Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Hu
Jinwei
J
Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. huj@cshs.org
Yuan
Xiangpeng
X
Ko
MinHee K
MK
Yin
Dali
D
Sacapano
Manuel R
MR
Wang
Xiao
X
Konda
Bindu M
BM
Espinoza
Andres
A
Prosolovich
Ksenia
K
Ong
John M
JM
Irvin
Dwain
D
Black
Keith L
KL
D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000556:secondary*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011199:Potentiometry; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2