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Title: Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation

Abstract

Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These resultsmore » demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.« less

Authors:
 [1];  [2]; ; ;  [1];  [3];  [2];  [1];  [4];  [4]
  1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI (United States)
  2. Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, MI (United States)
  3. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
21438021
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 78; Journal Issue: 3; Other Information: DOI: 10.1016/j.ijrobp.2010.04.024; PII: S0360-3016(10)00600-0; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANGIOGENESIS; COLONY FORMATION; HEAD; MICE; NECK; RADIATION DOSES; RADIOTHERAPY; ANIMALS; BODY; DOSES; MAMMALS; MEDICINE; NUCLEAR MEDICINE; RADIOLOGY; RODENTS; THERAPY; VERTEBRATES

Citation Formats

Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation. United States: N. p., 2010. Web. doi:10.1016/j.ijrobp.2010.04.024.
Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, & Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation. United States. doi:10.1016/j.ijrobp.2010.04.024.
Zeitlin, Benjamin D., Spalding, Aaron C., Campos, Marcia S., Ashimori, Naoki, Dong Zhihong, Wang Shaomeng, Lawrence, Theodore S., Noer, Jacques E., E-mail: jenor@umich.ed, Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI. Mon . "Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation". United States. doi:10.1016/j.ijrobp.2010.04.024.
@article{osti_21438021,
title = {Metronomic Small Molecule Inhibitor of Bcl-2 (TW-37) Is Antiangiogenic and Potentiates the Antitumor Effect of Ionizing Radiation},
author = {Zeitlin, Benjamin D. and Spalding, Aaron C. and Campos, Marcia S. and Ashimori, Naoki and Dong Zhihong and Wang Shaomeng and Lawrence, Theodore S. and Noer, Jacques E., E-mail: jenor@umich.ed and Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI and Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI},
abstractNote = {Purpose: To investigate the effect of a metronomic (low-dose, high-frequency) small-molecule inhibitor of Bcl-2 (TW-37) in combination with radiotherapy on microvascular endothelial cells in vitro and in tumor angiogenesis in vivo. Methods and Materials: Primary human dermal microvascular endothelial cells were exposed to ionizing radiation and/or TW-37 and colony formation, as well as capillary sprouting in three-dimensional collagen matrices, was evaluated. Xenografts vascularized with human blood vessels were engineered by cotransplantation of human squamous cell carcinoma cells (OSCC3) and human dermal microvascular endothelial cells seeded in highly porous biodegradable scaffolds into the subcutaneous space of immunodeficient mice. Mice were treated with metronomic TW-37 and/or radiation, and tumor growth was evaluated. Results: Low-dose TW-37 sensitized primary endothelial cells to radiation-induced inhibition of colony formation. Low-dose TW-37 or radiation partially inhibited endothelial cell sprout formation, and in combination, these therapies abrogated new sprouting. Combination of metronomic TW-37 and low-dose radiation inhibited tumor growth and resulted in significant increase in time to failure compared with controls, whereas single agents did not. Notably, histopathologic analysis revealed that tumors treated with TW-37 (with or without radiation) are more differentiated and showed more cohesive invasive fronts, which is consistent with less aggressive phenotype. Conclusions: These results demonstrate that metronomic TW-37 potentiates the antitumor effects of radiotherapy and suggest that patients with head and neck cancer might benefit from the combination of small molecule inhibitor of Bcl-2 and radiation therapy.},
doi = {10.1016/j.ijrobp.2010.04.024},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 3,
volume = 78,
place = {United States},
year = {Mon Nov 01 00:00:00 EDT 2010},
month = {Mon Nov 01 00:00:00 EDT 2010}
}
  • Cisplatin-based therapy is highly toxic, but moderately effective in most cancers. Concurrent inhibition of cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) results in antitumor activity and has organ-protective effects. The goal of this paper was to determine the antitumor activity of PTUPB, an orally bioavailable COX-2/sEH dual inhibitor, in combination with cisplatin and gemcitabine (GC) therapy. NSG mice bearing bladder cancer patient-derived xenografts were treated with vehicle, PTUPB, cisplatin, GC, or combinations thereof. Mouse experiments were performed with two different PDX models. PTUPB potentiated cisplatin and GC therapy, resulting in significantly reduced tumor growth and prolonged survival. PTUPB plus cisplatinmore » was no more toxic than cisplatin single-agent treatment as assessed by body weight, histochemical staining of major organs, blood counts, and chemistry. The combination of PTUPB and cisplatin increased apoptosis and decreased phosphorylation in the MAPK/ERK and PI3K/AKT/mTOR pathways compared with controls. PTUPB treatment did not alter platinum–DNA adduct levels, which is the most critical step in platinum-induced cell death. The in vitro study using the combination index method showed modest synergy between PTUPB and platinum agents only in 5637 cell line among several cell lines examined. However, PTUPB is very active in vivo by inhibiting angiogenesis. Finally, PTUPB potentiated the antitumor activity of cisplatin-based treatment without increasing toxicity in vivo and has potential for further development as a combination chemotherapy partner.« less
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  • Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation ofmore » breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo.« less