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Title: SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation

Abstract

Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecule indolinone that specifically inhibits this family of kinases. Methods and Materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.

Authors:
 [1];  [2];  [3];  [3];  [3];  [3];  [3];  [4];  [4];  [5]
  1. Vanderbilt University School of Medicine, Nashville, TN (United States)
  2. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN (United States)
  3. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TNUSA (United States)
  4. Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TNUSA (United States)
  5. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TNUSA (United States) and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN (United States). E-mail: dennis.hallahan@vanderbilt.edu
Publication Date:
OSTI Identifier:
20793401
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 64; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2005.11.014; PII: S0360-3016(05)02974-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; APOPTOSIS; CAPILLARIES; CARCINOMAS; COMBINED THERAPY; ENDOTHELIUM; FRACTIONATED IRRADIATION; IN VIVO; INHIBITION; IODIDES; IONIZING RADIATIONS; LIMBS; LUNGS; MICE; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RADIOTHERAPY; SKIN; TUBULES; VEINS

Citation Formats

Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, and Hallahan, Dennis E.. SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. United States: N. p., 2006. Web. doi:10.1016/J.IJROBP.2005.1.
Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, & Hallahan, Dennis E.. SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation. United States. doi:10.1016/J.IJROBP.2005.1.
Cuneo, Kyle C., Geng Ling, Tan Jiahuai, Brousal, Jeffrey, Shinohara, Eric T., Osusky, Katherine, Fu, Allie, Shyr, Yu, Wu Huiyun, and Hallahan, Dennis E.. Wed . "SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation". United States. doi:10.1016/J.IJROBP.2005.1.
@article{osti_20793401,
title = {SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation},
author = {Cuneo, Kyle C. and Geng Ling and Tan Jiahuai and Brousal, Jeffrey and Shinohara, Eric T. and Osusky, Katherine and Fu, Allie and Shyr, Yu and Wu Huiyun and Hallahan, Dennis E.},
abstractNote = {Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecule indolinone that specifically inhibits this family of kinases. Methods and Materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model. Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation. Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.},
doi = {10.1016/J.IJROBP.2005.1},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 4,
volume = 64,
place = {United States},
year = {Wed Mar 15 00:00:00 EST 2006},
month = {Wed Mar 15 00:00:00 EST 2006}
}
  • Purpose: Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. Methods and Materials: The combination of the selective PKC{beta} inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and humanmore » umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry. Results: ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. Conclusion: PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.« less
  • Exposure of MDA-MB-468 cells to ionizing radiation (IR) caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Specific epidermal growth factor receptor (EGFR) inhibitor AG1478 and specific Src inhibitor PP2 inhibited IR-induced ERK1/2 activation but phosphatidylinositol-3 kinase inhibitor wortmannin did not. IR caused EGFR tyrosine phosphorylation, whereas it did not induce EGFR autophosphorylation at Tyr992, Tyr1045, and Tyr1068 or Src-dependent EGFR phosphorylation at Tyr845. SHP-2, which positively regulates EGFR/Ras/ERK signaling cascade, became activated by IR as indicated by its phosphorylation at Tyr542. This activation was inhibited by PP2 not by AG1478, which suggests Src-dependent activation of SHP-2.more » Src and PTP{alpha}, which positively regulates Src, became activated as indicated by phosphorylation at Tyr416 and Tyr789, respectively. These data suggest that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation.« less
  • 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 treatedmore » 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.« less