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
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
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DOI：
10.1186/1471-2407-9-242
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发表时间：
2009-07-20
期刊：
影响因子：
3.8
通讯作者：
Boutonnat, Jean
中科院分区：
文献类型：
--
作者：
Boumendjel, Ahcene;McLeer-Florin, Anne;Boutonnat, Jean
背景：在过去的几十年里，尽管进行了深入的研究，但胶质母细胞瘤患者的生存率并未显着增加。血脑屏障 (BBB) 的作用，尤其是属于 ATP 结合盒 (ABC) 家族的外排泵的活性可能部分解释了这一缺陷。 方法：通过各种实验方法在四种人类和一种鼠胶质母细胞瘤细胞系中评估 JAI-51 对细胞增殖的体外活性。使用药物排除测定和流式细胞术，在敏感或耐药细胞系中评估 JAI-51 对 P-gp 和 BCRP 的潜在抑制作用。通过微管蛋白聚合测定和分析超速离心的直接结合测量来评估 JAI-51 对体外微管聚合的活性。最后，使用带有皮下GL26胶质母细胞瘤异种移植物的C57BL/6小鼠模型来评估标题化合物的体内活性。设计了一种 HPLC 方法来检测治疗动物的大脑和其他靶器官以及肿瘤中的 JAI-51。 结果：在测试的四种人类和小鼠胶质母细胞瘤细胞系中，10 μM JAI-51 通过其作为微管解聚剂的活性抑制增殖并阻断细胞周期的 M 期。该配体以 2 x 10(5) M-1 的缔合常数与微管蛋白结合，与秋水仙碱结合位点重叠。 JAI-51 还抑制 P-gp 和 BCRP 的活性，但不是这些外排泵的底物。我们对携带 GL26 胶质母细胞瘤异种移植物的 C57BL/6 小鼠进行的体内研究强化了这些体外研究，其中每周一次 96 mg/kg 腹膜内给药后，JAI-51 诱导肿瘤发生延迟和肿瘤生长抑制。根据这些结果，通过 HPLC 在治疗动物的肿瘤中检测到 JAI-51。此外，在大脑中检测到JAI-51，表明该分子也能够穿过血脑屏障。结论：这些体外和体内数据表明，JAI-51可能是中枢神经系统肿瘤新疗法的良好候选者。进一步的研究正在进行中，以在大鼠模型中将标题化合物化疗与放疗联系起来。
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 mu M 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 10(5) 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.Conclusion: 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.