gramicidin-a and Kidney-Neoplasms

gramicidin-a has been researched along with Kidney-Neoplasms* in 2 studies

Other Studies

2 other study(ies) available for gramicidin-a and Kidney-Neoplasms

ArticleYear
Gramicidin A blocks tumor growth and angiogenesis through inhibition of hypoxia-inducible factor in renal cell carcinoma.
    Molecular cancer therapeutics, 2014, Volume: 13, Issue:4

    Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel-forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1α and HIF-2α proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O(2)-dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF-dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHL-expressing RCC.

    Topics: Animals; Antineoplastic Agents; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Gramicidin; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Mice; Neoplasms, Experimental; Proteasome Endopeptidase Complex; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

2014
Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells.
    Molecular cancer therapeutics, 2013, Volume: 12, Issue:11

    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.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Death; Cell Line, Tumor; Dogs; Drug Screening Assays, Antitumor; Female; Glycolysis; Gramicidin; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Neoplasms; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Nude; Oxidative Phosphorylation; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

2013