Effects of dna-Dependent Protein Kinase Inhibition by NU7026 on dna Repair and Cell Survival in Irradiated Gastric Cancer Cell Line N87

Niazi, Mohammad; Mok, Greta S. P.; Heravi, Mitra; Lee, L.; Vuong, T.; Aloyz, Raquel; Panasci, Lawrence C.; Muanza, Thierry

doi:10.3747/co.21.1509

Cited by 13 publications

(6 citation statements)

References 18 publications

(18 reference statements)

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“…Previous studies have demonstrated that DNA-PK inhibitors can enhance the radiosensitivity of cancer cells (liver cancer HepG2, gastric cancer N87 and leukaemia MOLT-4) by increasing DNA damage leading to G 2 /M phase arrest and induction of apoptosis ( 22 – 28 ). Similarly, the present results demonstrated that a DNA-PK inhibitor exerted radiosensitization effects on xenograft tumors in vivo and on A549 cells in vitro .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response

Yang

Tang

et al. 2018

Mol Med Report

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Non-small cell lung cancer (NSCLC) is radioresistant to X-rays due to powerful cellular DNA damage repair mechanisms. DNA-dependent protein kinase (DNA-PK) is a key enzyme involved in DNA damage repair and the phenomenon and molecular mechanism of NSCLC radionsensitivity were investigated following inhibition of DNA-PK activity. In the present study A549 cells were treated with the DNA-PK inhibitor NU7026 and/or siRNA directed against ataxia telangiectasia mutated (ATM), followed by exposure to 4 Gy X-ray irradiation. Radiosensitivity, DNA damage, apoptosis and protein expression were measured by colony formation assay, γH2AX foci immunofluorescence, Annexin V/PI staining and western blotting, respectively. A Balb/c-nu/nu xenograft mouse model was established by subcutaneous injection of A549 cells and was used to examine the effect of administering NU7026 via intraperitoneal injection prior to 4 Gy X-ray exposure. The xenograft tumors were weighed and observed by hematoxylin and eosin staining after irradiation. NU7026 treatment followed by X-ray irradiation significantly decreased the colony formation ratio of A549 cells, and increased γH2AX foci and cell apoptosis. Furthermore, the combined treatment of NU7026 and X-rays resulted in growth inhibition and cell apoptosis in A549 xenograft tumors. Consequently, apoptosis regulators full-length transactivating (TA) p73 and an N-terminally truncated (DN) p73 were upregulated and downregulated respectively, leading to activation of glucosyltransferases and Rab-like GTPase activators and myotubularins domain-containing 4 (GRAMD4) protein to reduce the Bcl-2/Bax protein ratio. In addition, ATM siRNA efficiently prevented γH2AX foci formation, and enhanced NU7026-induced inhibition of survival and promoted apoptosis. In conclusion, inhibition of DNA-PK activity increased the radiosensitivity of A549 cells to X-ray irradiation. NU7026 treatment activated the ATM-dependent DNA damage response and induced p73 apoptosis pathway. DNA-PK inhibitor may be an effective constituent of radiosensitization products. DNA damage repair pathway could be a potential target for radiosensitization.

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Section: Discussionmentioning

confidence: 99%

Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response

Yang

Tang

et al. 2018

Mol Med Report

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“…In this study, we found that NU7441 did not change the protein expression level of DNA-PKcs, Ku70, and Ku80, but specifically decreased the DNA-PKcs (S2056) protein level. Combined with radiation treatment, NU7441 induced cell-cycle arrest, apoptosis, and enhanced the sensitivity of the cancer cells [25].…”

Section: Discussionmentioning

confidence: 99%

NU7441 Enhances the Radiosensitivity of Liver Cancer Cells

Yang

Wang

Liu

et al. 2016

Cell Physiol Biochem

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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.

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“…Lately, NU7026 has been shown to enhance the cytotoxic effect of irradiation gastric cancer cells. This heightened cytotoxicity was explained by an increase in DSB formation, resulting in G2/M cell arrest and possibly higher levels of apoptosis [ 254 ].…”

Section: The Non-homologous End-joining (Nhej) Proteinsmentioning

confidence: 99%

DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer

et al. 2015

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For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.

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Effects of dna-Dependent Protein Kinase Inhibition by NU7026 on dna Repair and Cell Survival in Irradiated Gastric Cancer Cell Line N87

Cited by 13 publications

References 18 publications

Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response

Inhibition of DNA‑PK activity sensitizes A549 cells to X‑ray irradiation by inducing the ATM‑dependent DNA damage response

NU7441 Enhances the Radiosensitivity of Liver Cancer Cells

DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer

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