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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.

Abstract
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 aplidine-induced 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.
AuthorsM Broggini, S V Marchini, E Galliera, P Borsotti, G Taraboletti, E Erba, M Sironi, J Jimeno, G T Faircloth, R Giavazzi, M D'Incalci
JournalLeukemia (Leukemia) Vol. 17 Issue 1 Pg. 52-9 (Jan 2003) ISSN: 0887-6924 [Print] England
PMID12529660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • DNA Primers
  • Depsipeptides
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Peptides, Cyclic
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Dactinomycin
  • Luciferases
  • Vascular Endothelial Growth Factor Receptor-1
  • plitidepsin
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Autocrine Communication
  • Cell Division (drug effects)
  • DNA Primers (chemistry)
  • Dactinomycin (pharmacology)
  • Depsipeptides
  • Electrophoretic Mobility Shift Assay
  • Endothelial Growth Factors (antagonists & inhibitors, genetics, metabolism)
  • Half-Life
  • Humans
  • Intercellular Signaling Peptides and Proteins (genetics, metabolism)
  • Leukemia, T-Cell (drug therapy, genetics, metabolism)
  • Luciferases (metabolism)
  • Lymphokines (antagonists & inhibitors, genetics, metabolism)
  • Peptides, Cyclic (pharmacology)
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic (drug effects)
  • Protein Synthesis Inhibitors (pharmacology)
  • RNA, Messenger (metabolism)
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured (drug effects)
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, genetics, metabolism)
  • Vascular Endothelial Growth Factors

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