Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase
- PDF / 1,122,526 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 92 Downloads / 169 Views
RESEARCH
Open Access
Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation Carmen Klein1,2,3,4, Ivana Dokic1,2,3,4, Andrea Mairani1,2,3,4,5, Stewart Mein1,2,3,4, Stephan Brons4, Peter Häring3,6, Thomas Haberer4, Oliver Jäkel3, Astrid Zimmermann7, Frank Zenke7, Andree Blaukat7, Jürgen Debus1,2,3,4 and Amir Abdollahi1,2,3,4,8*
Abstract Background: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. Methods: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). Results: The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. Conclusions: Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy. Keywords: Hypoxia, Lung cancer, Radioresistance, DNA-Pk, ATM, Serine/threonine kinase inhibitors, Carbon ions
* Correspondence: [email protected]; [email protected] 1 Division of Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany 2 German Cancer Consortium (DKTK), Heidelberg, Germany Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative C
Data Loading...
