Mithramycin A Enhances Tumor Sensitivity to Mitotic Catastrophe Resulting From DNA Damage.

Abstract

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.

• Authors: Bradley T Scroggins, Jeffrey Burkeen, Ayla O White, Eun Joo Chung, Darmood Wei, Su I Chung, Luca F Valle, Shilpa S Patil, Grace McKay-Corkum, Kathryn E Hudak, W Marston Linehan, Deborah E Citrin
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 100 Issue 2 Pg. 344-352 (02 01 2018) ISSN: 1879-355X [Electronic] United States
• PMID: 29157749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Radiation-Sensitizing Agents
• Sp1 Transcription Factor
• mithramycin A
• Plicamycin

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA Damage
• DNA Repair (drug effects)
• Humans
• Mice
• Mitosis (drug effects)
• Neoplasms, Experimental (pathology, radiotherapy)
• Plicamycin (analogs & derivatives, pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• Sp1 Transcription Factor (antagonists & inhibitors)