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.