Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation.

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.

• Authors: Carmen Klein, Ivana Dokic, Andrea Mairani, Stewart Mein, Stephan Brons, Peter Häring, Thomas Haberer, Oliver Jäkel, Astrid Zimmermann, Frank Zenke, Andree Blaukat, Jürgen Debus, Amir Abdollahi
• Journal: Radiation oncology (London, England) (Radiat Oncol) Vol. 12 Issue 1 Pg. 208 (Dec 29 2017) ISSN: 1748-717X [Electronic] England
• PMID: 29287602 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Nuclear Proteins
• Radiation-Sensitizing Agents
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• DNA-Activated Protein Kinase
• PRKDC protein, human

Topics

• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
• Carcinoma, Non-Small-Cell Lung (pathology, therapy)
• Cell Hypoxia
• Cell Survival (drug effects, radiation effects)
• Chemoradiotherapy
• DNA-Activated Protein Kinase (antagonists & inhibitors)
• Dose-Response Relationship, Radiation
• Enzyme Inhibitors (pharmacology)
• Heavy Ion Radiotherapy
• Humans
• Lung Neoplasms (pathology, therapy)
• Nuclear Proteins (antagonists & inhibitors)
• Photons (therapeutic use)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents
• Tumor Cells, Cultured