This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zeitlin, B. D. Articles by Nör, J. E. Search for Related Content PubMed PubMed Citation Articles by Zeitlin, B. D. Articles by Nör, J. E.

Antiangiogenic Effect of TW37, a Small-Molecule Inhibitor of Bcl-2

¹ Angiogenesis Research Laboratory, Department of Restorative Sciences, School of Dentistry, ² Department of Internal Medicine, School of Medicine, ³ Department of Biomedical Engineering, College of Engineering, and ⁴ Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Jacques E. Nör, Angiogenesis Research Laboratory, University of Michigan School of Dentistry, 1011 North University Room 2309, Ann Arbor, MI 48109-1078. Phone: 734-936-9300; Fax: 734-936-1597; E-mail: jenor{at}umich.edu.

Bcl-2 is an antiapoptotic protein that is up-regulated in several tumor types, and its expression levels have strong correlation to development of resistance to therapy and poor prognosis. We have shown recently that Bcl-2 also functions as a proangiogenic signaling molecule that activates a nuclear factor-B–mediated pathway resulting in up-regulation of the angiogenic chemokines CXCL1 and CXCL8 by neovascular endothelial cells. Here, we evaluate the antiangiogenic effect of the novel small-molecule inhibitor of Bcl-2 (TW37) developed using a structure-based design strategy. We observed that TW37 has an IC₅₀ of 1.8 µmol/L for endothelial cells but showed no cytotoxic effects for fibroblasts at concentrations up to 50 µmol/L. The mechanism of TW37-induced endothelial cell death was apoptosis, in a process mediated by mitochondrial depolarization and activation of caspase-9 and caspase-3. The effect of TW37 on endothelial cell apoptosis was not prevented by coexposure to the growth factor milieu secreted by tumor cells. Inhibition of the angiogenic potential of endothelial cells (i.e., migration and capillary sprouting assays) and expression of the angiogenic chemokines CXCL1 and CXCL8 were accomplished at subapoptotic TW37 concentrations (0.005-0.05 µmol/L). Notably, administration of TW37 i.v. resulted in a decrease in the density of functional human microvessels in the severe combined immunodeficient mouse model of human angiogenesis. In conclusion, we describe functionally separate proapoptotic and antiangiogenic mechanisms for a small-molecule inhibitor of Bcl-2 and show the potential for Bcl-2 inhibition as a target for antiangiogenic therapy. (Cancer Res 2006; 66(17): 8698-706)

This article has been cited by other articles:

				H. V. Jain, J. E. Nor, and T. L. Jackson Quantification of endothelial cell-targeted anti-Bcl-2 therapy and its suppression of tumor growth and vascularization Mol. Cancer Ther., October 1, 2009; 8(10): 2926 - 2936. [Abstract] [Full Text] [PDF]

				K. W. Kim, L. Moretti, L. R. Mitchell, D. K. Jung, and B. Lu Combined Bcl-2/Mammalian Target of Rapamycin Inhibition Leads to Enhanced Radiosensitization via Induction of Apoptosis and Autophagy in Non-Small Cell Lung Tumor Xenograft Model Clin. Cancer Res., October 1, 2009; 15(19): 6096 - 6105. [Abstract] [Full Text] [PDF]

				N. Ashimori, B. D. Zeitlin, Z. Zhang, K. Warner, I. M. Turkienicz, A. C. Spalding, T. N. Teknos, S. Wang, and J. E. Nor TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis Mol. Cancer Ther., April 1, 2009; 8(4): 893 - 903. [Abstract] [Full Text] [PDF]

				Z. Wang, A. S. Azmi, A. Ahmad, S. Banerjee, S. Wang, F. H. Sarkar, and R. M. Mohammad TW-37, a Small-Molecule Inhibitor of Bcl-2, Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer: Involvement of Notch-1 Signaling Pathway Cancer Res., April 1, 2009; 69(7): 2757 - 2765. [Abstract] [Full Text] [PDF]

				B. D. Zeitlin, I. J. Zeitlin, and J. E. Nor Expanding Circle of Inhibition: Small-Molecule Inhibitors of Bcl-2 as Anticancer Cell and Antiangiogenic Agents J. Clin. Oncol., September 1, 2008; 26(25): 4180 - 4188. [Abstract] [Full Text] [PDF]

				A. S. Azmi, Z. Wang, R. Burikhanov, V. M. Rangnekar, G. Wang, J. Chen, S. Wang, F. H. Sarkar, and R. M. Mohammad Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis Mol. Cancer Ther., September 1, 2008; 7(9): 2884 - 2893. [Abstract] [Full Text] [PDF]

				T. Kaneko, Z. Zhang, M. G. Mantellini, E. Karl, B. Zeitlin, M. Verhaegen, M. S. Soengas, M. Lingen, R. M. Strieter, G. Nunez, et al. Bcl-2 Orchestrates a Cross-talk between Endothelial and Tumor Cells that Promotes Tumor Growth Cancer Res., October 15, 2007; 67(20): 9685 - 9693. [Abstract] [Full Text] [PDF]