Abstract
PURPOSE: To investigate the mechanisms inducing and maintaining the permanent elimination of low dose hyper-radiosensitivity (HRS) in cells given a dose of 0.3 Gy at low dose-rate (LDR) (0.3 Gy/h).
MATERIALS AND METHODS: Two human HRS-positive cell lines (T-47D, T98G) were used. The effects of pretreatments with transforming growth factor beta (TGF-β) neutralizers, TGF-β3 or peroxynitrite scavenger on HRS were investigated using the colony assay. Cytoplasmic levels of TGF-β3 were measured using post-embedding immunogold electron microscopic analysis.
RESULTS: TGF-β3 neutralizer inhibited the removal of HRS by LDR irradiation. Adding 0.001 ng/ml TGF-β3 to cells removed HRS in T98G cells while 0.01 ng/ml additionally induced resistance to higher doses. Cytoplasmic levels of TGF-β3 were higher in LDR-primed cells than in unirradiated cells. The presence of the peroxynitrite scavenger uric acid inhibited the effect of LDR irradiation. Furthermore, the permanent elimination of HRS in LDR-primed cells was reversed by treatment with uric acid. The removal of HRS by medium from hypoxic cells was inhibited by adding TGF-β3 neutralizer to the medium before transfer or by adding hypoxia inducible factor 1 (HIF-1) inhibitor chetomin to the cell medium during hypoxia.
CONCLUSIONS: TGF-β3 is involved in the regulation of cellular responses to small doses of acute irradiation. TGF-β3 activation seems to be induced by low dose-rate irradiation by a mechanism involving inducible nitric oxide (iNOS) and peroxynitrite, or during cycling hypoxia by a mechanism most likely involving HIF-1. The study suggests methods to turn resistance to doses in the HRS-range on (by TGF-β3) or off (by TGF-β3 neutralizer or by peroxynitrite inhibition).
| Original language | English |
|---|---|
| Journal | International Journal of Radiation Biology |
| Volume | 90 |
| Issue number | 7 |
| Pages (from-to) | 527-37 |
| Number of pages | 11 |
| ISSN | 0955-3002 |
| DOIs | |
| Publication status | Published - 2014 |
| Externally published | Yes |
Keywords
- Cell Hypoxia/drug effects
- Cell Line
- Cell Survival/drug effects
- Cytoplasm/drug effects
- Humans
- Nitric Oxide Synthase Type II/metabolism
- Peroxynitrous Acid/pharmacology
- Radiation Dosage
- Radiation Tolerance/drug effects
- Time Factors
- Transforming Growth Factor beta3/pharmacology