A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models
- Equal contributors
1 CNRS, UMR 5063, Bâtiment E, Pôle Chimie, Grenoble, F-38700 France
2 RFMQ, TIMC, IMAG, CNRS, UMR 5525, Bâtiment Jean Roget, Faculté de Médecine, Grenoble, F-38700 France
3 GREPI-THEREX, TIMC, IMAG, CNRS, UMR 5525, Bâtiment Jean Roget, Faculté de Médecine, Grenoble, F-38700 France
4 CRO2, Inserm U911, Aix-Marseille Université, Faculté de Pharmacie de Marseille, 27 bd Jean Moulin, Marseille, F-13005 France
5 CHRU Grenoble, Hôpital Michallon, Département d'Anatomie et Cytologie Pathologiques (DACP), Grenoble, F-38000 France
6 CHRU Grenoble, Hôpital Michallon, Département de Biologie et Pathologie de la Cellule (DBPC), Grenoble, F-38000 France
BMC Cancer 2009, 9:242 doi:10.1186/1471-2407-9-242Published: 20 July 2009
Over the past decades, in spite of intensive search, no significant increase in the survival of patients with glioblastoma has been obtained. The role of the blood-brain barrier (BBB) and especially the activity of efflux pumps belonging to the ATP Binding Cassette (ABC) family may, in part, explain this defect.
The in-vitro activities of JAI-51 on cell proliferation were assessed by various experimental approaches in four human and a murine glioblastoma cell lines. Using drug exclusion assays and flow-cytometry, potential inhibitory effects of JAI-51 on P-gp and BCRP were evaluated in sensitive or resistant cell lines. JAI-51 activity on in-vitro microtubule polymerization was assessed by tubulin polymerization assay and direct binding measurements by analytical ultracentrifugation. Finally, a model of C57BL/6 mice bearing subcutaneous GL26 glioblastoma xenografts was used to assess the activity of the title compound in vivo. An HPLC method was designed to detect JAI-51 in the brain and other target organs of the treated animals, as well as in the tumours.
In the four human and the murine glioblastoma cell lines tested, 10 μM JAI-51 inhibited proliferation and blocked cells in the M phase of the cell cycle, via its activity as a microtubule depolymerising agent. This ligand binds to tubulin with an association constant of 2 × 105 M-1, overlapping the colchicine binding site. JAI-51 also inhibited the activity of P-gp and BCRP, without being a substrate of these efflux pumps. These in vitro studies were reinforced by our in vivo investigations of C57BL/6 mice bearing GL26 glioblastoma xenografts, in which JAI-51 induced a delay in tumour onset and a tumour growth inhibition, following intraperitoneal administration of 96 mg/kg once a week. In accordance with these results, JAI-51 was detected by HPLC in the tumours of the treated animals. Moreover, JAI-51 was detected in the brain, showing that the molecule is also able to cross the BBB.
These in vitro and in vivo data suggest that JAI-51 could be a good candidate for a new treatment of tumours of the CNS. Further investigations are in progress to associate the title compound chemotherapy to radiotherapy in a rat model.