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

Leukemia. 2003 Jan;17(1):52-9. doi: 10.1038/sj.leu.2402788.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / metabolism
  • Half-Life
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Leukemia, T-Cell / drug therapy*
  • Leukemia, T-Cell / genetics
  • Leukemia, T-Cell / metabolism
  • Luciferases / metabolism
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / genetics
  • Lymphokines / 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*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factors


  • 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