Abstract
Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization. Here we demonstrate that inhibition of the canonical NF-κB pathway by dimethylaminoparthenolide (DMAPT) radiosensitizes NSCLC by blocking DNA double-strand break (DSB) repair. NF-κB inhibition results in significant impairment of both homologous recombination (HR) and non-homologous end joining (NHEJ), as well as reductions in ionizing radiation (IR)-induced DNA repair biomarkers. NF-κB inhibition by DMAPT shows preclinical potential for further investigation as a NSCLC radiosensitizer.
Highlights
Radiation therapy (RT) is a critical modality in the treatment of locally advanced, e.g., Stage III, non-smallcell lung carcinoma (NSCLC), especially when the tumor is not surgically resectable[1,2]
While DMAPT has been characterized by its action on multiple pathways including reactive oxygen species (ROS) and c-Jun[28,29,30], the effect of parthenolide on NF-κB has been shown to be independent of p38 and c-Jun activation[31]
The ability to repair DNA double-strand break (DSB) is critical to cellular survival following ionizing radiation (IR)
Summary
Radiation therapy (RT) is a critical modality in the treatment of locally advanced, e.g., Stage III, non-smallcell lung carcinoma (NSCLC), especially when the tumor is not surgically resectable[1,2]. A limitation in locally advanced NSCLC therapy is our inability to treat the tumor to a sufficient dose of radiation to achieve consistently high rates of locoregional control. This is due to anticipated toxicities in surrounding radiosensitive structures including the heart, spinal cord, esophagus, and uninvolved lung[3,4,5,6].
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