Hu Jinwei, Yuan Xiangpeng, Ko MinHee K, Yin Dali, Sacapano Manuel R, Wang Xiao, Konda Bindu M, Espinoza Andres, Prosolovich Ksenia, Ong John M, Irvin Dwain, Black Keith L
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Mol Cancer. 2007 Mar 14;6:22. doi: 10.1186/1476-4598-6-22.
The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases.
In this study, we examined the function and regulation of calcium-activated potassium (KCa) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R) expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain), human brain microvessel endothelial cells (HBMEC) and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening.
These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.
血脑肿瘤屏障（BTB）阻碍治疗药物向脑肿瘤的递送。虽然药物在实体瘤中能实现充分递送，但BTB限制了抗肿瘤药物进入脑转移瘤。
在本研究中，我们在大鼠脑转移瘤模型中研究了钙激活钾（KCa）通道的功能和调节。我们发现静脉输注KCa通道激动剂NS1619和缓激肽可选择性增强脑肿瘤中的BTB通透性，但对正常脑组织无此作用。KCa通道拮抗剂iberiotoxin可显著减弱NS1619诱导的BTB通透性增加。我们发现KCa通道和缓激肽2型受体（B2R）在培养的人脑转移瘤细胞（CRL-5904，非小细胞肺癌脑转移）、人脑微血管内皮细胞（HBMEC）和人肺癌脑转移组织中表达。电位测定法证实了脑转移瘤细胞和HBMEC中KCa通道的活性。此外，与正常脑组织相比，我们在脑转移瘤组织和肿瘤毛细血管内皮中检测到KCa通道的表达更高。脑转移瘤细胞与人脑微血管内皮细胞共培养显示KCa通道上调，这可能导致肿瘤微血管中KCa通道的过度表达以及BTB开放的选择性。
这些发现表明，脑转移瘤中的KCa通道可能是对BTB通透性进行生化调节的有效靶点，以增强化疗药物向脑转移瘤的选择性递送。
