Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1784574575193882624 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8471855 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT chenchinchuan hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT chenchiyuan hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT chengshufang hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT shiehtzongming hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT leuyannlii hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT chuangwenyu hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT liukuangting hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT uengshirhwa hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT shihyinhwa hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT choulifang hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels AT wangtonghong hydroxygenkwaninincreasesthesensitivityoflivercancercellstochemotherapybyinhibitingdnadamageresponseinmousexenograftmodels |