Regulatory mechanisms of the radiosensitive effect of PARP-1 inhibitor on breast cancer cells with BRCA mutation

Objective: To investigate the radiosensitivity effects of poly ADP-ribose polymerase-1 (PARP-1) inhibitor 3-amion benzamide (3-AB) on the BRCA non-mutant and BRCA mutant breast cancer cells, and to explore the regulatory mechanism of PARP-1 and BRCA in radiation-induced DNA damage repair. Methods: MDA-MB-436 cells and MDA-MB-231 cells were divided into four groups respectively as the control (CTRL), ionizing radiation alone (IR), 3-AB alone (3-AB), and ionizing radiation combined with 3-AB(IR+3-AB) group. γ-H2AX foci were detected by immunofluorescence assay. The radiosensitivity of breast cancer cells was evaluated by clonogenic survival assay. The percentage of apoptotic cells was assessed by flow cytometry. Results: Compared with MDA-MB-231 cells, MDA-MB-436 cells had a higher radiosensitivity and produced more γ-H2AX foci(t = 4.57, P < 0.05), which was further increased by 3-AB. The DNA damage of MDA-MB-436 cells in the IR+3-AB group was the most remarkable (t = 3.26, P < 0.05). Flow cytometry showed that the cells in the IR+3-AB group had the highest rate of apoptosis(t = 3.81, P < 0.05), and the apoptosis rate of MDA-MB-436 cells was significantly higher than MDA-MB-231 cells(t = 2.96, P < 0.05). Conclusions: The radiosensetivity of BRCA mutant cells MDA-MB-436 is significantly higher than that of non-BRCA mutant cells MDA-MB-231. Inhibition of PARP-1 can further increase the apoptosis and radiosensitivity of BRCA-mutant cells by further blocking the repair of DNA single-strand break induced by ionizing radiation. (authors)