Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis.

Crews, Craig M.; Lane, William S.; Schreiber, Stuart L.

doi:10.1073/pnas.93.9.4316

Cited by 52 publications

(46 citation statements)

References 42 publications

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“…The antiproliferative effect of aplidine on cancer cells has been associated to perturbation in the cell cycle, since aplidine, at low concentrations, induces blockade of the cell cycle at G1 and at G2 (Geldof et al, 1999;Erba et al, 2002). Didemnins also block protein synthesis (Crews et al, 1994), inhibit ornithine decarboxylase, a regulator of intracellular polyamine levels (Urdiales et al, 1996;Gomez-Fabre et al, 1997;Erba et al, 2002) and bind to and inhibit the activity of the palmitoyil protein thioesterase, involved in signal transduction pathways associated to cell proliferation (Crews et al, 1996). However, the relevance of these activities in determining the antineoplastic activity of the compound is still debated.…”

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Antiangiogenic activity of aplidine, a new agent of marine origin

et al. 2004

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The antineoplastic compound aplidine, a new marine-derived depsipeptide, has shown preclinical activity in vitro on haematological and solid tumour cell lines. It is currently in early phase clinical trials. The exact mechanism of action of this anticancer agent still needs to be clarified. We have previously reported that aplidine blocks the secretion of the angiogenic factor vascular endothelial growth factor (VEGF) by the human leukaemia cells MOLT-4, suggesting a possible effect on tumour angiogenesis. This study was designed to investigate the antiangiogenic effect of aplidine. In vivo, in the chick embryo allantoic membrane (CAM) assay, aplidine inhibited spontaneous angiogenesis, angiogenesis elicited by exogenous VEGF and FGF-2, and induced by VEGF overexpressing 1A9 ovarian carcinoma cells. In vitro, at concentrations achievable in the plasma of patients, aplidine inhibited endothelial cell functions related to angiogenesis. It affected VEGF-and FGF-2-induced endothelial cell proliferation, inhibited cell migration and invasiveness assessed in the Boyden chamber and blocked the production of matrix metalloproteinases (MMP-2 and MMP-9) by endothelial cells. Finally, aplidine prevented the formation of capillary-like structures by endothelial cells on Matrigel. These findings indicate that aplidine has antiangiogenic activity in vivo and inhibits endothelial cell functional responses to angiogenic stimuli in vitro. This effect might contribute to the antineoplastic activity of aplidine.

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Antiangiogenic activity of aplidine, a new agent of marine origin

et al. 2004

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“…An ongoing study is currently addressing the elucidation of additional cellular protein receptors as targets for the didemnins. Preliminary data have identified palmitoyl thioesterase as a binding protein for aplidine and the biological consequences of the interaction with this lysosomal enzyme are under investigation (Crews et al, 1996).…”

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In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells

Depenbrock

Peter²,

Faircloth³

et al. 1998

Br J Cancer

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“…Also in leukaemia cells, Aplidin TM seems to cause a reduction in vascular endothelial growth factor (VEGF) secretion and downregulation of its receptor, VEGFR-1 (flt-1), involved in the process of vascularization and growth of certain tumours (Broggini et al, 2000). In addition, it has been described that its homologue didemnin B may interact with elongation factor 1a (Crews et al, 1994) and palmitoyl thioesterase (Crews et al, 1996).…”

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Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

et al. 2002

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AplidinTM , a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin TM effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of Aplidin TM induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by Aplidin TM , demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C delta (PKC-d) mediates the cytotoxic effect of Aplidin TM and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-d show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-d thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process.

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Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis.

Abstract: The marine natural product didemnin

Cited by 52 publications

References 42 publications

Antiangiogenic activity of aplidine, a new agent of marine origin

Antiangiogenic activity of aplidine, a new agent of marine origin

In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

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