Ultra-small gadolinium oxide nanocrystal sensitization of non-small-cell lung cancer cells toward X-ray irradiation by promoting cytostatic autophagy

Abstract

Feifei Li,1,2,* Zihou Li,2,3,* Xiaodong Jin,1 Yan Liu,1 Pengcheng Zhang,1,2 Ping Li,1 Zheyu Shen,3 Aiguo Wu,3 Weiqiang Chen,1 Qiang Li1 1Institute of Modern Physics, Chinese Academy of Sciences, Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; 2University of Chinese Academy of Sciences, Beijing 100049, China; 3Key Laboratory of Magnetic Materials and Devices, Chinese Academy of Sciences, Division of Functional Materials and Nano Devices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, Zhejiang 315201, China *These authors contributed equally to this work Background: Gadolinium-based nanoparticles (GdNPs) have been used as theranostic sensitizers in clinical radiotherapy studies; however, the biomechanisms underlying the radiosensitizing effects of GdNPs have yet to be determined. In this study, ultra-small gadolinium oxide nanocrystals (GONs) were employed to investigate their radiosensitizing effects and biological mechanisms in non-small-cell lung cancer (NSCLC) cells under X-ray irradiation.Method and materials: GONs were synthesized using polyol method. Hydroxyl radical production, oxidative stress, and clonogenic survival after X-ray irradiation were used to evaluate the radiosensitizing effects of GONs. DNA double-strand breakage, cell cycle phase, and apoptosis and autophagy incidences were investigated in vitro to determine the radiosensitizing biomechanism of GONs under X-ray irradiation.Results: GONs induced hydroxyl radical production and oxidative stress in a dose- and concentration-dependent manner in NSCLC cells after X-ray irradiation. The sensitizer enhancement ratios of GONs ranged between 19.3% and 26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of the cells treated with irradiation alone. Addition of 3-methyladenine to the cell medium decreased the incidence rate of autophagy and increased cell survival, supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray irradiation.Conclusion: This study examined the biological mechanisms underlying the radiosensitizing effects of GONs on NSCLC cells and presented the first evidence for the radiosensitizing effects of GONs via activation of cytostatic autophagy pathway following X-ray irradiation. Keywords: gadolinium oxide nanocrystal, radiosensitization, cytostatic autophagy, apoptosis, oxidative stress

Keywords

• gadolinium oxide nanocrystal
• radiosensitization
• cytostatic autophagy
• apoptosis
• oxidative stress