title: Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis.
abstract: BACKGROUND
  Glioblastomas are the most frequent and most aggressive primary brain tumors in adults. The median overall survival is limited to a few months despite surgery, radiotherapy, and chemotherapy. It is now clearly established that hyperactivity of cyclin-dependent kinases (CDKs) is one of the processes underlying hyperproliferation and tumoral growth. The marine natural products meridianins and variolins, characterized as CDK inhibitors, display a kinase-inhibitory activity associated with cytotoxic effects. In order to improve selectivity and efficiency of these CDK inhibitors, a series of hybrid compounds called meriolins have been synthesized.
  
  
  METHODS
  The potential antitumoral activity of meriolins was investigated in vitro on glioma cell lines (SW1088 and U87), native neural cells, and a human endothelial cell line (HUV-EC-C). The impact of intraperitoneal or intratumoral administrations of meriolin 15 was evaluated in vivo on 2 different nude mice-xenografted glioma models.
  
  
  RESULTS
  Meriolins 3, 5, and 15 exhibited antiproliferative properties with nanomolar IC50 and induced cell-cycle arrest and CDK inhibition associated with apoptotic events in human glioma cell lines. These meriolins blocked the proliferation rate of HUV-EC-C through cell cycle arrest and apoptosis. In vivo, meriolin 15 provoked a robust reduction in tumor volume in spite of toxicity for highest doses, associated with inhibition of cell division, activation of caspase 3, reduction of CD133 cells, and modifications of the vascular architecture.
  
  
  CONCLUSIONS
  Meriolins, and meriolin 15 in particular, exhibit antiproliferative and proapoptotic activities on both glioma and intratumoral endothelial cells, constituting key promising therapeutic lead compounds for the treatment of glioblastoma.
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Marie
authors.initials: M
authors.lastname: Jarry
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Céline
authors.initials: C
authors.lastname: Lecointre
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Céline
authors.initials: C
authors.lastname: Malleval
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Laurence
authors.initials: L
authors.lastname: Desrues
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Schouft
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Vadim
authors.initials: V
authors.lastname: Lejoncour
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: François
authors.initials: F
authors.lastname: Liger
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Gildas
authors.initials: G
authors.lastname: Lyvinec
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Nadège
authors.initials: N
authors.lastname: Loaëc
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Honnorat
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Pierrick
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), PRES Normandy, TC2N network, University of Rouen, Mont-Saint-Aignan, France (M.J., C.L., L.D., M.-T.S., V.L., P.G., H.C.); Neuro-oncology department, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France (C.M., J.H.); Lyon Neuroscience Research Center INSERM U1028/CNRS UMR 5292, Lyon, France (C.M., J.H.); University of Claude Bernard - Lyon 1, Villeurbanne, France (C.M., J.H.); Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR 5246, University of Claude Bernard - Lyon 1, Villeurbanne, France (F.L., G.L., B.J., N.L.); Protein Phosphorylation & Human Disease Group & USR3151, Station Biologique, Roscoff, France (N.L., L.M.); ManRos Therapeutics, Roscoff, France (L.M.).
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005910:Glioma / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D023041:Xenograft Model Antitumor Assays
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D011743:Pyrimidines; C523800:meriolin 3; D018844:Cyclin-Dependent Kinases
keywords: cyclin-dependent kinase; glioma; meriolin; nude mice; tumor growth