Regulation of Blood-Brain Tumor Barrier Permeability by Calcium-Activated Potassium Channels

Abstract

The blood-brain tumor barrier (BTB) limits the delivery of therapeutic drugs to brain tumors. We demonstrate in a rat brain tumor (RG2) model an enhanced drug delivery to brain tumor following intracarotid infusion of bradykinin (BK), nitric oxide (NO) donors, or agonists of soluble guanylate cyclase (sGC) and calcium-dependent potassium (K Ca ) channels. We modulated K Ca channels by specific agonists and agents that produce NO and cGMP in situ to obtain sustained enhancement of selective drug delivery to brain tumors. Immunoblot and immunolocalization studies demonstrate overexpression of K Ca channels in tumor cells and capillaries compared with normal brain. The potentiometric assays demonstrate the functional activity of K Ca channels in rat brain endothelial and glioma cells. Additionally, we show that BK and NS-1619 significantly increased the density of transport vesicles in the cytoplasm of brain tumor capillary endothelia and tumor cells. The cleft indices and cleft area indices in rat tumor capillaries were significantly higher than in normal brain capillaries, and BK infusion did not alter these indices. These data demonstrate that the cellular mechanism for K Ca channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. We conclude that K Ca channels serve as a convergence point in the biochemical regulation of BTB permeability.The blood-brain tumor barrier (BTB), formed by brain tumor capillaries, significantly limits delivery of therapeutic drugs to brain tumors (Groothuis, 2000). During the past decade, a considerable effort has been made and various strategies have been used to deliver selectively therapeutic drugs to brain tumors and injured brain. We developed the biochemical approach to increase BTB permeability and to enhance delivery of therapeutic drugs or small-to large-sized substances to brain tumors, including contrast-enhancing agents, antitumor compounds, therapeutic proteins, and viral vectors (Inamura et al

Ionic Channels in the Therapy of Malignant Glioma

“…By using quantitative autoradiographic method to quantify the radioactivity in the tumor area, the BTB permeability for [ 14 C]-AIB could be accurately measured. By using this animal model, NS1619 was found to increase BTB permeability and iberiotoxin could decrease BTB permeability (Ningaraj et al, 2002). It was also found that infusion NS1619 with bradykinin could selectively enhance BTB permeability in brain tumors, not in normal brain (Hu et al, 2007).…”

Increase in Brain Tumor Permeability in Glioma-Bearing Rats with Nitric Oxide Donors

“…[ 14 C]sucrose was used as the tracer to measure tumor permeability as described previously (7,8,11). In brief, saline was infused into the femoral vein at a rate of 66.7 AL/min for 15 min.…”

“…To study the duration of permeability increase by L-arginine or hydroxyurea, K i was measured at different time points from 30 to 120 min after the oral treatments (200 mg/kg L-arginine and 80 mg/kg hydroxyurea). Previous studies suggest an important role of K Ca channels in regulation of BTB permeability (11). Additional rats were infused with iberiotoxin (0.26 Ag/kg/min), a K Ca channel antagonist, to investigate whether inhibition of K Ca channels by iberiotoxin attenuates permeability increases induced by NO donors.…”

“…One approach to improve chemotherapy of brain tumors has taken advantage of these unique characteristics to pharmacologically modulate BTB permeability. We have identified previously certain vasoactive molecules including bradykinin, nitric oxide (NO), cGMP, and calcium-dependent potassium (K Ca ) channel agonists that act on a receptor, ion channel, and/or enzyme to selectively increase delivery of compounds to brain tumors (11). In particular, clinical attempts have been taken to improve chemotherapy by adjunctive administration of bradykinin and its analogue, RMP-7, agonists to the bradykinin-2 receptor, in brain tumor patients (10).…”

Factors Influencing Topotecan CNS Penetration in Mouse Models

“…It was also demonstrated that this increased transport was not mediated through tight junction opening but rather through enhanced vesicular transport . The authors further reported that the overexpressed calcium-dependent potassium (K Ca ) channels and the ATP-sensitive potassium (K ATP ) channel in tumor capillaries were responsible for the enhanced transport activity (Ningaraj et al, 2003;Ningaraj et al, 2002). These data suggest another approach is needed for specific drug delivery to brain tumors.…”