Calcium-dependent potassium channels as a target protein for modulation of the blood-brain tumor barrier.

Abstract

Even though the blood-brain tumor barrier (BTB) is more permeable than the blood-brain barrier (BBB), the BTB still significantly restricts the delivery of anticancer drugs to brain tumors. Brain tumor capillaries that form the BTB, however, express certain unique protein markers that are absent or barely detectable in normal brain capillaries. We were able to biochemically modulate one such protein marker, the calcium-dependent potassium (K(Ca)) channel, by using a specific K(Ca) channel agonist, NS-1619, to obtain sustained enhancement of selective drug delivery, including molecules of varying sizes, to tumors in rat syngeneic and xenograft brain tumor models. Immunolocalization and potentiometric studies showed increased K(Ca) channel distribution on tumor cells compared with normal cells, suggesting that tumor cell-specific signals might induce overexpression of K(Ca) channels in capillary endothelial cells, leading to increased BTB permeability. We also demonstrated that the cellular mechanism for K(Ca) channel-mediated BTB permeability increase is due to accelerated formation of pinocytotic vesicles, which can transport therapeutic molecules across the BTB. This concept was investigated by using NS-1619 to facilitate increased delivery of carboplatin to brain tumor leading to enhanced survival in rats with brain tumors. Additionally, we showed that K(Ca) channel modulation resulted in enhanced permeability to macromolecules, including Her-2 monoclonal antibody and green fluorescent protein-adenoviral vectors, in a human, primary brain-tumor xenograft model. Therefore, K(Ca) channels are a potential, promising target for biochemical modulation of BTB permeability to increase antineoplastic drug delivery selectively to brain tumors.