|
|
Blood, 15 February 2008, Vol. 111, No. 4, pp. 1951-1961.
Prepublished online as a Blood First Edition Paper on November 16, 2007; DOI 10.1182/blood-2007-05-089219.
 Previous Article | Next Article 
Submitted May 9, 2007
Accepted October 28, 2007
The microtubule targeting agent, CA4P, regresses leukemic xenografts by disrupting interaction with vascular cells and mitochondrial-dependent cell death
Isabelle Petit, Matthias A Karajannis, Loic Vincent, Lauren Young, Jason Butler, Andrea T Hooper, Koji Shido, Hermann Steller, David J Chaplin, Eric Feldman, and Shahin Rafii*
Department of Genetic Medicine, Division of Hematology-Oncology, Howard Hughes Medical Inst., Ansary Center for Stem Cell Therapeutics, Weill Cornell Medical College, New York, NY, United States
Strang Laboratory of Cancer Research, Howard Hughes Medical Inst., The Rockefeller University, New York, NY, United States
Oxigene, Inc., Waltham, MA, United States
* Corresponding author; email: srafii{at}med.cornell.edu.
Adhesion of leukemic cells to vascular cells may confer resistance to chemotherapeutic agents. Therefore, we hypothesized that disruption of leukemic cell cytoskeletal stability and interference with vascular cell interactions would promote leukemic cell death. Herein, we demonstrate that low and non-toxic doses of the microtubule-destabilizing agent combretastatin-A4-phosphate (CA4P), inhibit leukemic cell proliferation in vitro and induce mitotic arrest and cell death. Treatment of acute myeloid leukemias (AMLs) with CA4P leads to disruption of mitochondrial membrane potential, release of pro-apoptotic mitochondrial membrane proteins and DNA fragmentation, resulting in cell death in part-through a caspase-dependent manner. Furthermore, CA4P increases intracellular reactive oxygen species (ROS), and antioxidant treatment imparts partial protection from cell death, suggesting that ROS accumulation contributes to CA4P-induced cytotoxicity in AML. In vivo, CA4P inhibited proliferation and circulation of leukemic cells and diminished the extent of peri-vascular leukemic infiltrates, prolonging survival of xenotransplanted mice, without inducing hematological toxicity. CA4P decreases the interaction of leukemic cells with neo-vessels by down-regulating the expression of adhesion-molecule, VCAM-1, thereby augmenting leukemic cell death. These data suggest that, CA4P target both circulating and vascular-adherent leukemic cells through mitochondrial damage and downregulation of VCAM-1, without incurring hematological toxicities. As such, CA4P provides for an effective means to treat refractory organ-infiltrating leukemias.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
Y. Shaked, T. Tang, J. Woloszynek, L. G. Daenen, S. Man, P. Xu, S.-R. Cai, J. M. Arbeit, E. E. Voest, D. J. Chaplin, et al.
Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents
Cancer Res.,
October 1, 2009;
69(19):
7524 - 7528.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. Tozer, V. E. Prise, G. Lewis, S. Xie, I. Wilson, and S. A. Hill
Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-O-Phosphate at Clinically Relevant Doses
Clin. Cancer Res.,
June 1, 2009;
15(11):
3781 - 3790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
