The vascular disrupting activity of OXi8006 in endothelial cells and its phosphate prodrug OXi8007 in breast tumor xenografts.
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.
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Tracy E
TE
Strecker
Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA.
Samuel O
SO
Odutola
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA.
Ramona
R
Lopez
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Morgan S
MS
Cooper
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Justin K
JK
Tidmore
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Amanda K
AK
Charlton-Sevcik
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA.
Li
L
Li
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Matthew T
MT
MacDonough
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Mallinath B
MB
Hadimani
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Anjan
A
Ghatak
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA.
Li
L
Liu
OXiGENE Inc., South San Francisco, CA 94080, USA.
David J
DJ
Chaplin
Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9058, USA.
Ralph P
RP
Mason
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA; Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA.
Kevin G
KG
Pinney
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA; Institute of Biomedical Studies, Baylor University, Waco, TX 76798-7224, USA. Electronic address: mary_lynn_trawick@baylor.edu.
Mary Lynn
ML
Trawick
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000187:drug effects / Q000473:pathology; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D016513:Mice, SCID; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
C000588466:2-(3'-hydroxy-4'-methoxyphenyl)-3-(3'',4'',5''-trimethoxybenzoyl)-6-methoxyindole; D000970:Antineoplastic Agents; D007211:Indoles
Bioluminescence imaging (BLI); Breast cancer; Focal adhesion kinase (FAK); Microtubules; Vascular disrupting agent (VDA)