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.