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Vascular Disrupting Activity of OXi8006 in Endothelial Cells and Its Phosphate Prodrug OXi8007 in Breast Tumor Xenografts in Vivo
Author(s) -
Odutola Samuel,
Strecker Tracy,
Cooper Morgan,
Tidmore Justin,
CharltonSevcik Amanda,
MacDonough Matthew,
Hadimani Mallinath,
Ghatak Anjan,
Lopez Ramona,
Li Li,
Liu Li,
Mason Ralph,
Chaplin David,
Pinney Kevin,
Trawick Mary Lynn
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.897.5
Subject(s) - rhoa , chemistry , focal adhesion , microbiology and biotechnology , umbilical vein , microtubule , cancer research , in vivo , prodrug , phosphorylation , in vitro , biochemistry , biology , signal transduction
Tubulin‐binding, small‐molecule vascular disrupting agents (VDAs) are anticancer agents that rapidly depolymerize microtubules, and cause a pronounced shutdown in blood flow to solid tumors while leaving the blood flow in normal tissues intact. The indole‐based tubulin‐binding compound OXi8006 and its phosphate prodrug OXi8007 were investigated as VDAs. OXi8006 and OXi8007 were cytotoxic towards rapidly proliferating human umbilical vein endothelial cells (HUVECs), and disrupted tubular networks of HUVECs. OXi8006 and OXi8007 also disrupted microtubules, caused cell cycle blockade at G2/M, and extensive reorganization of the cytoskeletal network in activated HUVECs. The mechanism of action involved an increase in focal adhesion formation associated with an increased phosphorylation of both non‐muscle myosin light chain and focal adhesion kinase. These effects were diminished by an inhibitor of RhoA kinase, a downstream effector of RhoA. OXi8007 caused potent dose‐dependent antivascular activity assessed by bioluminescence imaging in an MDA‐MB‐231‐luc breast cancer xenograft mouse model. These findings were confirmed by histology. The results demonstrated that OXi8006 and OXi8007 are potent VDAs. (This work was supported by the NIH NCI [Grant 5R01CA140674] and OXiGENE, Inc.)