Mithramycin A Enhances Tumor Sensitivity to Mitotic Catastrophe Resulting From DNA Damage
| Autor: | Su I. Chung, Darmood Wei, Luca F. Valle, Grace McKay-Corkum, Ayla O. White, Eun Joo Chung, Kathryn E. Hudak, W. Marston Linehan, Jeffrey Burkeen, Shilpa S. Patil, Bradley T. Scroggins, Deborah Citrin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Radiation-Sensitizing Agents Cancer Research Small interfering RNA DNA Repair Sp1 Transcription Factor DNA damage Mitosis Apoptosis Article Toxicology Mice 03 medical and health sciences 0302 clinical medicine Transcription (biology) Cell Line Tumor Gene expression Animals Humans Medicine Radiology Nuclear Medicine and imaging Radiosensitivity Fibroblast Mitotic catastrophe Gene knockdown Radiation business.industry Cell Cycle Neoplasms Experimental Plicamycin 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research business DNA Damage |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 100:344-352 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2017.09.049 |
| Popis: | Purpose Specificity protein 1 (SP1) is involved in the transcription of several genes implicated in tumor maintenance. We investigated the effects of mithramycin A (MTA), an inhibitor of SP1 DNA binding, on radiation response. Methods and Materials Clonogenic survival after irradiation was assessed in 2 tumor cell lines (A549, UM-UC-3) and 1 human fibroblast line (BJ) after SP1 knockdown or MTA treatment. DNA damage repair was evaluated using γH2AX foci formation, and mitotic catastrophe was assessed using nuclear morphology. Gene expression was evaluated using polymerase chain reaction arrays. In vivo tumor growth delay was used to evaluate the effects of MTA on radiosensitivity. Results Targeting of SP1 with small interfering RNA or MTA sensitized A549 and UM-UC-3 to irradiation, with no effect on the BJ radiation response. MTA did not alter γH2AX foci formation after irradiation in tumor cells but did enhance mitotic catastrophe. Treatment with MTA suppressed transcription of genes involved in cell death. MTA administration to mice bearing A549 and UM-UC-3 xenografts enhanced radiation-induced tumor growth delay. Conclusions These results support SP1 as a target for radiation sensitization and confirm MTA as a radiation sensitizer in human tumor models. |
| Databáze: | OpenAIRE |
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