The Radiosensitizing Potential of CC-115, PIK-75 and M3814 DNA-PK Inhibitors for Breast Cancer Targeted Radiotherapy
- 1Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 37 Dionisie Lupu Street, 020021 Bucharest, Romania
- 2Horia Hulubei National Institute for Physics and Nuclear Engineering, 30 Reactorului Street, 077125 Magurele, Romania
Abstract
NHEJ is one of the preferred DNA-damage-repairing mechanisms for human cells, due to its rapid onset and activity throughout the cell cycle. It is, nevertheless, error-prone and highly relevant in numerous oncological malignancies. In recent years, it has gained a lot of attention as a target either for cancer treatment or as pharmacological- and radio-sensitization approaches. This study evaluated the genotoxicity and radiosensitization potential of three DNA-PK inhibitors (PIK-75, M3814, and CC-115) in breast cancer by comparing MDA-MB-231 and MCF-7 breast cancer cell lines, selected based on reported differences in DNA-repair characteristics and relative NHEJ dependence. Cells were preincubated with the DNA-PK inhibitors, using four different concentrations either in monotherapy or in combination with a DNA damage inducer (doxorubicin or [64Cu]CuCl2). Viability was measured by MTS assays at 24, 48, and 72 h, while the DNA damage was measured by γH2AX and flow cytometry. DNA-PK inhibitor combinations produced greater reductions in MTS viability in MDA-MB-231 than in MCF-7 under experimental conditions when combined with doxorubicin and 64Cu. Combination treatments generally reduced viability relative to inhibitor monotherapy, with clearer concentration dependence and stronger effects in MDA-MB-231. In the case of [64Cu]CuCl2 alone, MDA-MB-231 viability was reduced to 70–75% at 24 h, whereas several inhibitor combinations reduced it further; MCF-7 showed weaker or inconsistent potentiation. The reduction in metabolic viability became more pronounced at 72 h, particularly in MDA-MB-231 cells. Overall, the results highlight the potential of exploiting repair-pathway dependence to improve targeted radiotherapy in breast cancer.
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BibTeX
@article{niculae2026radiosensitizing,
title = {{The Radiosensitizing Potential of CC-115, PIK-75 and M3814 DNA-PK Inhibitors for Breast Cancer Targeted Radiotherapy}},
author = {Dragoș Andrei Niculae and Radu Marian Șerban and Doina Drăgănescu and Dana Niculae},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219782},
url = {https://www.mdpi.com/1422-0067/27/21/9782},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Radiosensitizing Potential of CC-115, PIK-75 and M3814 DNA-PK Inhibitors for Breast Cancer Targeted Radiotherapy
AU - Dragoș Andrei Niculae
AU - Radu Marian Șerban
AU - Doina Drăgănescu
AU - Dana Niculae
PY - 2026
DA - 2026/10/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219782
UR - https://www.mdpi.com/1422-0067/27/21/9782
AB - NHEJ is one of the preferred DNA-damage-repairing mechanisms for human cells, due to its rapid onset and activity throughout the cell cycle. It is, nevertheless, error-prone and highly relevant in numerous oncological malignancies. In recent years, it has gained a lot of attention as a target either for cancer treatment or as pharmacological- and radio-sensitization approaches. This study evaluated the genotoxicity and radiosensitization potential of three DNA-PK inhibitors (PIK-75, M3814, and CC-115) in breast cancer by comparing MDA-MB-231 and MCF-7 breast cancer cell lines, selected based on reported differences in DNA-repair characteristics and relative NHEJ dependence. Cells were preincubated with the DNA-PK inhibitors, using four different concentrations either in monotherapy or in combination with a DNA damage inducer (doxorubicin or [64Cu]CuCl2). Viability was measured by MTS assays at 24, 48, and 72 h, while the DNA damage was measured by γH2AX and flow cytometry. DNA-PK inhibitor combinations produced greater reductions in MTS viability in MDA-MB-231 than in MCF-7 under experimental conditions when combined with doxorubicin and 64Cu. Combination treatments generally reduced viability relative to inhibitor monotherapy, with clearer concentration dependence and stronger effects in MDA-MB-231. In the case of [64Cu]CuCl2 alone, MDA-MB-231 viability was reduced to 70–75% at 24 h, whereas several inhibitor combinations reduced it further; MCF-7 showed weaker or inconsistent potentiation. The reduction in metabolic viability became more pronounced at 72 h, particularly in MDA-MB-231 cells. Overall, the results highlight the potential of exploiting repair-pathway dependence to improve targeted radiotherapy in breast cancer.
SN - 1422-0067
ER -