A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivoglioblastoma models

Abstract

BackgroundOver 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.MethodsThe 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.ResultsIn 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.ConclusionThese 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.

Pharmacogenetics of Membrane Transporters: An Update on Current Approaches

“…To date, the influx of Rhodamine 123, JAI-51, calceine, doxorubicin, and daunorubicin have been evaluated using such methods and are still used in drug-drug interaction studies [59]. The same technique has been used with mitoxantrone to assess transport by, and inhibition of, ABCG2.…”

Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

“…A trimethoxychalcone derivative was detected in implanted glioblastoma tumors and in the brain of i.p. treated mice, showing that at least this specific chalcone crosses the BBB (Boumendjel et al 2009). Previously, we used a computational approach to predict some pharmacokinetic parameters that helped us select the most promising compounds to assay in vivo.…”

Dietary chalcones with chemopreventive and chemotherapeutic potential

“…It has been reported that chalcone (10) provided two distinct cytoprotective mechanisms, depending on the duration of pre-treatment. Initially, chalcone (10) abrogated time and dose dependently the activation of signal transducer and activator of transcription (STAT)3 and NF-jB in IL-6 and lipopolysaccharide (LPS)- stimulated endothelial cells via depletion of intracellular glutathione (GSH) levels. Prolonged chalcone treatment (after 6 h and 12 h), however, rescued the intracellular GSH level, indicating the activation of thiol-related genes.…”

“…Although there are few known inhibitors of tubulin assembly among naturally occurring chalcones, a large library of chalcone analogues was synthesized. Many showed convincing antimitotic properties as microtubuledepolymerizing agents with IC 50 values of sub-lM and low lM concentrations (see Table 1) [10,31,69,87].…”