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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents

ID: 711854.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency
Authors:Subtil, F. S.; Wilhelm, J.; Bill, V.; Westholt, N.; Rudolph, S.; Fischer, J.; Scheel, S.; Seay, U.; Fournier, C.; Taucher-Scholz, G.; Scholz, M.; Seeger, W.; Engenhart-Cabillic, R.; Rose, F.; Dahm-Daphi, J.; Hanze, J.
Date of Publication (YYYY-MM-DD):2014-03
Title of Journal:FASEB J
Issue / Number:3
Start Page:1412
End Page:1421
Audience:Not Specified
Abstract / Description:Carbon ion irradiation is an emerging therapeutic option for various tumor entities. Radiation resistance of solid tumors toward photon irradiation is caused by attenuation of DNA damage in less oxygenated tumor areas and by increased hypoxia-inducible factor (HIF)-1 signaling. Carbon ion irradiation acts independently of oxygen; however, the role of HIF-1 is unclear. We analyzed the effect of HIF-1 signaling after carbon ions in comparison to photons by using biological equivalent radiation doses in a human non-small-cell cancer model. The studies were performed in cultured A549 and H1299 cell lines and in A549 xenografts. Knockdown of HIF-1alpha in vivo combined with photon irradiation delayed tumor growth (23 vs. 13 d; P<0.05). Photon irradiation induced HIF-1alpha and target genes, predominantly in oxygenated cells (1.6-fold; P<0.05), with subsequent enhanced tumor angiogenesis (1.7-fold; P<0.05). These effects were not observed after carbon ion irradiation. Micro-DNA array analysis indicated that photons, but not carbon ions, significantly induced components of the mTOR (mammalian target of rapamycin) pathway (gene set enrichment analysis; P<0.01) as relevant for HIF-1alpha induction. After carbon ion irradiation in vivo, we observed substantially decreased HIF-1alpha levels (8.9-fold; P<0.01) and drastically delayed tumor growth (P<0.01), an important finding that indicates a higher relative biological effectiveness (RBE) than anticipated from the cell survival data. Taken together, the evidence showed that carbon ions mediate an improved therapeutic effectiveness without tumor-promoting HIF-1 signaling.
Free Keywords:Animals; Base Sequence; Carbon Radioisotopes/*therapeutic use; Carcinoma, Non-Small-Cell Lung/radiotherapy; DNA Primers; Down-Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism; Lung Neoplasms/*radiotherapy; Mice; Mice, Inbred BALB C; Polymerase Chain Reaction; Rbe; RNA silencing; Vegf; angiogenesis; relative biological effectiveness; vascular endothelia growth factor
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:%^ 1435822045
Identifiers:ISSN:1530-6860 (Electronic) 0892-6638 (Linking) %R 10.1096/fj.13-242230
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