Hydroxygenkwanin increases the sensitivity of liver cancer cells to chemotherapy by inhibiting dna damage response in mouse xenograft models

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*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

5 Scopus citations

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.

Original languageEnglish
Article number9766
JournalInternational Journal of Molecular Sciences
Volume22
Issue number18
DOIs
StatePublished - 09 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • DNA damage response
  • Homologous recombination
  • Hydroxygenkwanin
  • Liver cancer
  • RAD51

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