Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure
Abstract
:1. Introduction
2. Results
2.1. Cellular Toxicity and Cell Cycle Distribution from SAHA Treatment
2.2. Radiosensitization of Exponentially Growing Cancer Cells Exposed to γ-Rays, Protons and Clinical Grade Carbon Ions
2.3. Minimum Radiosensitization Effect of SAHA for Exponentially Growing Normal Cells
2.4. G0/G1 Phase Cells and Potentially Lethal Damage Repair with Immediate or Delayed Subculture
2.5. DSB (Double Starand Break) Repair
2.6. Chromosomal Aberrations
2.7. Rad51 and RPA (Replication Protein A) Focus Formation
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Cell Cycle Synchronization
4.3. Irradiation
4.4. Cellular Toxicity and Cell Cycle Analysis
4.5. Cell Survival Curves and RBE Analysis
4.6. Potentially Lethal Damage Repair Analysis with Immediate or Delayed Subculture
4.7. Immunostaining and DNA Damage Response Analysis
4.8. Chromosome Aberration Analysis
4.9. Statistics
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
SAHA | Suberoylanilide hydroxamic acid |
HDACi | Histone deacetylase inhibitor |
LET | Linear energy transfer |
RBE | Relative biological effectiveness |
SER | Sensitization Enhancement Ratio |
D10 | Dose to achieve 10% cell survival |
PMRC | Proton Medical Research Center |
HIMAC | Heavy ion medical accelerator |
SOBP | Spread out Bragg peak |
ANOVA | Analysis of valiance |
References
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Irradiation Condition | A549 | AG1522 | ||||
---|---|---|---|---|---|---|
D10 (Gy) | SER | RBE | D10 (Gy) | SER | RBE | |
γ-rays Control | 6.52 ± 0.33 | NA | NA | 4.42 ± 0.13 | NA | NA |
SAHA 0.2 μM | 5.66 ± 0.44 | 1.18 ± 0.13 | NA | 4.30 ± 0.01 | 1.03 ± 0.05 | NA |
SAHA 2 μM | 4.67 ± 0.16 | 1.43 ± 0.09 | NA | 4.08 ± 0.05 | 1.08 ± 0.03 | NA |
Proton SOBP Control | 5.37 ± 0.24 | NA | 1.24 ± 0.07 | 3.55 ± 0.11 | NA | 1.25 ± 0.04 |
SAHA 0.2 μM | 4.50 ± 0.01 | 1.27 ± 0.03 | 1.26 ± 0.09 | 3.16 ± 0.13 | 1.13 ± 0.05 | 1.38 ± 0.05 |
SAHA 2 μM | 4.16 ± 0.32 | 1.31 ± 0.05 | 1.06 ± 0.09 | 3.15 ± 0.21 | 1.16 ± 0.09 | 1.33 ± 0.09 |
Carbon ion SOBP Control | 2.56 ± 0.16 | NA | 2.59 ± 0.23 | 2.12 ± 0.04 | NA | 2.18 ± 0.31 |
SAHA 0.2 μM | 2.24 ± 0.13 | 1.15 ± 0.16 | 2.43 ± 0.11 | 2.17 ± 0.25 | 1.05 ± 0.20 | 2.10 ± 0.32 |
SAHA 2 μM | 2.18 ± 0.06 | 1.18 ± 0.05+ | 2.12 ± 0.04 | 2.25 ± 0.08 | 0.95 ± 0.12 | 1.82 ± 0.06 |
AG1522, D10 (Gy) | A549, D10 (Gy) | ||||
---|---|---|---|---|---|
SAHA Treatment Started Subculture Time after Irradiation | 24 h Before | 24 h Before | After Irradiation | ||
0 h | 24 h | 0 h | 24 h | 24 h | |
γ-rays Control | 4.31 ± 0.41 | 6.35 ± 0.44 | 6.57 ± 0.37 | 8.43 ± 0.29 | NA |
SAHA 0.2 μM | 4.49 ± 0.45 | 6.96 ± 0.36 | 6.01 ± 0.42 | 6.97 ± 1.13 | 8.77 ± 0.41 |
SAHA 2 μM | 4.21 ± 0.73 | 7.02 ± 0.59 | 4.85 ± 0.95 | 6.15 ± 0.59 | 8.04 ± 0.24 |
Proton SOBP Control | 3.90 ± 0.36 | 5.35 ± 1.30 | |||
SAHA 0.2 μM | 3.78 ± 0.47 | 5.53 ± 1.90 | |||
SAHA 2 μM | 2.81 ± 0.39 | 4.14 ± 0.89 | |||
Carbon ion SOBP Control | 2.11 ± 0.75 | 3.09 ± 0.13 | |||
SAHA 0.2 μM | 2.03 ± 0.25 | 2.93 ± 0.52 | |||
SAHA 2 μM | 1.98 ± 0.06 | 2.57 ± 0.51 |
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Gerelchuluun, A.; Maeda, J.; Manabe, E.; Brents, C.A.; Sakae, T.; Fujimori, A.; Chen, D.J.; Tsuboi, K.; Kato, T.A. Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure. Int. J. Mol. Sci. 2018, 19, 496. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020496
Gerelchuluun A, Maeda J, Manabe E, Brents CA, Sakae T, Fujimori A, Chen DJ, Tsuboi K, Kato TA. Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure. International Journal of Molecular Sciences. 2018; 19(2):496. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020496
Chicago/Turabian StyleGerelchuluun, Ariungerel, Junko Maeda, Eri Manabe, Colleen A. Brents, Takeji Sakae, Akira Fujimori, David J. Chen, Koji Tsuboi, and Takamitsu A. Kato. 2018. "Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure" International Journal of Molecular Sciences 19, no. 2: 496. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020496