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

doi:10.3390/ijms22189766

Open AccessArticle

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

by

Chin-Chuan Chen

^1,2,†,

Chi-Yuan Chen

^1,3,†,

Shu-Fang Cheng

²

,

Tzong-Ming Shieh

⁴

,

Yann-Lii Leu

^1,2

,

Wen-Yu Chuang

^5,6

,

Kuang-Ting Liu

^7,8,

Shir-Hwa Ueng

^5,6,

Yin-Hwa Shih

⁹,

Li-Fang Chou

^10,* and

Tong-Hong Wang

^1,3,11,*

¹

Tissue Bank, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

²

Graduate Institute of Natural Products, Chang Gung University, Taoyuan 33303, Taiwan

³

Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan

⁴

School of Dentistry, College of Dentistry, China Medical University, Taichung 40402, Taiwan

⁵

Department of Anatomic Pathology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

⁶

College of Medicine, Chang Gung University, Taoyuan 33303, Taiwan

⁷

Department of Biomedical Sciences, National Chung Hsing University, Taichung 40227, Taiwan

⁸

Department of Pathology & Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 32551, Taiwan

⁹

Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan

¹⁰

Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

¹¹

Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan

Show full affiliation list

Hide full affiliation list

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to the work.

Int. J. Mol. Sci. 2021, 22(18), 9766; https://doi.org/10.3390/ijms22189766

Submission received: 3 August 2021 / Revised: 1 September 2021 / Accepted: 7 September 2021 / Published: 9 September 2021

(This article belongs to the Special Issue Nutritional Biochemistry)

Download

Browse Figures

Versions Notes

Abstract

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.

Keywords: hydroxygenkwanin; liver cancer; DNA damage response; RAD51; homologous recombination

Share and Cite

MDPI and ACS Style

Chen, C.-C.; Chen, C.-Y.; Cheng, S.-F.; Shieh, T.-M.; Leu, Y.-L.; Chuang, W.-Y.; Liu, K.-T.; Ueng, S.-H.; Shih, Y.-H.; Chou, L.-F.; et al. Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models. Int. J. Mol. Sci. 2021, 22, 9766. https://doi.org/10.3390/ijms22189766

AMA Style

Chen C-C, Chen C-Y, Cheng S-F, Shieh T-M, Leu Y-L, Chuang W-Y, Liu K-T, Ueng S-H, Shih Y-H, Chou L-F, et al. Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models. International Journal of Molecular Sciences. 2021; 22(18):9766. https://doi.org/10.3390/ijms22189766

Chicago/Turabian Style

Chen, Chin-Chuan, 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, and et al. 2021. "Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models" International Journal of Molecular Sciences 22, no. 18: 9766. https://doi.org/10.3390/ijms22189766

APA Style

Chen, C.-C., Chen, C.-Y., Cheng, S.-F., Shieh, T.-M., Leu, Y.-L., Chuang, W.-Y., Liu, K.-T., Ueng, S.-H., Shih, Y.-H., Chou, L.-F., & Wang, T.-H. (2021). Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models. International Journal of Molecular Sciences, 22(18), 9766. https://doi.org/10.3390/ijms22189766

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Hydroxygenkwanin Increases the Sensitivity of Liver Cancer Cells to Chemotherapy by Inhibiting DNA Damage Response in Mouse Xenograft Models

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI