title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  In the four human and the murine glioblastoma cell lines tested, 10 muM 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 x 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Bâtiment Jean Roget, Faculté de Médecine, Grenoble, F-38700 France. ahcene.boumendjel@ujf-grenoble.fr
authors.forename: Ahcene
authors.initials: A
authors.lastname: Boumendjel
authors.forename: Anne
authors.initials: A
authors.lastname: McLeer-Florin
authors.forename: Pierre
authors.initials: P
authors.lastname: Champelovier
authors.forename: Diane
authors.initials: D
authors.lastname: Allegro
authors.forename: Dima
authors.initials: D
authors.lastname: Muhammad
authors.forename: Florence
authors.initials: F
authors.lastname: Souard
authors.forename: Madiha
authors.initials: M
authors.lastname: Derouazi
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.forename: Bertrand
authors.initials: B
authors.lastname: Toussaint
authors.forename: Jean
authors.initials: J
authors.lastname: Boutonnat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002599:Chalcone / Q000031:analogs & derivatives*; D047188:Chalcones / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism*; D051562:Proto-Oncogene Proteins c-bcr / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D047188:Chalcones; C545474:JAI-51; D002599:Chalcone; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr