Modification of Gramicidin Through Reaction with Formaldehyde

Lewis, John B.; Dimick, K. P.; Feustel, I. C.; Fevold, H. L.; Olcott, Henry Steel; Fraenkel-Conrat, H.

doi:10.1126/science.102.2646.274

Cited by 21 publications

(5 citation statements)

References 6 publications

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“…Nevertheless, systemic administration of gramicidin A may be possible in the near future. Chemical modification of gramicidin A has been shown to change the characteristics of the peptide enough to increase microbial targeting and/or decrease nonspecific toxicity (18,19,52,53), and encapsulation of gramicidin A within a targeted drug carriers such as nanoparticles may be a plausible method to safely deliver gramicidin A to only the tumor (54). Whether these approaches can be effectively applied to the use of gramicidin A as a novel cancer therapy is an essential area of future investigation.…”

Section: Discussionmentioning

confidence: 99%

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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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-1a and HIF-2a 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 VHLexpressing RCC. Mol Cancer Ther; 13(4); 788-99. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

David

Owens

Inge

et al. 2014

Molecular Cancer Therapeutics

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“…Within the past year, a few groups developed sensitive assays that employ ion channels to detect the activity of various enzymes [22,23 • ,112,271 • ]. In one of these assays, chemically modified gramicidin [312] peptides probed the enzymatic activity of picomolar concentrations of alkaline phosphatase and nanomolar concentrations of anthrax lethal factor in solution (Figure 11) [22]. In this assay, the enzyme-induced modification of individual gramicidin-derived substrates led to measurable changes in single-channel conductance through gramicidin pores.…”

Section: Applications Of Biological Pores For Sensingmentioning

confidence: 99%

Applications of biological pores in nanomedicine, sensing, and nanoelectronics

Majd

Yusko

Billeh

et al. 2010

Current Opinion in Biotechnology

307

319

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Biological protein pores and pore-forming peptides can generate a pathway for the flux of ions and other charged or polar molecules across cellular membranes. In nature, these nanopores have diverse and essential functions that range from maintaining cell homeostasis and participating in cell signaling to activating or killing cells. The combination of the nanoscale dimensions and sophisticated – often regulated – functionality of these biological pores make them particularly attractive for the growing field of nanobiotechnology. Applications range from single-molecule sensing to drug delivery and targeted killing of malignant cells. Potential future applications may include the use of nanopores for single strand DNA sequencing and for generating bio-inspired, and possibly, biocompatible visual detection systems and batteries. This article reviews the current state of applications of pore-forming peptides and proteins in nanomedicine, sensing, and nanoelectronics.

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“…Chemical modification or mutation of the GA peptide has proven effective at increasing microbial targeting and decreasing non-specific toxicity (7, 8, 51, 52). Such mutagenesis approach could be utilized to identify a non-toxic but efficacious form of GA that could be used systemic delivery for treating tumors in in vivo.…”

Section: Future Development Of Gamentioning

confidence: 99%

Gramicidin A: A New Mission for an Old Antibiotic

David

Rajasekaran

2015

jkcvhl

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Gramicidin A (GA) is a channel-forming ionophore that renders biological membranes permeable to specific cations which disrupts cellular ionic homeostasis. It is a well-known antibiotic, however it’s potential as a therapeutic agent for cancer has not been widely evaluated. In two recently published studies, we showed that GA treatment is toxic to cell lines and tumor xenografts derived from renal cell carcinoma (RCC), a devastating disease that is highly resistant to conventional therapy. GA was found to possess the qualities of both a cytotoxic drug and a targeted angiogenesis inhibitor, and this combination significantly compromised RCC growth in vitro and in vivo. In this review, we summarize our recent research on GA, discuss the possible mechanisms whereby it exerts its anti-tumor effects, and share our perspectives on the future opportunities and challenges to the use of GA as a new anticancer agent.

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Modification of Gramicidin Through Reaction with Formaldehyde

Cited by 21 publications

References 6 publications

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Gramicidin A Blocks Tumor Growth and Angiogenesis through Inhibition of Hypoxia-Inducible Factor in Renal Cell Carcinoma

Applications of biological pores in nanomedicine, sensing, and nanoelectronics

Gramicidin A: A New Mission for an Old Antibiotic

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