A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor
A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor
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DOI：
10.3390/cancers11060848
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发表时间：
2019-06-01
期刊：
影响因子：
5.2
通讯作者：
Schenone, Silvia
中科院分区：
文献类型：
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作者：
Fallacara, Anna Lucia;Zamperini, Claudio;Schenone, Silvia
多药耐药（MDR）癌细胞中p糖蛋白（P-gp）和其他atp结合盒（ABC）转运体的过度表达导致细胞内药物积累减少，从而降低化疗药物的疗效。P-gp也存在于血脑屏障的内皮细胞膜上，在那里它限制了药物向中枢神经系统（CNS）肿瘤的输送。我们之前已经开发了一组吡唑[3,4-d]嘧啶及其前药作为新型Src酪氨酸激酶抑制剂（TKIs），在体内对中枢神经系统肿瘤显示出显着的活性。在这里，我们研究了最有希望的药物/前药对与P-gp在细胞水平上的相互作用。实验发现，这些化合物增加了Rho 123在细胞内的积累，并增强了紫杉醇在P-gp过表达细胞中的作用。还观察到令人鼓舞的药代动力学性质和体内耐受性。我们的研究结果揭示了吡唑[3,4-d]嘧啶的新作用，这可能有助于开发一种新的有效疗法，用于耐多药癌症治疗，特别是针对胶质母细胞瘤。
Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells' membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.