Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models
Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quali...
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MDPI AG
2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/18/9766 |
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| author | Chin-Chuan Chen Chi-Yuan Chen Shu-Fang Cheng Tzong-Ming Shieh Yann-Lii Leu Wen-Yu Chuang Kuang-Ting Liu Shir-Hwa Ueng Yin-Hwa Shih Li-Fang Chou Tong-Hong Wang |
| author_facet | Chin-Chuan Chen Chi-Yuan Chen Shu-Fang Cheng Tzong-Ming Shieh Yann-Lii Leu Wen-Yu Chuang Kuang-Ting Liu Shir-Hwa Ueng Yin-Hwa Shih Li-Fang Chou Tong-Hong Wang |
| author_sort | Chin-Chuan Chen |
| collection | DOAJ |
| description | Molecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant. |
| first_indexed | 2024-03-10T07:35:40Z |
| format | Article |
| id | doaj.art-55bd12ecc3944fd18183cb84cce50799 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:35:40Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-55bd12ecc3944fd18183cb84cce507992023-11-22T13:27:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-012218976610.3390/ijms22189766Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft ModelsChin-Chuan Chen0Chi-Yuan Chen1Shu-Fang Cheng2Tzong-Ming Shieh3Yann-Lii Leu4Wen-Yu Chuang5Kuang-Ting Liu6Shir-Hwa Ueng7Yin-Hwa Shih8Li-Fang Chou9Tong-Hong Wang10Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanTissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanGraduate Institute of Natural Products, Chang Gung University, Taoyuan 33303, TaiwanSchool of Dentistry, College of Dentistry, China Medical University, Taichung 40402, TaiwanTissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanDepartment of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanDepartment of Biomedical Sciences, National Chung Hsing University, Taichung 40227, TaiwanDepartment of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanDepartment of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, TaiwanKidney Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanTissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, TaiwanMolecules involved in DNA damage response (DDR) are often overexpressed in cancer cells, resulting in poor responses to chemotherapy and radiotherapy. Although treatment efficacy can be improved with the concomitant use of DNA repair inhibitors, the accompanying side effects can compromise the quality of life of patients. Therefore, in this study, we identified a natural compound that could inhibit DDR, using the single-strand annealing yeast-cell analysis system, and explored its mechanisms of action and potential as a chemotherapy adjuvant in hepatocellular carcinoma (HCC) cell lines using comet assay, flow cytometry, Western blotting, immunofluorescence staining, and functional analyses. We developed a mouse model to verify the in vitro findings. We found that hydroxygenkwanin (HGK) inhibited the expression of RAD51 and progression of homologous recombination, thereby suppressing the ability of the HCC cell lines to repair DNA damage and enhancing their sensitivity to doxorubicin. HGK inhibited the phosphorylation of DNA damage checkpoint proteins, leading to apoptosis in the HCC cell lines. In the mouse xenograft model, HGK enhanced the sensitivity of liver cancer cells to doxorubicin without any physiological toxicity. Thus, HGK can inhibit DDR in liver cancer cells and mouse models, making it suitable for use as a chemotherapy adjuvant.https://www.mdpi.com/1422-0067/22/18/9766hydroxygenkwaninliver cancerDNA damage responseRAD51homologous recombination |
| spellingShingle | Chin-Chuan Chen Chi-Yuan Chen Shu-Fang Cheng Tzong-Ming Shieh Yann-Lii Leu Wen-Yu Chuang Kuang-Ting Liu Shir-Hwa Ueng Yin-Hwa Shih Li-Fang Chou Tong-Hong Wang Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models International Journal of Molecular Sciences hydroxygenkwanin liver cancer DNA damage response RAD51 homologous recombination |
| title | Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models |
| title_full | Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models |
| title_fullStr | Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models |
| title_full_unstemmed | Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models |
| title_short | Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models |
| title_sort | hydroxygenkwanin increases the sensitivity of liver cancer cells to chemotherapy by inhibiting dna damage response in mouse xenograft models |
| topic | hydroxygenkwanin liver cancer DNA damage response RAD51 homologous recombination |
| url | https://www.mdpi.com/1422-0067/22/18/9766 |
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