title: 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.
authors.affiliation: Laboratory of Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Broggini
authors.forename: S V
authors.initials: SV
authors.lastname: Marchini
authors.forename: E
authors.initials: E
authors.lastname: Galliera
authors.forename: P
authors.initials: P
authors.lastname: Borsotti
authors.forename: G
authors.initials: G
authors.lastname: Taraboletti
authors.forename: E
authors.initials: E
authors.lastname: Erba
authors.forename: M
authors.initials: M
authors.lastname: Sironi
authors.forename: J
authors.initials: J
authors.lastname: Jimeno
authors.forename: G T
authors.initials: GT
authors.lastname: Faircloth
authors.forename: R
authors.initials: R
authors.lastname: Giavazzi
authors.forename: M
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D003609:Dactinomycin / Q000494:pharmacology; D047630:Depsipeptides; D024202:Electrophoretic Mobility Shift Assay; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D047630:Depsipeptides; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D010456:Peptides, Cyclic; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003609:Dactinomycin; D008156:Luciferases; D040281:Vascular Endothelial Growth Factor Receptor-1; C098980:plitidepsin