Antiproliferative effect of dehydrodidemnin B (DDB), a depsipeptide isolated from Mediterranean tunicates

Urdiales, José Luis; Morata, Pilar; Castro, Ignacio Núñez de; Sánchez‐Jiménez, Francisca

doi:10.1016/0304-3835(96)04151-1

Cited by 131 publications

(85 citation statements)

References 25 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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“…It has shown activity against both human haematological and solid tumour cell lines growing in vitro (Urdiales et al, 1996;Lobo et al, 1997;Depenbrock et al, 1998;Geldof et al, 1999), in vivo murine B16 melanoma and in several human tumours xenografts (Faircloth et al, 1995.…”

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“…Recently, a G 2 block was described for Aplidin in human leukaemia Molt-4 cell line (Erba et al, 2002). Inhibition of protein synthesis via GTP-dependent elongation factor 1-alpha in vitro (Crews et al, 1994), DNA and RNA syntheses in different cell lines (Crampton et al, 1984;Sakai et al, 1996) and inhibition of ornithine decarboxylase have been reported for Didemnins as well as for Aplidin (Urdiales et al, 1996;Erba et al, 2002).…”

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Effect of Aplidin in acute lymphoblastic leukaemia cells

et al. 2003

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The cytotoxic effect of Aplidin was investigated on fresh leukaemia cells derived from children with B-cell-precursor (BCP) acute lymphoblastic leukaemia (ALL) by using stromal-layer culture system and on four cell lines, ALL-PO, Reh, ALL/MIK and TOM-1, derived from patients with ALL with different molecular genetic abnormalities. In ALL cell lines Aplidin was cytotoxic at nanomolar concentrations. In the ALL cell lines the drug-induced cell death was clearly related to the induction of apoptosis and appeared to be p53-independent. Only in ALL-PO 20 nM Aplidin treatment caused a block of vascular endothelial growth factor (VEGF) secretion and downregulation of VEGF-mRNA, but Aplidin cytotoxicity does not seem to be related to VEGF inhibition since the sensitivity of ALL-PO cells to Aplidin is comparable to that observed for the other cells used. Aplidin induced a G 1 and a G 2 M block in ALL cell lines. In patient-derived leukaemia cells, Aplidin induced a strong cytotoxicity evidenced in a stroma-supported immunocytometric assay. Cells from children with genetic abnormalities such as t(9;22) and t(4;11) translocations, associated with an inferior treatment outcome, were sensitive to Aplidin to the same extent as that observed in other BCP-ALL cases. Aplidin exerted a strong cell killing effect (488%) against primary culture cells from five relapsed ALL cases, at concentrations much lower than those reported to be achieved in plasma of patients receiving Aplidin at recommended doses. Taken together these data suggest that Aplidin could be a new anticancer drug to be investigated in ALL patients resistant to available therapy.

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“…The didemnins exert their anti-tumour effect by interfering with protein synthesis via GTP-dependent inhibition of the elongation factor 1-alpha, a protein translation component (Crews et al, 1994). Aplidine induces, in vitro and in vivo, a total inhibition of omithine decarboxylase activity at very low concentrations (10-10 M) (Urdiales et al, 1996). However, the importance of this finding has to be investigated further to understand whether this biochemical effect might be of relevance as a therapeutic intervention (Auvinen, 1997).…”

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