Screening of a Small Molecule Compound Library Identifies Potential Drugs that Synergize with PARP Inhibitors against Ovarian Cancer Cells
10.13865/j.cnki.cjbmb.2022.03.1619
- Author:
Han-Xiao LI
1
;
Xiao-Man LI
1
;
Ye-Fei LUO
1
;
Jia-Dong WANG
1
Author Information
1. Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center
- Publication Type:Journal Article
- Keywords:
homologous recombination repair;
Niraparib;
poly (ADP-ribose) polymerase inhibitor;
tropomyosin receptor kinase A
- From:
Chinese Journal of Biochemistry and Molecular Biology
2022;38(4):452-464
- CountryChina
- Language:Chinese
-
Abstract:
PARP inhibitors are a new class of drugs that target cancer cells with defective DNA repair. Early trials have shown that PARP inhibitors have achieved satisfactory results, but the mechanism of resistance after drug treatment has not been fully revealed. Therefore, it is necessary to find more targeted drugs in combination with PARP inhibitors to kill tumor cells. In this paper, several potential drugs that can synergistically kill ovarian cancer cells with PARP inhibitors were identified based on the combined drug screening of 379 small molecule compound libraries and PARP inhibitor Niraparib through cell proliferation experiments, colony-formation survival experiments and immunofluorescence staining experiments. The results showed that there are eight small molecule compounds with good combination effects, including two small molecule inhibitors STF-118804 and Disulfiram that have been reported to have combined effects with PARP inhibitors. We selected GW441756, an inhibitor of tropomyosin receptor kinase A (TrKA), to verify a variety of tumor cells and explore the preliminary mechanism. The combined therapeutic effects of the Niraparib and the TrKA inhibitor increased the sensitivity of tumor cells to PARP inhibitors (P < 0. 05). Mechanistically, the number of γH2AX foci in the combined treatment group was significantly increased (P<0. 05), indicating that the TrKA inhibitor hindered the DNA damage repair ability. Moreover, combination therapy significantly reduced the formation of RAD51 foci (P<0. 05), a marker of homologous recombination repair (HRR), suggesting that TrKA inhibitors may inhibit DNA damage repair by inhibiting HRR efficiency. Overall, these results suggest that TrKA inhibitor can be used as a potential drug to kill ovarian cancer cells in combination with PARP inhibitors.
