title: Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells.
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.
authors.affiliation: 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.
authors.forename: Justin M
authors.initials: JM
authors.lastname: David
authors.forename: Tori A
authors.initials: TA
authors.lastname: Owens
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Barwe
authors.forename: Ayyappan K
authors.initials: AK
authors.lastname: Rajasekaran
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006096:Gramicidin / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006096:Gramicidin; D051794:Von Hippel-Lindau Tumor Suppressor Protein