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.

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 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.
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.
AuthorsAhcene Boumendjel, Anne McLeer-Florin, Pierre Champelovier, Diane Allegro, Dima Muhammad, Florence Souard, Madiha Derouazi, Vincent Peyrot, Bertrand Toussaint, Jean Boutonnat
JournalBMC cancer (BMC Cancer) Vol. 9 Pg. 242 ( 2009) ISSN: 1471-2407 [Electronic] England
PMID19619277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Chalcones
  • JAI-51
  • P-Glycoprotein
  • Chalcone
  • BCR protein, human
  • Proto-Oncogene Proteins c-bcr
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • Blood-Brain Barrier
  • Brain Neoplasms (metabolism)
  • Cell Line, Tumor
  • Chalcone (analogs & derivatives)
  • Chalcones (pharmacology)
  • Glioblastoma (metabolism)
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microtubules (metabolism)
  • P-Glycoprotein (antagonists & inhibitors, metabolism)
  • Proto-Oncogene Proteins c-bcr (antagonists & inhibitors, metabolism)
  • Rats

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