@article{0d353bfe5a954160b3a8c6d3f61e72e2,
title = "The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts",
abstract = "This study describes the vascular disrupting ability and the mechanism of action of the indole-based tubulin-binding compound, OXi8006, and its water-soluble phosphate prodrug OXi8007. Treatment of rapidly proliferating human umbilical vein endothelial cells (HUVECs), used as a model for the tumor vasculature, with OXi8006 or OXi8007, caused potent microtubule disruption followed by extensive reorganization of the cytoskeletal network. The mechanism of action involved an increase in focal adhesion formation associated with an increase in phosphorylation of both non-muscle myosin light chain and focal adhesion kinase. These effects were dramatically diminished by an inhibitor of RhoA kinase, a downstream effector of RhoA. Cell cycle blockade at G2/M and cytotoxicity toward rapidly proliferating HUVECs were also observed. Capillary-like networks of HUVECs were disrupted by the action of both OXi8006 and OXi8007. The prodrug OXi8007 exhibited potent and rapid dose-dependent antivascular activity assessed by dynamic bioluminescence imaging (BLI) in an MDA-MB-231-luc breast cancer xenograft mouse model. By 6 hours post treatment, over 93% of the BLI signal was abolished with only a slight recovery at 24 hours. These findings were confirmed by histology. The results from this study demonstrate that OXi8007 is a potent vascular disrupting agent acting through an anti-microtubule mechanism involving RhoA.",
keywords = "Bioluminescence imaging (BLI), Breast cancer, Focal adhesion kinase (FAK), Microtubules, Vascular disrupting agent (VDA)",
author = "Strecker, {Tracy E.} and Odutola, {Samuel O.} and Ramona Lopez and Cooper, {Morgan S.} and Tidmore, {Justin K.} and Charlton-Sevcik, {Amanda K.} and Li Li and MacDonough, {Matthew T.} and Hadimani, {Mallinath B.} and Anjan Ghatak and Li Liu and Chaplin, {David J.} and Mason, {Ralph P.} and Pinney, {Kevin G.} and Trawick, {Mary Lynn}",
note = "Funding Information: The authors thank Dr. A. Ramirez (Mass Spectrometry Core Facility, Baylor University) and Dr. J. Karban, Dr. C. Moehnke and Dr. M. Nemec (Director) for use of the shared Molecular Biosciences Center at Baylor University. Dr. Kate Luby-Phelps provided invaluable assistance with fluorescent microscopy in the Microscopy Resource of the Cancer Center at UT Southwestern Medical Center. This work was supported by the National Institutes of Health National Cancer Institute [Grant 5R01CA140674 ] (to K.G.P. and M.L.T. with subcontract to R.P.M.), and OXiGENE, Inc . (Grant to K.G.P. and M.L.T). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Imaging was facilitated with the assistance of Resources of the Harold C. Simmons Cancer Center supported through a National Institutes of Health National Cancer Institute Cancer Center Support Grant [Grant 1P30 CA142543 ], specifically, the Southwestern Small Animal Imaging Resource, and Live Cell Imaging Resource. The IVIS Spectrum was purchased with support of 1S10RR024757 . Publisher Copyright: {\textcopyright} 2015 Elsevier Ireland Ltd.",
year = "2015",
month = dec,
day = "1",
doi = "10.1016/j.canlet.2015.08.021",
language = "English (US)",
volume = "369",
pages = "229--241",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",
}