NF-κB inhibition by dimethylaminoparthenolide radiosensitizes non-small-cell lung carcinoma by blocking DNA double-strand break repair.
Peter V DeraskaColin O'LearyHunter D ReavisShelby LabeTru-Khang DinhJean-Bernard LazaroChristopher SweeneyAlan D' AndreaDavid E KozonoPublished in: Cell death discovery (2018)
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.
Keyphrases
- dna repair
- signaling pathway
- small cell lung cancer
- locally advanced
- dna damage
- lps induced
- pi k akt
- oxidative stress
- nuclear factor
- advanced non small cell lung cancer
- squamous cell carcinoma
- cell therapy
- single cell
- early stage
- rectal cancer
- dna damage response
- minimally invasive
- radiation therapy
- neoadjuvant chemotherapy
- single molecule
- inflammatory response
- cell proliferation
- toll like receptor
- brain metastases
- coronary artery bypass
- radiation induced
- high glucose
- human health
- open label
- phase ii study