and /or overexpressed in approximately 30% of human breast carcinomas and in many other types of human malignancies and individuals with ErbB2-overexpressing tumours have significantly poor clinical outcome. Taking into consideration this fact, we have assessed the anti tumour activity of UVI5008 in one more mouse breast cancer model MMTV-ErbB2, which revealed that UVI5008 is equally active in ErbB2 overexpressing breast tumours. To date there is not a single drug that simultaneously targets all these three families of enzymes namely HDACs, DNMTs and SIRTs. Taken together, our data strongly suggest that targeting these enzymes simultaneously by a single drug is a feasible and an attractive paradigm for new cancer therapies.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF
Molecular evidence for increased antitumor activity of gemcitabine in combination with a cyclin-dependent kinase inhibitor, P276-00 in pancreatic cancers
Abstract Background P276-00 is a novel cyclin-dependent kinase inhibitor currently in Phase II clinical trials. Gemcitabine is a standard of care for the treatment of pancreatic cancer. The present study investigated the effect of the combination of P276-00 and gemcitabine in five pancreatic cancer cell lines. Methods Cytotoxic activity was evaluated by Propidium Iodide assay. Cell cycle and apoptosis was analyzed by flow cytometry. Genes and proteins known to inhibit apoptosis and contribute to chemoresistance were analysed using western blot analysis and RT-PCR. In vivo efficacy was studied in PANC-1 xenograft model. Results The combination of gemcitabine followed by P276-00 was found to be highly to weakly synergistic in various pancreatic cancer cell lines as assessed by the combination index. Enhancement of apoptosis in PANC-1 cells and decrease in the antiapoptotic protein Bcl-2 and survivin was seen. P276-00 potentiated the gemcitabine-induced cytotoxicity by modulation of proteins involved in chemoresistance to gemcitabine and cell cycle viz. antiapoptotic proteins p8 and cox-2, proapoptotic protein BNIP3 and cell cycle related proteins Cdk4 and cyclin D1. The above results could explain the novel mechanisms of action of the combination therapy. We also show here that gemcitabine in combination with P276-00 is much more effective as an antitumor agent compared with either agent alone in the PANC-1 xenograft tumor model in SCID mice. Conclusions The chemosensitzation of pancreatic tumors to gemcitabine would likely be an important and novel strategy for treatment of pancreatic cancer and enable the use of lower and safer concentrations, to pave the way for a more effective treatment in this devastating disease. Phase IIb clinical trials of P276-00 in combination with gemcitabine in pancreatic cancer patients are ongoing.</p
New retinoid chemotypes: 9-cis-retinoic acid analogs with hydrophobic rings derived from terpenes as selective RAR agonists.
International audienceA series of 9-cis-retinoic acid analogs modified at the hydrophobic ring with a (bi)cyclohexenyl moiety derived from natural terpenes has been stereoselectively prepared using a Suzuki cross-coupling as key step. Transient transactivation studies indicate that modification of the hydrophobic ring impacts dramatically on RXR-binding and transactivation, with most retinoids being inactive on RXRbeta, while preserving their RAR pan-agonist profile. Furthermore, only the RARgamma subtype was capable of enantiomeric discrimination with some pairs of enantiomeric terpene-retinoids
Retinoid receptor subtype-selective modulators through synthetic modifications of RARgamma agonists.
International audienceA series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARgamma antagonists based on the structure of known RARgamma agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARgamma antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARalpha than TTNPB and synergizes at low concentration with TTNPB-bound RARalpha but not RARbeta or RARgamma. Similarly, 24c synergizes with TTNPB-bound RARgamma and exhibits RARalpha,beta antagonist activity. Compounds 24b and 25b are strong RARalpha,beta-selective antagonists without agonist or antagonist activities for RARgamma. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined
Dual RXR Agonists and RAR Antagonists Based on the Stilbene Retinoid Scaffold.
Arotinoids containing a C5,C8-diphenylnaphthalene-2-yl ring linked to a (C3-halogenated) benzoic acid via an ethenyl connector (but not the corresponding naphthamides), which are prepared by Horner-Wadsworth-Emmons reaction of naphthaldehydes and benzylphosphonates, display the rather unusual property of being RXR agonists (15-fold induction of the RXR reporter cell line was achieved at 3- to 10-fold lower concentration than 9-cis-retinoic acid) and RAR antagonists as shown by transient transactivation studies. The binding of such bulky ligands suggests that the RXR ligand-binding domain is endowed with some degree of structural elasticity
Growth factor-antagonized rexinoid apoptosis involves permissive PPARgamma/RXR heterodimers to activate the intrinsic death pathway by NO.
International audienceGrowth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This "rexinoid apoptosis" involves activation of both iNOS and eNOS by RXR-PPARgamma and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPARgamma-mediated default apoptosis to sustain cell life
Synthesis and pharmacological characterization of Disila-AM80 (Disila-tamibarotene) and Disila-AM580, silicon analogues of the RARalpha-selective retinoid agonists AM80 (Tamibarotene) and AM580.
International audienc