NU7441 Enhances the Radiosensitivity of Liver Cancer Cells

Abstract

Objective: Radiation therapy, one of the major treatments for liver cancer, causes DNA damage and cell death. Since the liver cancer cells have a strong capacity to repair irradiative injury, new medicines to enhance this treatment are urgently required. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-dependent protein kinase (DNA-PK) in radiosensitization of hepatocellular carcinoma HepG2 cells. Methods: Cell Counting Kit-8 (CCK-8) was first used to evaluate the proliferation of HepG2 cells under NU7441 treatment. SDS-PAGE and Western blot were then performed to study the protein expression leading to the DNA damage repair. Further, neutral single cell gel electrophoresis and immunofluorescence assay were carried out to assess DNA repair. Finally, flow cytometry was implemented to examine the changes in cell cycle. Results: NU7441 reduced the CCK-8 counts in the HepG2 culture, further enhanced ⁶⁰Coγ radiation injury to HepG2 cells, which was manifested by decreasing the DNA-PKcs (S2056) protein expression, increasing γH2AX foci number, prolonging the tail moment of the comet cells, and inducing cell cycle arrest at G2/M phase. Conclusion: NU7441 inhibited the growth of liver cancer cells, enhanced the radiosensitization of these cancer cells by interfering with the DNA repair and cell cycle checkpoint. These data implicate NU7441 as a potential radiotherapy sensitizer for the treatment of liver cancer.

Targeting DNA-dependent protein kinase sensitizes hepatocellular carcinoma cells to proton beam irradiation through apoptosis induction

“…Deregulation of DNA repair pathway genes including DNA-PKcs is frequently seen during HCC progression [34,35] and DNA-PKcs is considered a promising therapeutic target in HCC [21,22]. Pharmacological inhibition or gene silencing of DNA-PKcs enhances the radiosensitivity of liver cancer cells such as HepG2 [19], which is in accordance with our data using HepG2, SNU-449 and Hep3B cells. Proton radiosensitization by the depletion of DNA-PKcs in HCC cells may be caused by accumulating unrepairable DNA damage.…”

Haplotype Based Analysis of XRCC3 Gene Polymorphisms in Thyroid Cancer

“…Targeting DNA damage becomes an effective approach to increase the efficiency of radiation therapy [27]. X-ray repair complementing defective repair in Chinese hamster cells 3 ( XRCC3 ) belongs to a family of genes responsible for repairing DNA double strand breaks caused by normal metabolic processes or exposure to ionizing radiation [20].…”

DNA Repair Pathways in Cancer Therapy and Resistance

“…It has been reported that DNA-PK activity plays a role in chemo-radiotherapy resistance ( Wang Y. et al, 2018 ; Stefanski et al, 2019 ; Alikarami et al, 2017 ; Liu et al, 2015 ). Selective DNA-PK inhibitor have been developed, including NU7026 ( Dolman et al, 2015 ), NU7441 ( Yang et al, 2016 ), IC87361 and SU11752 ( Shinohara et al, 2005 ). They could inhibit DSBs repair pathway and enhance the sensitivity of cancer cells to ionizing radiation or/and chemo-potentiation such as doxorubicin ( Ciszewski et al, 2014 ).…”