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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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Autores principales: Chen, Chin-Chuan, Chen, Chi-Yuan, Cheng, Shu-Fang, Shieh, Tzong-Ming, Leu, Yann-Lii, Chuang, Wen-Yu, Liu, Kuang-Ting, Ueng, Shir-Hwa, Shih, Yin-Hwa, Chou, Li-Fang, Wang, Tong-Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471855/
https://www.ncbi.nlm.nih.gov/pubmed/34575923
http://dx.doi.org/10.3390/ijms22189766
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author Chen, Chin-Chuan
Chen, Chi-Yuan
Cheng, Shu-Fang
Shieh, Tzong-Ming
Leu, Yann-Lii
Chuang, Wen-Yu
Liu, Kuang-Ting
Ueng, Shir-Hwa
Shih, Yin-Hwa
Chou, Li-Fang
Wang, Tong-Hong
author_facet Chen, Chin-Chuan
Chen, Chi-Yuan
Cheng, Shu-Fang
Shieh, Tzong-Ming
Leu, Yann-Lii
Chuang, Wen-Yu
Liu, Kuang-Ting
Ueng, Shir-Hwa
Shih, Yin-Hwa
Chou, Li-Fang
Wang, Tong-Hong
author_sort Chen, Chin-Chuan
collection PubMed
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.
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spelling pubmed-84718552021-09-28 Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models Chen, Chin-Chuan Chen, Chi-Yuan Cheng, Shu-Fang Shieh, Tzong-Ming Leu, Yann-Lii Chuang, Wen-Yu Liu, Kuang-Ting Ueng, Shir-Hwa Shih, Yin-Hwa Chou, Li-Fang Wang, Tong-Hong Int J Mol Sci Article 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. MDPI 2021-09-09 /pmc/articles/PMC8471855/ /pubmed/34575923 http://dx.doi.org/10.3390/ijms22189766 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Chin-Chuan
Chen, Chi-Yuan
Cheng, Shu-Fang
Shieh, Tzong-Ming
Leu, Yann-Lii
Chuang, Wen-Yu
Liu, Kuang-Ting
Ueng, Shir-Hwa
Shih, Yin-Hwa
Chou, Li-Fang
Wang, Tong-Hong
Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471855/
https://www.ncbi.nlm.nih.gov/pubmed/34575923
http://dx.doi.org/10.3390/ijms22189766
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