Inhibition of cyclin-dependent kinases by roscovitine induces suppression of proliferation and migration in human glioma cells

Introduction: Cyclin-dependent kinases (CDK) play an important role in numerous cellular processes. CDK1, 2, 3, 4 and 6 are potent regulators of the cell cycle machinery, whereas CDK5 activity is limited to the CNS as a key regulator of neural development and neuronal cytoarchitecture. Galectins are overexpressed in different types of neoplasms and are also involved in various cellular processes, including resistance to apoptosis, proliferation and migration.

Roscovitine is an orally available small-molecule inhibitor mainly of CDK5, and with lower activity of CDK-1, -2, -7 and -9. Davanat is a polysaccharide-galactomannan polymer directed against some galectins (i.e., Davanat binds with Galectin-1 [data by Pro-Pharmaceuticals, Inc., Newton, Massachusetts]). We tested here the effect of Roscovitine and Davanat (obtained from Pro-Pharmaceuticals) on migration and proliferation in human glioma cell lines in monotherapy and combination.

Methods: five human glioma cell lines (A172, U87MG, U118, U373, T98G) were treated with 25 or 50µM Roscovitine, with 1µg/µl Davanat, and with both compounds in combination. Proliferation was assessed after 48h with cell titer blue reagent. Migration was assessed with a transwell assay.

Results: Proliferation and Migration was suppressed significantly with Roscovitine in both concentrations. While Davanat alone showed no effect, it enhanced the migration-inhibiting effect of Roscovitine by two- to four-fold in combination.

Discussion: we present here evidence that inhibitors of CDKs suppress migration of human glioma cells. Effects on migration in other cell types have been previously described for Roscovitine. Suppressed proliferation has been described only when Roscovitine was combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In view of these observations, CDK inhibition appears to be a promising strategy for the treatment of human malignant gliomas which may be further enhanced by galectin-inhibition. The exact value of additional galectin inhibition and/or conventional chemotherapy has to be assessed in future studies.