1. Academic Validation
  2. Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells

Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells

  • Mol Cancer Ther. 2013 Nov;12(11):2296-307. doi: 10.1158/1535-7163.MCT-13-0445.
Justin M David 1 Tori A Owens Sonali P Barwe Ayyappan K Rajasekaran
Affiliations

Affiliation

  • 1 Corresponding Author: Ayyappan K. Rajasekaran, Nemours Center for Childhood Cancer Research, A.I. duPont Hospital for Children, 1701 Rockland Road, Wilmington, DE 19803. araj@nemoursresearch.org.
Abstract

Ionophores are lipid-soluble organic molecules that disrupt cellular transmembrane potential by rendering biologic membranes permeable to specific ions. They include mobile-carriers that complex with metal cations and channel-formers that insert into the membrane to form hydrophilic pores. Although mobile-carriers possess Anticancer properties, investigations on channel-formers are limited. Here, we used the channel-forming ionophore gramicidin A to study its effects on the growth and survival of renal cell carcinoma (RCC) cells. RCC is a histologically heterogeneous malignancy that is highly resistant to conventional treatments. We found that gramicidin A reduced the in vitro viability of several RCC cell lines at submicromolar concentrations (all IC50 < 1.0 μmol/L). Gramicidin A exhibited similar toxicity in RCC cells regardless of histologic subtype or the expression of either the von Hippel-Lindau tumor suppressor gene or its downstream target, hypoxia-inducible factor-1α. Gramicidin A decreased cell viability equal to or greater than the mobile-carrier monensin depending on the cell line. Mechanistic examination revealed that gramicidin A blocks ATP generation by inhibiting Oxidative Phosphorylation and glycolysis, leading to cellular energy depletion and nonapoptotic cell death. Finally, gramicidin A effectively reduced the growth of RCC tumor xenografts in vivo. These results show a novel application of gramicidin A as a potential therapeutic agent for RCC therapy.

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