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

Sep 10, 2009Cancer biology & therapy

Increasing potassium channel activity improves anticancer drug delivery to brain tumors and extends survival in a mouse model

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Abstract

Co-infusion of potassium channel agonist NS-1619 with Temozolomide (TMZ) and Herceptin significantly enhances drug delivery to brain tumor cells.

TMZ and Herceptin alone do not cross the blood-brain tumor barrier (BTB) in significant amounts.
The combination of NS-1619 with TMZ and Herceptin improved drug delivery to human glial tumor cells in nude mice.
This combination treatment resulted in a greater antitumor effect compared to either drug alone.
Survival rates in mice with brain tumors increased when treated with the combination of TMZ, Herceptin, and K(Ca) channel agonists.
K(Ca) channel agonists may provide a novel approach to enhance the efficacy of anticancer drugs in brain tumor patients.

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Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.

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

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