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

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• 作者：Satoshi Anai M.D.^a ; Noboru Sakamoto M.D.^b ; Yoshihisa Sakai M.D.^b ; Motoyoshi Tanaka M.D. ; Ph.D.^c ; Stacy Porvasnik M.S.^b ; Cydney Urbanek B.S.^b ; Wengang Cao M.D.^b ; Steve Goodison Ph.D.^d ; Charles J. Rosser M.D.^b ; ^e ; ^{charles.rosser@urology.ufl.edu"" rel=""nofollow}
• 关键词：Bcl-2 ; Vascular endothelial growth factor ; Angiogenesis ; Therapeutic
• 刊名：Urologic Oncology: Seminars and Original Investigations
• 出版年：2011
• 出版时间：July-August 2011
• 年：2011
• 卷：29
• 期：4
• 页码：421-429
• 全文大小：2423 K

文摘

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.