Premium
Regulation of the pro‐angiogenic microenvironment by carboxyamido‐triazole
Author(s) -
Oliver Vyta Kulpa,
Patton Angela M.,
Desai Sudhen,
Lorang Dominique,
Libutti Steven K.,
Kohn Elise C.
Publication year - 2003
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10350
Subject(s) - angiogenesis , vascular endothelial growth factor , matrigel , in vivo , endothelial stem cell , interleukin 8 , cytokine , umbilical vein , human umbilical vein endothelial cell , cell growth , angiogenesis inhibitor , endocrinology , cancer research , chemistry , vascular endothelial growth factor a , medicine , biology , in vitro , immunology , biochemistry , vegf receptors , microbiology and biotechnology
Anti‐angiogenic agents regulate tumor growth by inhibiting endothelial cell proliferation and invasion. Carboxyamido‐triazole (CAI), an inhibitor of non‐voltage‐operated calcium entry and calcium influx‐mediated pathways, has angiogenesis and invasion inhibitory activity. We hypothesized that CAI may express its anti‐angiogenic effects through negative regulation of pro‐angiogenic cytokine production and/or function. In vivo, orally administered CAI prevented A2058 human melanoma xenograft growth and concomitantly resulted in a marked reduction in circulating vascular endothelial growth factor (VEGF) and interleukin‐8 (IL‐8). In vitro, A2058 cell secretion of VEGF was inhibited by CAI treatment under limiting micronutrient conditions that approximate the tumor microenvironment, media restriction, and acidification to pH 6.8 ( P = 0.0003 and P = 0.0006, respectively). VEGF and HIF‐1α message and protein were also reduced by CAI treatment. Oral CAI treatment reduced vascular ingrowth in vivo into VEGF‐containing Matrigel plugs. Commensurate with those findings, human umbilical vein endothelial cell (HUVEC) migration towards VEGF was reduced below background by exposure to CAI in the migration chamber ( P < 0.0001). An 88% reduction in circulating IL‐8 concentration was measured in CAI‐treated animals. However, IL‐8 protein secretion and gene expression were increased by CAI treatment in culture ( P ≤ 0.01), where CAI caused a dose‐dependent acidification of the culture milieu ( P ≤ 0.005). This paradox suggests that IL‐8 production in vitro may be more sensitive to ambient pH than cytosolic calcium. These observations suggest that CAI inhibition of tumor cell VEGF production and endothelial cell response to VEGF results in disruption of signaling between the tumor and its microenvironment, causing a net anti‐angiogenic effect. J. Cell. Physiol. 197: 139–148, 2003© 2003 Wiley‐Liss, Inc.