Betsy N. Perry, Baskaran Govindarajan, Sulochana S. Bhandarkar, Ulla G

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Pharmacologic Blockade of Angiopoietin-2 Is Efficacious against Model Hemangiomas in Mice Betsy N. Perry, Baskaran Govindarajan, Sulochana S. Bhandarkar, Ulla G. Knaus, Monika Valo, Celina Sturk, Carol O. Carrillo, Allie Sohn, Francesca Cerimele, Dan Dumont, Albert Losken, Joseph Williams, Lawrence F. Brown, Xiaolian Tan, Ella Ioffe, George D. Yancopoulos, Jack L. Arbiser Journal of Investigative Dermatology Volume 126, Issue 10, Pages 2316-2322 (October 2006) DOI: 10.1038/sj.jid.5700413 Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Ang-2 and tie-2 are expressed in bEnd. 3 hemangioma tissue in vivo.In situ hybridization studies of subcutaneous bEnd.3 tumors. Tumor cells express mRNAs for ang-2 (a, bright field; b, corresponding dark field), (c, d) tie-1, and (e, f) tie-2. Original magnification × 200. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Expression of VEGF receptors and low-level VEGF expression in bEnd.3 hemangioma tissue in vivo. Tumors are located in the center and right side of the field, with normal subcutaneous tissue to the left-hand side of the field. Tumor cells strongly express Flt-1 (a, bright field; b, corresponding dark field) and (c, d) Flk-1 mRNAs. (e, f) A lower level of expression of VEGF mRNA was seen. (g, h) A low background level of grains is seen with control VEGF sense probe. Original magnification × 200. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Inhibition of ang-2 signaling by a soluble tie-2 receptor inhibits bEnd.3 growth in vivo. The top panel shows mice with control Fc-treated tumor (left) and tie-2/Fc-treated hemangioma (right). The bottom panel shows that hemangioma volume in mice treated with tie-2/Fc differs significantly from control mice (P<0.05). Three mice were used in each group, and the error bars represent the standard error of the mean. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Tie-2 activation is not required for in vivo growth of bEnd.3 cells. Wild-type and tie-2-deficient polyoma-transformed cells were tested in mice for their ability to form hemangiomas in mice. No significant difference in tumor volume was observed. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Chemical structures of Nox enzyme inhibitors. Structural similarity between known inhibitor of Nox genes, (a) DPI, and novel inhibitors, (b) brilliant green, and (c) gentian violet. The common structural feature is a cation surrounded by two or more aromatic rings. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Brilliant green (BG) and gentian violet (GV) inhibit (a) Nox2 (Cos-phox) and (b) Nox4 activity, along with hydrogen peroxide (H2O2) production in a dose-dependent manner in Cos-phox and HEK293 Nox4-11 cells. Cells were treated with different concentrations of vehicle control, BG, or GV; Cos-phox cells were additionally either left unstimulated or stimulated with phorbol 12-myristate 13-acetate. After 1hour incubation at 37°C, the reaction was stopped and H2O2 production was measured using the homovanillic acid assay. The abililty of these drugs to inhibit production of H2O2 is shown as a percentage relative to the untreated control (100%). Cox-phox cells did not produce H2O2 without phorbol 12-myristate 13-acetate stimulation with or without the addition of BG or GV (not shown). Optimal Nox2 activity requires phorbol 12-myristate 13-acetate stimulation whereas Nox4 activity is constitutive. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Treatment of bEnd.3 cells with (a) brilliant green and (b) gentian violet decreases levels of ang-2 mRNA (corrected for 18S RNA). Bars shown represent the average of triplicate experiments, and error bars indicate the standard error of the mean. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 8 Effect of brilliant green and gentian violet on bEnd.3 hemangiomas in vivo. For each treatment condition, three mice were injected with 1,000,000 bEnd.3 cells and received intralesional injection with either vehicle control, brilliant green or gentian violet (from left to right in photo) on days 9 and 14. Animals were euthanized on day 20, secondary to tumor burden in the control animals. (a) Photos above represent average tumor burden in each of the three groups and tumor volume (mm3) is graphically depicted. (b) Error bars represent the standard error of the mean. Journal of Investigative Dermatology 2006 126, 2316-2322DOI: (10.1038/sj.jid.5700413) Copyright © 2006 The Society for Investigative Dermatology, Inc Terms and Conditions