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

Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model

“…3,[35][36][37] More recently, we showed that brain tumor capillaries are highly responsive to potassium channel agonists such as NS-1619. 4 We also showed that the effect of selective K Ca channel agonists are due to overexpression of K Ca channels on both tumor cells and tumor microvessels.…”

“…Our investigative approach is to create selective drug delivery to the tumor by noninvasive biochemical modification of the BTB by K Ca channel agonist, such as NS-1619, 3,4 which has the advantage of increasing the BTB permeability transiently for selective and enhanced anticancer drug delivery only to brain tumor cells. 5 Our strategy is to modify systemic drug delivery through cerebral microvessels/ capillaries to enable delivering anti-cancer agents to the dispersed pockets of tumor cells that remain after standard therapy.…”

“…Previously we reported the enhanced delivery of anticancer agents such as carboplatin by means of potassium channel activation through a mechanism involving accelerated formation of pinocytotic vesicles, which can transport drugs across BTB. 3,4 TMZ (8-carbamoyl-3-methyl-imidazo [5,1-d]-1,2,3,5-tetrazin-4 (3H) one) is an imidazotetrazine derivative of dacarbazine. It is an inactive prodrug that undergoes rapid nonenzymatic hydrolysis at physiologic pH to the highly reactive metabolite, 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which is further degraded to an active cytotoxic metabolite 4-Amino-5-imidazole-carboxamide (AIC).…”

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

“…In other cases, the expression profile of specific ion channels may change as a result of a local reaction to a pathological state, such as trauma, infection or the tumour itself (Saadoun et al, 2003). A recent report indicates that, when expressed at the blood -brain barrier at the tumour site, potassium channels can even restrict the delivery of anticancer drugs (Ningaraj et al, 2003). On the whole, it appears that ion channels/transporters, normally functioning to control ion homeostasis in a healthy brain, may contribute to the establishment of the malignant phenotype of brain tumours.…”

The Potential and Challenges of siRNA-Based Targeted Therapy for Treatment of Patients with Glioblastoma

“…Some success in delivering molecules across the BBB has been made with long circulating carrier systems (see section 8) that can take advantage of the fact that tumorassociated BBB consists of poorly formed vascular endothelium that is more permeable to circulating macromolecules than the normal BBB (Patel et al, 2009). Strategies to open the BBB have also been explored and include osmotic disruption (Bellavance et al, 2008), the use of vasomodulators to increase permeability (Ningaraj et al, 2003), or the use of potassium channel agonists to increase the formation of transport vesicles (Ningaraj, 2006).…”