Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.
Adenosine A2A Receptor Activation Enhances Blood-Tumor Barrier Permeability in a Rodent Glioma Model.
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DOI：
10.1158/1541-7786.mcr-19-0995
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发表时间：
2021-12
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影响因子：
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通讯作者：
Jackson S
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文献类型：
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作者：
Vézina A;Manglani M;Morris D;Foster B;McCord M;Song H;Zhang M;Davis D;Zhang W;Bills J;Nagashima K;Shankarappa P;Kindrick J;Walbridge S;Peer CJ;Figg WD;Gilbert MR;McGavern DB;Muldoon LL;Jackson S
血肿瘤屏障（BTB）限制了有效的化疗药物进入大脑，以治疗恶性肿瘤，如胶质母细胞瘤。通过BTB的不良药物进入允许浸润性胶质瘤干细胞逃避治疗并产生治疗抗性。Regadenoson是一种FDA批准的腺苷A2A受体（A2AR）激动剂，已被证明可以增加非肿瘤啮齿动物中穿过血脑屏障的药物递送，而没有明确的增强BTB渗透性的机制。在这里，我们的特点的时间依赖性影响regadenoson脑内皮细胞的相互作用和细胞旁运输，使用小鼠和大鼠脑内皮细胞和肿瘤模型。在体外，A2AR激活导致细胞骨架肌动蛋白丝的解体30分钟，下调连接蛋白的表达4小时，并重建内皮细胞的完整性8小时。在患有颅内胶质瘤的大鼠中，regadenoson治疗导致肿瘤内替莫唑胺浓度增加，但联合替莫唑胺治疗未观察到生存率增加。这些发现表明regadenoson能够诱导胶质瘤中脑内皮结构的变化，以增加BTB的渗透性。血管活性介质，如regadenoson，短暂影响细胞旁转运的使用，应进一步探索，以评估其增强侵袭性脑肿瘤中枢神经系统治疗的潜力。本研究提供了关于使用血管活性剂增加BTB对化疗的暴露以改善胶质瘤治疗疗效的见解。
The blood–tumor barrier (BTB) limits the entry of effective chemotherapeutic agents into the brain for treatment of malignant tumors like glioblastoma. Poor drug entry across the BTB allows infiltrative glioma stem cells to evade therapy and develop treatment resistance. Regadenoson, an FDA-approved adenosine A2A receptor (A2AR) agonist, has been shown to increase drug delivery across the blood–brain barrier in non–tumor-bearing rodents without a defined mechanism of enhancing BTB permeability. Here, we characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. In vitro, A2AR activation leads to disorganization of cytoskeletal actin filaments by 30 minutes, downregulation of junctional protein expression by 4 hours, and reestablishment of endothelial cell integrity by 8 hours. In rats bearing intracranial gliomas, regadenoson treatment results in increase of intratumoral temozolomide concentrations, yet no increased survival noted with combined temozolomide therapy. These findings demonstrate regadenoson's ability to induce brain endothelial structural changes among glioma to increase BTB permeability. The use of vasoactive mediators, like regadenoson, which transiently influences paracellular transport, should further be explored to evaluate their potential to enhance central nervous system treatment delivery to aggressive brain tumors. This study provides insight on the use of a vasoactive agent to increase exposure of the BTB to chemotherapy with intention to improve glioma treatment efficacy.