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The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma Hemant K

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The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma Hemant K Published OnlineFirst February 23, 2016; DOI: 10.1158/1535-7163.MCT-15-0567 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma Hemant K. Bid1, Doris A. Phelps1, Linlin Xaio1, Denis C. Guttridge2, Jiayuh Lin1, Cheryl London3, Laurence H. Baker4, Xiaokui Mo5, and Peter J. Houghton1,6 Abstract The bromodomain and extra-terminal domain inhibitor similar sensitivity in vivo as xenografts. Further investigation JQ1 has marked antitumor activity against several hematologic showed that JQ1 reduced tumor vascularization. This was malignanciesaswellassolidtumormodels.Here,weinves- secondary to both drug-induced downregulation of tumor- tigated its activity in vitro and in vivo against models of child- derived growth factors and direct effects of JQ1 on vascular hood rhabdomyosarcoma and Ewing sarcoma. In vitro,JQ1 elements. JQ1 suppressed VEGF-stimulated vascularization of (but not the inactive enantiomer JQ1R) inhibited cell prolif- Matrigel plugs in mice, and in vitro suppressed differentiation, eration and increased G1 fraction of cells, although there was proliferation, and invasion of human umbilical cord vascular no correlation between cell line sensitivity and suppression of endothelial cells (HUVEC). In HUVECs, JQ1 partially sup- c-MYC or MYCN. In vivo,xenograftsshowedsignificant inhi- pressed c-MYC levels, but dramatically reduced AP-1 levels bition of growth during the period of treatment, and rapid and activity through suppression of the AP-1–associated pro- regrowth after treatment was stopped, activity typical of anti- tein FOSL1. Our data suggest that the antitumor activity of JQ1 angiogenic agents. Furthermore, xenografts derived from cell in these sarcoma models is largely a consequence of its anti- lines intrinsically resistant or sensitive to JQ1 in vitro had angiogenic activity. Mol Cancer Ther; 15(5); 1–11. Ó2016 AACR. Introduction (7). Thus, c-MYC oncogene amplification or overexpression may play an important role in the development of childhood sarcomas The transcriptional regulator c-MYC is the most frequently as it has been found for other human malignancies. c-MYC deregulated oncogene in human tumors including pediatric regulates cell proliferation, inflammation, suppression of differ- cancer. Both c-MYC and MYCN are frequently amplified or over- entiation, apoptosis, and stimulation of angiogenesis. Thus, as expressed in rhabdomyosarcoma (RMS; refs. 1–3) and musculo- with many other malignancies, downregulation of c-MYC would skeletal neoplasms (4). c-MYC is overexpressed in Ewing sarcoma be predicted to retard tumor progression of childhood sarcoma. (EWS; ref. 5), and expression of the EWS-FLI1 fusion protein Recently, small-molecule inhibitors of BRD4, a member of the upregulates c-MYC expression (6) through an indirect mechanism bromodomain and extra-terminal domain (BET) protein family have been described that bind competitively to acetyl-lysine recognition motifs, or bromodomains (8). The most studied 1Center for Childhood Cancer and Blood Diseases, Nationwide Chil- dren's Hospital, Columbus, Ohio. 2Center for Regenerative Medicine, compound, JQ1, exerts broad-spectrum antitumor activity, pos- Ohio State University, Columbus, Ohio. 3College of Veterinary Medi- sibly by selective inhibition of oncogenes, including c-MYC, cine, Ohio State University, Columbus, Ohio. 4Division of Hematology/ through disruption of superenhancers (9). Notable activity has Oncology, Department of Internal Medicine, University of Michigan, been demonstrated in nonclinical models of several hematologic Ann Arbor, Michigan. 5Center for Biostatistics, Ohio State University, Columbus, Ohio. 6Greehey Children's Cancer Research Institute, San malignancies (10, 11), and in MYC "driven" tumors such as Antonio, Texas. neuroblastoma (12) and medulloblastoma (13). Sensitivity to Note: Supplementary data for this article are available at Molecular Cancer JQ1 in a series of serous ovarian cancer cells correlated with Therapeutics Online (http://mct.aacrjournals.org/). elevated expression of MYCN (14), whereas GLI2-dependent Current address for H.K. Bid: Resonant Therapeutics, Inc., Life Sciences Institute, upregulation of c-MYC was shown to mediate JQ1 resistance in University of Michigan, Ann Arbor, MI; and current address for D.A. Phelps: pancreatic cancer cell lines (15). Downregulation of c-MYC by Greehey Children's Cancer Research Institute, The University of Texas JQ1-induced cell-cycle arrest and apoptosis in ovarian cancer cell Health Science Center at San Antonio, 8403 Floyd Curl Drive, San Antonio, TX lines and downregulated lactate dehydrogenase A (LDHA) result- 