Abstract
BackgroundThe 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.ResultsIn 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.ConclusionThese 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.
Highlights
The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors
KCa channel mediates BTB permeability increase in a CRL5904 metastatic brain tumor model To determine whether KCa channels mediate BTB permeability in a metastatic brain tumor model, intracranial CRL5904 tumor bearing-rats received intravenous infusion of NS1619 (0~120 μg/kg/min), bradykinin, IBTX, or PBS
NS1619- and bradykinin- induced BTB permeability increases resulted in enhanced delivery of radiotracer [14C] sucrose to the tumor center without any increase to tumor adjacent brain tissue and contralateral normal brain (Figure 1A)
Summary
The blood-brain tumor barrier (BTB) impedes the delivery of therapeutic agents to brain tumors. Our laboratory has focused on pharmacologic modulations to increase BTB permeability and increase delivery of therapeutic drugs selectively to brain tumors with little or no drug delivery to normal brain tissue [6,7,8,9]. It has been demonstrated that bradykinin [10], leukotriene (LTC4) [11,12,13], nitric oxide (NO) [14], c-GMP [8], and potassium channel agonists [15,16] can selectively increase capillary permeability in primary brain tumors, while leaving normal brain unaffected These findings have already been translated into clinical studies to increase drug delivery selectively to tumor tissue in brain tumor patients [7,17,18,19]. Modulation of critical molecules involved in selectively increasing BTB permeability could lead to the development of effective strategy to increase chemotherapy delivery to brain tumors
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