Minamiguchi K, Kumagai H, Masuda T, Kawada M, Ishizuka M,
Takeuchi T.Thiolutin, an inhibitor of HUVEC adhesion to
vitronectin, reduces paxillin in HUVECs and suppresses tumor
cell-induced angiogenesis.
Int J Cancer. 2001 Aug 1;93(3):307-16.
Institute for Chemotherapy, M.C.R.F., Numazu, Shizuoka,
Japan.
Recent studies have shown that integrin alpha v beta 3, a
receptor for vitronectin, plays an important role in
tumor-induced angiogenesis and tumor growth and that antagonists
of alpha v beta 3 inhibit angiogenic processes including
endothelial cell adhesion and migration. On the other hand, most
inhibitors of integrin alpha v beta 3 are peptide antagonists
that include the Arg-Gly-Asp (RGD) motif. We therefore reasoned
that non-peptide inhibitors of endothelial cell adhesion to
vitronectin might be useful for inhibition of tumor angiogenesis
in vivo. We screened for low-molecular-weight natural products
able to inhibit adhesion of human umbilical vein endothelial
cells (HUVECs) to vitronectin, and pyrrothine group compounds
including aureothricin, thioaurin and thiolutin were isolated
from microbial culture broths. Of these compounds, thiolutin
inhibited adhesion of HUVECs to vitronectin the most effectively
(IC(50), 0.83 microM). In vivo experiments showed that thiolutin
significantly suppressed angiogenesis induced by tumor cells
(S-180), a pathological form of neovascularization, in a mouse
dorsal air sac assay system. To explore the mechanism of
inhibition of HUVEC adhesion to vitronectin by thiolutin, we
examined the effect of this agent on intracellular cell adhesion
signaling. We found that the amount of paxillin in HUVECs was
significantly reduced by thiolutin treatment, while those of
other focal adhesion proteins including vinculin and focal
adhesion kinase (FAK) were not. Metabolic labeling experiments
showed that thiolutin enhanced degradation of paxillin in
HUVECs. Protease inhibitors (MG115 and E64-D) decreased the rate
of degradation of the paxillin induced by thiolutin and
partially restored thiolutin-induced inhibition of HUVEC
adhesion to vitronectin. Based on these findings, we concluded
that thiolutin, an inhibitor of HUVEC adhesion to vitronectin,
reduces the paxillin level in HUVECs and suppresses tumor
cell-induced angiogenesis in vivo. Copyright 2001 Wiley-Liss,
Inc.
PMID: 11433393
|