78229-3000. ing in decreased lactate production and reduced energy supply Corresponding Author: Peter J. Houghton, Greehey Children's Cancer Research (16). JQ1 has been shown to impair estrogen-mediated growth Institute, The University of Texas Health Science Center at San Antonio, 8403 and transcription (17), and inhibit androgen receptor variants Floyd Curl Drive, Mail Code 7794, San Antonio, TX 78229-3000. Phone: 210-562- from chromatin binding in prostate cancer cells thereby over- 9000; Fax: 210-567-6791; E-mail: [email protected] coming resistance to endocrine-based therapies (18). JQ1 reduced doi: 10.1158/1535-7163.MCT-15-0567 oncogenic IkB activity in diffuse large B-cell lymphoma (DLBCL; Ó2016 American Association for Cancer Research. ref. 19), and has been proposed for the treatment of DLBCL, www.aacrjournals.org OF1 Downloaded from mct.aacrjournals.org on September 30, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst February 23, 2016; DOI: 10.1158/1535-7163.MCT-15-0567 Bid et al. although the in vivo activity against the one xenograft model tested In vitro growth inhibition studies was marginal with an increase in event-free survival advantage of Sarcoma cells were cultured in RPMI medium and HUVECs in only 3 days for JQ1-treated mice over control animals (20). JQ1 M200. Cells were seeded on 6-well plates at a density of approx- suppressed TNFa-mediated NF-kB activation and NF-kB–depen- imately 1 Â 105 cells/well and allowed to attach overnight. JQ1 dent target gene activation in A549 lung adenocarcinoma cells was dissolved in DMSO, and used at final concentrations of (21). Furthermore, a subset of lung adenocarcinoma cell lines was <0.1% DMSO in medium. Cells were treated with various con- sensitive to JQ1 through a mechanism independent of c-MYC centrations of JQ1 1 day after seeding. After 4 days, Calcein AB downregulation (22). JQ1 reduces osteosarcoma viability and is a (Life Technologies) was added directly into culture media at a potent inhibitor of osteoblast and osteoclast differentiation asso- final concentration of 10% and the plates were incubated at 37C. ciated with suppression of MYC and RUNX2 expression (23). JQ1 Optical density was measured spectrophotometrically at 540 and has also been reported to synergize with rapamycin in osteosar- 630 nm after adding Calcein AB for 3 to 4 hours. As a negative coma models (24). control, Calcein AB was added to medium without cells. Tumor progression and maintenance requires the development of an ample blood supply therefore neovascularization is critical Cell invasion assays to tumor growth and metastasis. c-MYC not only promotes cell For the invasion assays, 1 Â 105 cells were added into the top proliferation and transformation, but also vascular and hemato- chamber of the insert precoated with Matrigel (BD Biosciences). poietic development, by functioning as a master regulator of Cells were plated in medium without serum, and medium contain- À/À angiogenic factors (25). In mice, lethality of c-myc embryos ing 10% FBS in the bottom chamber served as chemoattractant. is associated with profound defects in vasculogenesis and prim- After several hours of incubation, the cells that did not invade itive erythropoiesis (25). Oncogenes such as c-myc suppress the through the pores were carefully wiped away from the upper side of expression of the antiangiogenic factor thrombospondin-1 (26), the membrane using an absorbent cotton swab. Then, the inserts and transgenic studies have shown that transformation induced were stained with 20% methanol and 0.2% crystal violet, imaged, by several oncoproteins, including c-MYC, is sufficient to induce and counted with an IX71 inverted microscope (Olympus). All the an angiogenic response and the expression of VEGF (27, 28). experiments were repeated three times independently. Here we present evidence that BRD4 inhibitor JQ1 has potent antiangiogenic activity in pediatric sarcoma models. Our data Cell-cycle analysis demonstrate that JQ1 can regulate angiogenesis to block tumor- Distinct phases of the cell cycle were distinguished by DNA derived angiogenic factors, directly suppress VEGF-driven angio- staining with the fluorescent dye propidium iodide (PI) and genesis, and impair the proliferation and differentiation of measured by flow cytometry. Cells were washed in ice-cold PBS, fi human vascular endothelial cells. These ndings support the fixed in 70% ethanol, and stained for 30 minutes at 37 C with notion that BRD4 may represent a relevant target for therapeutic PI (50 mg/mL PI in hypotonic sodium citrate solution containing intervention in pediatric sarcomas. 50 mg/mL RNase) followed by flow cytometric analysis. The percentages of cells in G1-, S-, and G2–M phases was determined Materials and Methods using the cell-cycle analysis program
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