Abstract
The mechanism of action of elisidepsin (PM02734, Irvalec®) is assumed to involve membrane permeabilization via attacking lipid rafts and hydroxylated lipids. Here we investigate the role of hypoxia in the mechanism of action of elisidepsin. Culturing under hypoxic conditions increased the half-maximal inhibitory concentration and decreased the drug’s binding to almost all cell lines which was reversed by incubation of cells with 2-hydroxy palmitic acid. The expression of fatty acid 2-hydroxylase was strongly correlated with the efficiency of the drug and inversely correlated with the effect of hypoxia. Number and brightness analysis and fluorescence anisotropy experiments showed that hypoxia decreased the clustering of lipid rafts and altered the structure of the plasma membrane. Although the binding of elisidepsin to the membrane is non-cooperative, its membrane permeabilizing effect is characterized by a Hill coefficient of ~3.3. The latter finding is in agreement with elisidepsin-induced clusters of lipid raft-anchored GFP visualized by confocal microscopy. We propose that the concentration of elisidepsin needs to reach a critical level in the membrane above which elisidepsin induces the disruption of the cell membrane. Testing for tumor hypoxia or the density of hydroxylated lipids could be an interesting strategy to increase the efficiency of elisidepsin.
Highlights
Significant progress has been made in the understanding of cancer at the molecular and cellular level, the potency of chemotherapy of advanced malignant tumors is still limited and based on conventional cytotoxic drugs calling for medications with new mechanism of action [1]
We show that the sensitivity of cell lines to elisidepsin is proportional to their fatty acid 2-hyroxylase (FA2H) level and hypoxia reduces the efficiency of the drug
We suspected that hypoxia would lead to a diminished synthesis of hydroxylated fatty acids thereby reducing the sensitivity of cells to elisidepsin
Summary
Significant progress has been made in the understanding of cancer at the molecular and cellular level, the potency of chemotherapy of advanced malignant tumors is still limited and based on conventional cytotoxic drugs calling for medications with new mechanism of action [1]. Elisidepsin has been found to have synergistic effects when combined with several different conventional chemotherapeutic agents and tyrosine kinase inhibitors in cell lines and mouse xenograft models most likely due to its unique mechanism of action [6,7]. ErbB proteins have been implicated as the target of elisidepsin based on weak correlations between the drug’s efficiency and ErbB protein expression levels [6,7,13], we have refuted this hypothesis by showing that the expression of ErbB1, ErbB2 or ErbB3 proteins have no influence on the sensitivity of cell lines to elisidepsin [14]. Based on experiments with RNA interference-mediated knock-down of fatty acid
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