Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro
Radiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-<i>O</i>-sulfamoyl-...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3592 |
| _version_ | 1797620566996287488 |
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| author | Elsie Magdalena Nolte Anna Margaretha Joubert Laurence Lafanechère Anne Elisabeth Mercier |
| author_facet | Elsie Magdalena Nolte Anna Margaretha Joubert Laurence Lafanechère Anne Elisabeth Mercier |
| author_sort | Elsie Magdalena Nolte |
| collection | DOAJ |
| description | Radiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-<i>O</i>-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) disrupts microtubule dynamics and induces apoptosis. Here, we investigated whether pre-exposure of breast cancer cells to low-dose ESE-16 would affect radiation-induced deoxyribonucleic acid (DNA) damage and the consequent repair pathways. MCF-7, MDA-MB-231, and BT-20 cells were exposed to sub-lethal doses of ESE-16 for 24 h before 8 Gy radiation. Flow cytometric quantification of Annexin V, clonogenic studies, micronuclei quantification, assessment of histone H2AX phosphorylation and Ku70 expression were performed to assess cell viability, DNA damage, and repair pathways, in both directly irradiated cells and cells treated with conditioned medium. A small increase in apoptosis was observed as an early consequence, with significant repercussions on long-term cell survival. Overall, a greater degree of DNA damage was detected. Moreover, initiation of the DNA-damage repair response was delayed, with a subsequent sustained elevation. Radiation-induced bystander effects induced similar pathways and were initiated via intercellular signaling. These results justify further investigation of ESE-16 as a radiation-sensitizing agent since pre-exposure appears to augment the response of tumor cells to radiation. |
| first_indexed | 2024-03-11T08:43:24Z |
| format | Article |
| id | doaj.art-db1402002e694f6c83451e94eca6adf1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:43:24Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-db1402002e694f6c83451e94eca6adf12023-11-16T21:02:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244359210.3390/ijms24043592Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In VitroElsie Magdalena Nolte0Anna Margaretha Joubert1Laurence Lafanechère2Anne Elisabeth Mercier3Department of Physiology, University of Pretoria, Pretoria 0007, South AfricaDepartment of Physiology, University of Pretoria, Pretoria 0007, South AfricaDepartment of Physiology, University of Pretoria, Pretoria 0007, South AfricaDepartment of Physiology, University of Pretoria, Pretoria 0007, South AfricaRadiation resistance and radiation-related side effects warrant research into alternative strategies in the application of this modality to cancer treatment. Designed in silico to improve the pharmacokinetics and anti-cancer properties of 2-methoxyestradiol, 2-ethyl-3-<i>O</i>-sulfamoyl-estra-1,3,5(10)16-tetraene (ESE-16) disrupts microtubule dynamics and induces apoptosis. Here, we investigated whether pre-exposure of breast cancer cells to low-dose ESE-16 would affect radiation-induced deoxyribonucleic acid (DNA) damage and the consequent repair pathways. MCF-7, MDA-MB-231, and BT-20 cells were exposed to sub-lethal doses of ESE-16 for 24 h before 8 Gy radiation. Flow cytometric quantification of Annexin V, clonogenic studies, micronuclei quantification, assessment of histone H2AX phosphorylation and Ku70 expression were performed to assess cell viability, DNA damage, and repair pathways, in both directly irradiated cells and cells treated with conditioned medium. A small increase in apoptosis was observed as an early consequence, with significant repercussions on long-term cell survival. Overall, a greater degree of DNA damage was detected. Moreover, initiation of the DNA-damage repair response was delayed, with a subsequent sustained elevation. Radiation-induced bystander effects induced similar pathways and were initiated via intercellular signaling. These results justify further investigation of ESE-16 as a radiation-sensitizing agent since pre-exposure appears to augment the response of tumor cells to radiation.https://www.mdpi.com/1422-0067/24/4/3592cancerradiation2-methoxyestradiol analogueESE-16apoptosisradiosensitization |
| spellingShingle | Elsie Magdalena Nolte Anna Margaretha Joubert Laurence Lafanechère Anne Elisabeth Mercier Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro International Journal of Molecular Sciences cancer radiation 2-methoxyestradiol analogue ESE-16 apoptosis radiosensitization |
| title | Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro |
| title_full | Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro |
| title_fullStr | Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro |
| title_full_unstemmed | Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro |
| title_short | Radiosensitization of Breast Cancer Cells with a 2-Methoxyestradiol Analogue Affects DNA Damage and Repair Signaling In Vitro |
| title_sort | radiosensitization of breast cancer cells with a 2 methoxyestradiol analogue affects dna damage and repair signaling in vitro |
| topic | cancer radiation 2-methoxyestradiol analogue ESE-16 apoptosis radiosensitization |
| url | https://www.mdpi.com/1422-0067/24/4/3592 |
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