Journal ArticleDOI
TS-1 enhances the effect of radiotherapy by suppressing radiation-induced hypoxia-inducible factor-1 activation and inducing endothelial cell apoptosis.
Lihua Zeng,Lihua Zeng,Guangfei Ou,Satoshi Itasaka,Hiroshi Harada,Xuejun Xie,Xuejun Xie,Keiko Shibuya,Shinae Kizaka-Kondoh,Akiyo Morinibu,Kazumi Shinomiya,Masahiro Hiraoka +11 more
Reads0
Chats0
TLDR
Results indicate that TS‐1 enhances radiation‐induced apoptosis of endothelial cells by suppressing HIF‐1 activity, resulting in an increase in radiosensitivity of the tumor cells.Abstract:
The therapeutic effect of concurrent chemoradiotherapy with TS-1 has been confirmed in various solid tumors; however, the detailed mechanism of action has not yet been fully elucidated. In the present study, we identified hypoxia-inducible factor-1 (HIF-1) as one of the targets of TS-1 in chemoradiotherapy. In growth delay assays using a tumor xenograft of non-small-cell lung carcinoma, H441, TS-1 treatment enhanced the therapeutic effect of single γ-ray radiotherapy (14 Gy) and significantly delayed tumor growth by 1.58-fold compared to radiotherapy alone (P < 0.01). An optical in vivo imaging experiment using a HIF-1-dependent 5HRE-luc reporter gene revealed that TS-1 treatment suppressed radiation-induced activation of HIF-1 in the tumor xenografts. The suppression led to apoptosis of endothelial cells resulting in both a significant decrease in microvessel density (P < 0.05; vs radiation therapy alone) and a significant increase in apoptosis of tumor cells (P < 0.01; vs radiation therapy alone) in tumor xenografts. All of these results indicate that TS-1 enhances radiation-induced apoptosis of endothelial cells by suppressing HIF-1 activity, resulting in an increase in radiosensitivity of the tumor cells. Our findings strengthen the importance of both HIF-1 and its downstream gene, such as vascular endothelial cell growth factor, as therapeutic targets to enhance the effect of radiotherapy. (Cancer Sci 2008; 99: 2327–2335)read more
Citations
More filters
Journal ArticleDOI
Targeting the hypoxia-inducible factor (HIF) pathway in cancer.
TL;DR: This review outlines the preclinical and clinical advances in this arena and discusses which cancers may benefit from HIF-targeted therapy.
Journal ArticleDOI
Radiation, inflammation, and immune responses in cancer.
Gabriele Multhoff,Jürgen Radons +1 more
TL;DR: Since inflammation and sex steroids also impact tumorigenesis, a therapeutic approach targeting glucocorticoid receptors and radiation-induced production of tumorigenic factors might be effective in sensitizing certain tumors to IR.
Journal ArticleDOI
The Akt/mTOR Pathway Assures the Synthesis of HIF-1α Protein in a Glucose- and Reoxygenation-dependent Manner in Irradiated Tumors
Hiroshi Harada,Satoshi Itasaka,Shinae Kizaka-Kondoh,Keiko Shibuya,Akiyo Morinibu,Kazumi Shinomiya,Masahiro Hiraoka +6 more
TL;DR: Results indicate that Akt/mTOR-dependent translation of HIF-1α plays a critical role in the postirradiation up-regulation of intratumoral Hif-1 activity in response to radiation-induced alterations of glucose and oxygen availability in a solid tumor.
Journal ArticleDOI
How Can We Overcome Tumor Hypoxia in Radiation Therapy
TL;DR: Fundamental problems surrounding tumor hypoxia in current radiation therapy, the function of HIF-1 in tumor radioresistance, the dynamics of hypoxic tumor cells during tumor growth and after radiation Therapy, and how to overcome the difficulties with radiation therapy using innovative interdisciplinary technologies are overviewed.
Journal ArticleDOI
Microenvironment and Radiation Therapy
TL;DR: How the tumor microenvironment influences the effects of radiation and how HIF-1 is a potent target to enhance the therapeutic effects of therapy by modifying the tumormicroenvironment is examined.
References
More filters
Journal ArticleDOI
Targeting HIF-1 for cancer therapy
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Journal ArticleDOI
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension
TL;DR: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells.
Journal ArticleDOI
Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation
Panu Jaakkola,David R. Mole,Ya-Min Tian,Michael I. Wilson,Janine Gielbert,Simon J. Gaskell,Alex von Kriegsheim,Holger F. Hebestreit,Mridul Mukherji,Christopher J. Schofield,Patrick H. Maxwell,Christopher W. Pugh,Peter J. Ratcliffe +12 more
TL;DR: It is shown that the interaction between human pVHL and a specific domain of the HIF-1α subunit is regulated through hydroxylation of a proline residue by an enzyme the authors have termed Hif-α prolyl-hydroxylase (HIF-PH).
Journal ArticleDOI
Hypoxia — a key regulatory factor in tumour growth
TL;DR: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death, and many elements of the hypoxia-response pathway are good candidates for therapeutic targeting.
Journal ArticleDOI
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.
Jo A. Forsythe,Bing-Hua Jiang,Narayan V. Iyer,Faton Agani,Sandra W. Leung,Robert D. Koos,Gregg L. Semenza +6 more
TL;DR: HIF-1 is implicate in the activation of VEGF transcription in hypoxic cells and this work demonstrates the involvement of Hif-1 in theactivation of V EGF transcription.