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

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.

Microsatellite instability states serve as predictive biomarkers for tumors chemotherapy sensitivity

“… 47 Hydroxygenkwanin ( HGK ) increases the sensitivity of hepatocellular carcinoma to doxorubicin by downregulating RAD51 . 55 Interferon-regulatory factor-1 can bind to the promoter of RAD51 to inhibit its expression in gastric cancer cells to reverse chemoresistance. 56 (3) In terms of chemotherapy combination with immunotherapy, it has been shown that TNBC with HRD has higher levels of lymphocytic infiltration and that immune checkpoint blockade therapy is an option for this subtype despite the presence of chemoresistance (a more specific analysis of immune infiltration is presented later).…”

Hydroxygenkwanin Improves the Efficacy of Cytotoxic Drugs in ABCG2-Overexpressing Multidrug-Resistant Cancer Cells

“…Moreover, hydroxygenkwanin was shown to suppress the cell growth and invasion of hepatocellular carcinoma cells (HCC) by inducing the expression of the microRNA, miR-320a [ 42 ]. Recently, hydroxygenkwanin was found to enhance the chemosensitivity of HCC cells by inhibiting the expression of class I histone deacetylase (HDAC) [ 40 ] and by inhibiting the DNA damage response [ 39 ]. In this study, we investigated the modulatory effect of hydroxygenkwanin on ABCB1- and ABCG2-mediated MDR in multidrug-resistant cancer cells.…”

“…Our results demonstrate that hydroxygenkwanin is a more potent inhibitor of ABCG2, compared with ABCB1, and is more specific to ABCG2. It is worth noting that in previous studies, high concentrations of hydroxygenkwanin (20–50 μM) were used in biochemical assays [ 39 , 40 , 41 , 42 ]. In contrast, at the highest tested concentration of 1 μM, hydroxygenkwanin reversed ABCG2-mediated MDR in a manner similar to the reference inhibitor, Ko143 ( Table 3 ).…”

“…It has been found to exhibit anti-inflammatory and immunomodulatory properties [ 34 , 35 ], antimicrobial and antifungal activities [ 36 ], and it promotes pigmented hair regeneration [ 37 ]. In addition, the antiproliferative activity of hydroxygenkwanin has been demonstrated in a variety of cancer cell lines and animal models [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]; however, the potential chemosensitizing effect of hydroxygenkwanin on multidrug-resistant cancer cells has not been studied.…”

Nutritional Biochemistry

“…In the last study, Chen et al [5] hypothesized that hydroxygenkwanin (HGK) has an inhibitory effect on DNA damage response (DDR)-induced damage and tested it in yeast cells. In addition, the author used liver cancer cells to detect related indicators such as apoptosis and homologous recombination repair and developed a mouse model to confirm the results of in vitro experiments.…”