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Updated: Aug 16, 2026
Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer
Published on: May 20, 2016
Murine double minute 2 as a therapeutic target for radiation sensitization of lung cancer
Carolyn Cao1, Eric T Shinohara, Kenneth J Niermann
1Department of Radiation Oncology, Vanderbilt University, 1301 22nd Avenue South, B-902 The Vanderbilt Clinic, Nashville, TN 37232-5671, USA.
Abstract:
Murine double minute 2 (MDM2) inhibits p53-mediated functions, which are essential for therapies using DNA-damaging agents. The purpose of this study was to determine whether MDM2 inhibition enhances the radiosensitivity of a lung cancer model. The effects of MDM2 inhibition on tumor vasculature were also studied. Transient transfection of H460 lung cancer cells and human umbilical vascular endothelial cells (HUVEC) with antisense oligonucleotides (ASODN) against MDM2 resulted in a reduced level of MDM2 and increased levels of p21 and p53. Clonogenic assays showed that inhibition of MDM2 greatly decreased cell survival following irradiation. Quantification of apoptotic cells by 7-aminoactinomycin D staining and of senescent cells by X-gal staining showed that both processes were significantly increased in H460 cells treated with MDM2-specific ASODN and radiation. H460 xenografts that were treated with MDM2 ASODN plus radiotherapy also showed significant growth delay (P < 0.001) and increased apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling staining. HUVECs transfected with MDM2-specific ASODN showed impaired viability and migration with decreased tube formation. Doppler studies showed that tumor blood flow was compromised when H460 xenografts were treated with MDM2-specific ASODN and radiation. A combination of radiotherapy and inhibition of MDM2 through the antisense approach results in improved tumor control in the H460 lung cancer model. This implies that a similar strategy should be investigated among patients with locally advanced lung cancer, receiving thoracic radiotherapy.
Insights
Inhibiting murine double minute 2 (MDM2) with antisense oligonucleotides (ASODN) significantly enhances lung cancer radiosensitivity. This combination therapy also impairs tumor vasculature, suggesting potential for advanced lung cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Murine double minute 2 (MDM2) protein negatively regulates p53, a critical tumor suppressor.
- p53-mediated functions are vital for DNA-damaging cancer therapies, including radiotherapy.
- MDM2 inhibition represents a potential strategy to enhance cancer treatment efficacy.
Purpose of the Study:
- To investigate if MDM2 inhibition improves radiosensitivity in a lung cancer model.
- To evaluate the impact of MDM2 inhibition on tumor vasculature.
- To assess the combined effects of MDM2 inhibition and radiotherapy on tumor growth and apoptosis.
Main Methods:
- Transient transfection of H460 lung cancer cells and HUVECs with MDM2-specific antisense oligonucleotides (ASODN).
- Clonogenic assays to assess cell survival post-irradiation.
- Quantification of apoptosis and senescence.
- In vivo studies using H460 xenografts and Doppler studies for tumor blood flow.
- Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.
Main Results:
- MDM2 inhibition reduced MDM2 levels and increased p53 and p21.
- Combined MDM2 ASODN and radiation significantly decreased H460 cell survival and increased apoptosis and senescence.
- H460 xenografts treated with MDM2 ASODN plus radiotherapy showed significant growth delay and increased apoptosis.
- MDM2 inhibition impaired HUVEC viability, migration, and tube formation, compromising tumor blood flow.
- Tumor blood flow was reduced in xenografts treated with MDM2 ASODN and radiation.
Conclusions:
- Combination of radiotherapy and MDM2 inhibition via ASODN improves tumor control in a lung cancer model.
- This strategy warrants investigation in patients with locally advanced lung cancer undergoing thoracic radiotherapy.
- Targeting MDM2 offers a promising approach to enhance radiotherapy outcomes in lung cancer.
