Abstract 3451: Gramicidin-based nanopores induce cellular energy depletion and cell death in renal cell carcinoma.

Abstract

Abstract The plasma membrane physically separates the intracellular components of a cell from the extracellular environment and its integrity is absolutely essential to sustain cellular functions. Ionophores are lipid soluble organic molecules that disrupt cellular transmembrane potential by rendering biological membranes permeable to specific ions. They are classified on the basis of their mechanism of action; mobile carriers complex with metal cations to shield their hydrophilic charge from the interior of the lipid bilayer and channel-formers insert into the membrane to form hydrophilic pores that permit the rapid passage of selected ions through membranes. Research over the past decade has described an new role for mobile carrier ionophores as novel anticancer therapeutics yet the potential anticancer attributes of channel-forming ionophores have not been explored. In this study we utilized the channel-forming ionophore gramicidin A (GA) as a model nanopore to study its effects upon the growth and survival of renal cell carcinoma (RCC) cells. RCC is a histologically heterogeneous malignancy that is highly resistant to conventional chemotherapy. We found that disruption of plasma membrane integrity with GA reduced the in vitro viability of several RCC cell lines when treated at sub-micromolar concentrations (all IC50 < 1.0μM). Comparison of GA with the mobile carrier ionophore monensin revealed that cell viability was decreased by GA to a degree that was equal to or greater than monensin depending on the cell line. Mechanistic examination determined that GA induced cell death that was associated with cellular energy depletion. Importantly, GA exhibited similar toxicity in RCC cells regardless of histological subtype or the expression of either the von Hippel-Lindau (VHL) tumor suppressor or its downstream target hypoxia-inducible factor (HIF) -1α. Taken together, these results demonstrate the utility of nanopore-forming drugs as a new strategy for cancer therapy. Citation Format: Justin M. David, Ayyappan K. Rajasekaran. Gramicidin-based nanopores induce cellular energy depletion and cell death in renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3451. doi:10.1158/1538-7445.AM2013-3451