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 (K_Ca) channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a K_Ca channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a K_Ca channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found K_Ca 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 K_Ca channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of K_Ca 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 K_Ca channels, which may contribute to the overexpression of K_Ca channels in tumor microvessels and selectivity of BTB opening. Conclusion: These findings suggest that K_Ca 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. [ABSTRACT FROM AUTHOR]