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Neuro Oncol. 2014 Nov;16(11):1484-98. doi: 10.1093/neuonc/nou102. Epub 2014 Jun 2.

Impact of meriolins, a new class of cyclin-dependent kinase inhibitors, on malignant glioma proliferation and neo-angiogenesis.

Author information

1
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.).

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.

CONCLUSION:

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.

KEYWORDS:

cyclin-dependent kinase; glioma; meriolin; nude mice; tumor growth

PMID:
24891448
PMCID:
PMC4201071
DOI:
10.1093/neuonc/nou102
[Indexed for MEDLINE]
Free PMC Article

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