title: Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma.
abstract: OBJECTIVE
  High constitutive expression of Nrf2 has been found in many types of cancers, and this high level of Nrf2 also favors resistance to drugs and radiation. Here we investigate how isoliquiritigenin (ISL), a natural antioxidant, inhibits the Nrf2-dependent antioxidant pathway and enhances the radiosensitivity of HepG2 cells and HepG2 xenografts.
  
  
  RESULTS
  Treatment of HepG2 cells with ISL for 6 h selectively enhanced transcription and expression of Keap1. Keap1 effectively induced ubiquitination and degradation of Nrf2, and inhibited translocation of Nrf2 to the nucleus. Consequently, expression of Nrf2 downstream genes was reduced, and the Nrf2-dependent antioxidant system was suppressed. Endogenous ROS was higher than before ISL treatment, causing redox imbalance and oxidative stress in HepG2 cells. Moreover, pretreatment with ISL for 6 h followed by X-ray irradiation significantly increased γ-H2AX foci and cell apoptosis, and reduced clonogenic potential compared with cells irradiated with X-rays alone. In addition, HepG2 xenografts, ISL, and X-ray co-treatments induced greater apoptosis and tumor growth inhibition, when compared with X-ray treatments alone. Additionally, HepG2 xenografts, in which Nrf2 was expressed at very low levels due to ectopic expression of Keap1, showed that ISL-mediated radiosensitization was Keap1 dependent.
  
  
  CONCLUSIONS
  ISL inhibited the Nrf2-antioxidant pathway by increasing the levels of Keap1 and ultimately inducing oxidative stress via disturbance of the redox status. The antioxidant ISL possessed pro-oxidative properties, and enhanced the radiosensitivity of liver cancer cells, both in vivo and in vitro. Taken together, these results demonstrated the effectiveness of using ISL to decrease radioresistance, suggesting that ISL could be developed as an adjuvant radiosensitization drug. Disturbance of redox status could be a potential target for radiosensitization.
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: College of Life Sciences, Yantai University Yantai 264005, PR China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Xiong-Xiong
authors.initials: XX
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Lanzhou University Lanzhou 730000, PR China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Yang
authors.affiliation: School of Life Sciences, Lanzhou University Lanzhou 730000, PR China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Mao
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Cui-Xia
authors.initials: CX
authors.lastname: Di
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Chinese Academy of Sciences Lanzhou 730000, PR China ; Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province Lanzhou 730000, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
keywords: Keap1/Nrf-2; ROS; Redox state; isoliquiritigenin; radiosensitization