NSCLC cells demonstrate differential mode of cell death in response to the combined treatment of radiation and a DNA-PKcs inhibitor.

Abstract

The current standard of care for lung cancer consists of concurrent chemotherapy and radiation. Several studies have shown that the DNA-PKcs inhibitor NU7441 is a highly potent radiosensitizer, however, the mechanism of NU7441's anti-proliferation effect has not been fully elucidated. In this study, the combined effect of NU7441 and ionizing radiation (IR) in a panel of non-small cell lung cancer cell lines (A549, H460 and H1299) has been investigated. We found that NU7441 significantly enhances the effect of IR in all cell lines. The notable findings in response to this combined treatment are (i) prolonged delay in IR-induced DNA DSB repair, (ii) induced robust G2/M checkpoint, (iii) increased aberrant mitosis followed by mitotic catastrophe specifically in H1299, (iv) dramatically induced autophagy in A549 and (v) IR-induced senescence specifically in H460. H1299 cells show greater G2 checkpoint adaptation after combined treatment, which can be attributed to higher expression level of Plk1 compared to A549 and H460. The enhanced autophagy after NU7441 treatment in A549 is possibly due to the higher endogenous expression of pS6K compared to H1299 and H460 cells. In conclusion, choice of cell death pathway is dependent on the mutation status and other genetic factors of the cells treated.

• Authors: Lan Yu, Zeng-Fu Shang, Feng-Ming Hsu, Zhang Zhang, Vasu Tumati, Yu-Fen Lin, Benjamin P C Chen, Debabrata Saha
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 6 Pg. 3848-60 (Feb 28 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25714019 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
• Chromones
• Morpholines
• Protein Kinase Inhibitors
• Radiation-Sensitizing Agents
• DNA-Activated Protein Kinase

Topics

• Animals
• Autophagy (drug effects, radiation effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology, radiotherapy)
• Cell Line, Tumor
• Chemoradiotherapy
• Chromones (pharmacology)
• DNA Breaks, Double-Stranded (drug effects, radiation effects)
• DNA Repair (drug effects, radiation effects)
• DNA-Activated Protein Kinase (antagonists & inhibitors)
• Female
• Humans
• Lung Neoplasms (drug therapy, enzymology, pathology, radiotherapy)
• Mice
• Mice, Nude
• Morpholines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• Signal Transduction
• Xenograft Model Antitumor Assays