ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment

Váradi, Tímea; Roszik, Jason; Lisboa, Duarte; Vereb, György; Molina-Guijarro, José Manuel; Galmarini, Carlos M.; Szöllősi, János; Nagy, Péter

doi:10.1016/j.ejphar.2011.05.064

Cited by 15 publications

(21 citation statements)

References 40 publications

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“…We observed a relatively rapid (2 and 4 h) specific downregulation of ErbB3 upon elisidepsin treatment in the breast cancer cell line MCF-7, whereas the other ErbB family members were not affected. These data, obtained in a breast cell line model, agree with previous results obtained in a lung cancer model (13), supporting the hypothesis of a selective role of ErbB3 in the cellular response to this drug, although other authors proposed this ErbB role as a secondary process upon cell membrane alterations by elisidepsin treatment (35). The lower tyrosine kinase activity of ErbB3 receptor prompts heterodimerization with other HER receptors and ErbB2/ErbB3 heterodimers have been shown to be the most transforming and mitogenic receptor complex of the ErbB family (25)(26)(27).…”

Section: Discussionsupporting

confidence: 82%

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

et al. 2012

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Abstract.Irvalec ® (elisidepsin trifluoroacetate, PM02734) is a novel marine-derived cyclic peptide belonging to the Kahaladide family of compounds, currently in clinical trials with preliminary evidence of antitumor activity. Previous studies have shown a correlation between elisidepsin sensitivity and expression of the ErbB3 receptor in a panel of NSCLC cell lines. We have studied the effect of elisidepsin on the ErbB3 pathway, characterizing the expression of all members of the ErbB (HER) family of receptors and their main downstream signaling effectors, such as Akt and MAPK. Interestingly, we observed a downregulation of ErbB3 upon elisidepsin treatment that correlates with a reduction in the Akt phosphorylation levels in the most sensitive cell lines, whereas ErbB3 levels are not affected in the less sensitive ones. Also, we observed that the basal levels of ErbB3 protein expression show a significant correlation with cell viability response against elisidepsin treatment in 14 different cell lines. Furthermore, we analyzed the combination of elisidepsin with different chemotherapeutics agents, such as cisplatin, paclitaxel and gemcitabine, in a panel of different breast (MDA-MB-435, MDA-MB-231 and MCF7), lung (HOP62, DV90 and A549) and colorectal cancer cell lines (DLD1 and HT29). IC 50 values for the different drugs were tested. We observed a synergistic effect in all cell lines tested with any chemotherapeutic agent. More importantly, the two in vitro elisidepsin-resistant cell lines (MDA-MB-231 and HOP62) presented a synergistic effect in combination with cisplatin and paclitaxel, respectively. These results provide a rationale for further development of these combinations in an ongoing clinical trial.

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Section: Discussionsupporting

confidence: 82%

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

et al. 2012

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“…Although 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]. According to the most widely accepted view the primary mechanism of action of elisidepsin involves a direct hit on the membrane by binding to lipid rafts [5,14].…”

Section: Introductionmentioning

confidence: 99%

“…According to the most widely accepted view the primary mechanism of action of elisidepsin involves a direct hit on the membrane by binding to lipid rafts [5,14]. Based on experiments with RNA interference-mediated knock-down of fatty acid 2-hydroxylase (FA2H) and incorporation of exogenous hydroxylated fatty acids, 2-hydroxylated sphingolipids have been suggested as the binding site of elisidepsin [15].…”

Section: Introductionmentioning

confidence: 99%

“…Based on experiments with RNA interference-mediated knock-down of fatty acid 2-hydroxylase (FA2H) and incorporation of exogenous hydroxylated fatty acids, 2-hydroxylated sphingolipids have been suggested as the binding site of elisidepsin [15]. It has been postulated that elisidepsin binds to hydroxylated lipids in rafts and induces rapid permeabilization of the cell membrane [14]. All other effects of the drug, including autophagy [16], necrosis [2,13], disruption of lysosomal membranes [17], inhibition of Akt signaling [6,16] and downregulation of ErbB3 expression and activation [13,14], are thought to be secondary effects pursuant to the primary hit on the membrane.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts

et al. 2013

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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.

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“…The primary mechanisms of action of elisidepsin have not been yet identified, although multiple cellular targets have been described, many of which, due to the hydrophobic nature of the compound, are associated with the cell membrane [5,6]. Indeed, elisidepsin induces necrosis rather than apoptotic cell death; proposed mechanisms of action for cell necrosis include cell membrane damage [7,8].…”

Section: Introductionmentioning

confidence: 99%

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors

et al. 2015

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This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m(2) (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m(2)). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m(2) (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.

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ErbB protein modifications are secondary to severe cell membrane alterations induced by elisidepsin treatment

Cited by 15 publications

References 40 publications

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

ErbB3 expression predicts sensitivity to elisidepsin treatment: inï¿½vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

Hypoxia Reduces the Efficiency of Elisidepsin by Inhibiting Hydroxylation and Altering the Structure of Lipid Rafts

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors

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