Dual targeting of Bcl-2 and VEGF: a potential strategy to improve therapy for prostate cancer.

Abstract

We previously demonstrated that Bcl-2 overexpression stimulates angiogenesis in PC-3 human prostate cancer cells, thus giving these tumors a growth advantage. To further elucidate the relationship between Bcl-2 and vascular endothelial growth factor (VEGF) in PC-3-Bcl-2 cells, tumorigenicity and angiogenesis were evaluated in our in vitro and in vivo model treated with antisense Bcl-2 oligodeoxynucleotide (ASO) and bevacizumab. In vitro and in vivo angiogenesis assays, as well as a xenograft tumor model of the human prostate cancer cell line PC-3-Bcl-2, were subjected to ASO alone, bevacizumab alone, or the combination of ASO and bevacizumab. Protein-based assays (e.g., immunohistochemical staining and enzyme-linked immunosorbent assay [ELISA]) were utilized to detect molecular changes. Interestingly, targeting Bcl-2 with ASO resulted in the inhibition of in vitro tube formation and inhibition of angiogenesis in Matrigel plugs similar to treatment with bevacizumab. In our PC-3-Bcl-2 xenograft model, ASO alone resulted in 41% reduction in tumor size, bevacizumab alone resulted in a 50% reduction in tumor size, whereas the combination of ASO with bevacizumab was associated with >95% reduction in tumor volume. Reduction in tumor size in all groups was associated with reduction in Bcl-2 and VEGF expression, induction of apoptosis, and inhibition of angiogenesis and its associated chemokine production. These findings confirm that Bcl-2 is a pivotal target for cancer therapy and thus, further study of this novel combination of Bcl-2 reduction and angiogenic targeting in human tumors is warranted.

• Authors: Satoshi Anai, Noboru Sakamoto, Yoshihisa Sakai, Motoyoshi Tanaka, Stacy Porvasnik, Cydney Urbanek, Wengang Cao, Steve Goodison, Charles J Rosser
• Journal: Urologic oncology (Urol Oncol) 2011 Jul-Aug Vol. 29 Issue 4 Pg. 421-9 ISSN: 1873-2496 [Electronic] United States
• PMID: 19576799 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal, Humanized
• DNA, Antisense
• Platelet Endothelial Cell Adhesion Molecule-1
• Proto-Oncogene Proteins c-bcl-2
• Vascular Endothelial Growth Factor A
• Bevacizumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage, immunology, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Bevacizumab
• Blood Vessels (drug effects, metabolism)
• Cell Line
• Cell Line, Tumor
• DNA, Antisense (administration & dosage, genetics, pharmacology)
• Drug Synergism
• Enzyme-Linked Immunosorbent Assay
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (metabolism, prevention & control)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Prostatic Neoplasms (drug therapy, pathology)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Tumor Burden (drug effects)
• Vascular Endothelial Growth Factor A (immunology, metabolism)
• Xenograft Model Antitumor Assays