Kang Bongkyun, Lee Sun-Jae, Seol Ki Ho, Jeong Yoon Young, Choi Jung-Hye, Choi Bo-Hyun, Ryu Jung Min, Choi Youn Seok
Department of Chemistry, College of Natural Science, Kyungpook National University, Daegu 41944, Republic of Korea.
Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
Int J Mol Sci. 2025 Mar 24;26(7):2921. doi: 10.3390/ijms26072921.
This study investigated whether combining niraparib and trabectedin in BRCA-proficient epithelial ovarian cancer induces deficiencies in ssDNA break repair and dsDNA homologous recombination, leading to synthetic lethality. A2780 and SKOV3 ovarian cancer cell lines were treated with niraparib and trabectedin. Cell viability was assessed using CCK-8 assays, while RT-qPCR and Western blot analyzed the expression of DNA repair and apoptosis-related genes. Apoptosis was evaluated via Annexin V/PI assays. The combination therapy exhibited a synergistic effect on A2780 cells but not on SKOV3 cells. Treatment reduced BRCA1, BRCA2, RAD51, PARP1, and PARP2 expression, indicating impaired DNA repair. γ-H2AX levels increased, suggesting DNA damage. The therapy also upregulated p53, PUMA, NOXA, BAX, BAK, and p21, promoting p53-mediated apoptosis and cell cycle arrest. Apoptosis induction was confirmed via Annexin V/PI assays. Silencing p53 with siRNA abolished all synergistic effects in A2780 cells. Niraparib and trabectedin combination therapy impairs DNA repair in BRCA-proficient ovarian cancer, leading to synthetic lethality through p53-dependent apoptosis.
本研究调查了在BRCA功能正常的上皮性卵巢癌中联合使用尼拉帕利和曲贝替定是否会导致单链DNA断裂修复和双链DNA同源重组缺陷，从而导致合成致死。用尼拉帕利和曲贝替定处理A2780和SKOV3卵巢癌细胞系。使用CCK-8法评估细胞活力，同时通过RT-qPCR和蛋白质印迹分析DNA修复和凋亡相关基因的表达。通过Annexin V/PI法评估细胞凋亡。联合治疗对A2780细胞显示出协同作用，但对SKOV3细胞没有协同作用。治疗降低了BRCA1、BRCA2、RAD51、PARP1和PARP2的表达，表明DNA修复受损。γ-H2AX水平升高，提示DNA损伤。该治疗还上调了p53、PUMA、NOXA、BAX、BAK和p21，促进了p53介导的细胞凋亡和细胞周期停滞。通过Annexin V/PI法证实了细胞凋亡的诱导。用siRNA沉默p53消除了A2780细胞中的所有协同作用。尼拉帕利和曲贝替定联合治疗损害了BRCA功能正常的卵巢癌中的DNA修复，通过p53依赖性细胞凋亡导致合成致死。
