Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts

• Published in: Molecular cancer therapeutics 2007-01, Vol.6 (1), p.101-111
• Main Authors: Anai, Satoshi, Goodison, Steve, Shiverick, Kathleen, Hirao, Yoshihiko, Brown, Bob D, Rosser, Charles J
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; Bcl-2; Cell Cycle - drug effects; Cell Cycle - radiation effects; Cell Death - drug effects; Cell Death - radiation effects; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - pathology; Endothelial Cells - radiation effects; Gene Expression - drug effects; Gene Expression - radiation effects; Humans; Male; Mice; Mice, Nude; Neovascularization, Pathologic - radiotherapy; oligodeoxynucleotide; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - metabolism; Oligonucleotides, Antisense - pharmacology; prostate; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - pathology; Prostatic Neoplasms - radiotherapy; Proto-Oncogene Proteins c-bcl-2 - deficiency; Proto-Oncogene Proteins c-bcl-2 - genetics; radiation; Radiation Tolerance - drug effects; Tumor Stem Cell Assay; Vascular Endothelial Growth Factors - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-06-0367

Expression of the proto-oncogene Bcl-2 is associated with tumor progression. Bcl-2's broad expression in tumors, coupled with its role in resistance to chemotherapy and radiation therapy–induced apoptosis, makes it a rational target for anticancer therapy. Antisense Bcl-2 oligodeoxynucleotide (ODN) reagents have been shown to be effective in reducing Bcl-2 expression in a number of systems. We investigated whether treating human prostate cancer cells with antisense Bcl-2 ODN (G3139, oblimersen sodium, Genasense) before irradiation would render them more susceptible to radiation effects. Two prostate cancer cell lines expressing Bcl-2 at different levels (PC-3-Bcl-2 and PC-3-Neo) were subjected to antisense Bcl-2 ODN, reverse control (CTL), or mock treatment. Antisense Bcl-2 ODN alone produced no cytotoxic effects and was associated with G 1 cell cycle arrest. The combination of antisense Bcl-2 ODN with irradiation sensitized both cell lines to the killing effects of radiation. Both PC-3-Bcl-2 and PC-3-Neo xenografts in mice treated with the combination of antisense Bcl-2 ODN and irradiation were more than three times smaller by volume compared with xenografts in mice treated with reverse CTL alone, antisense Bcl-2 ODN alone, irradiation alone, or reverse CTL plus radiotherapy ( P = 0.0001). Specifically, PC-3-Bcl-2 xenograft tumors treated with antisense Bcl-2 ODN and irradiation had increased rates of apoptosis and decreased rates of angiogenesis and proliferation. PC-3-Neo xenograft tumors had decreased proliferation only. This is the first study which shows that therapy directed at Bcl-2 affects tumor vasculature. Together, these findings warrant further study of this novel combination of Bcl-2 reduction and radiation therapy, as well as Bcl-2 reduction and angiogenic therapy. [Mol Cancer Ther 2007;6(1):101–11]