Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays

Geldof, Albert A.; Mastbergen, S.C.; Henrar, R.E.C.; Faircloth, Glynn

doi:10.1007/s002800050983

Cited by 63 publications

(37 citation statements)

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“…Aplidine was at first selected for its enhanced cytotoxicity against different tumour cells lines and lower myelotoxicity relative to didemnin B (Geldof et al, 1999;Albella et al, 2002). In vitro, aplidine inhibited tumour cell proliferation with an IC 50 in the nanomolar/subnanomolar range, with complete inhibition achieved at 10 nM (Lobo et al, 1997;Erba et al, 2002;Erba et al, 2003).…”

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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).…”

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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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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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“…[1][2][3][4][5] It has completed phase I trials and is under phase II development. [6][7][8][9] Although its precise mechanism of action is still unknown, aplidine is able to induce rapid p53-independent apoptosis in different cancer cell lines growing in vitro.…”

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Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

et al. 2003

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The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8-10 times more VEGF than parental cells, was less sensitive to aplidineinduced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells.

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Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays

Cited by 63 publications

References 19 publications

Antiangiogenic activity of aplidine, a new agent of marine origin

Antiangiogenic activity of aplidine, a new agent of marine origin

Effect of Aplidin in acute lymphoblastic leukaemia cells

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

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