2. Academic Validation
  3. Trabectedin Induces Synthetic Lethality via the p53-Dependent Apoptotic Pathway in Ovarian Cancer Cells Without BRCA Mutations When Used in Combination with Niraparib

Trabectedin Induces Synthetic Lethality via the p53-Dependent Apoptotic Pathway in Ovarian Cancer Cells Without BRCA Mutations When Used in Combination with Niraparib

  • Int J Mol Sci. 2025 Mar 24;26(7):2921. doi: 10.3390/ijms26072921.
Bongkyun Kang 1,  Sun-Jae Lee 2,  Ki Ho Seol 3,  Yoon Young Jeong 4,  Jung-Hye Choi 5,  Bo-Hyun Choi 6,  Jung Min Ryu 4,  Youn Seok Choi 4
Affiliations

Affiliations

  • 1 Department of Chemistry, College of Natural Science, Kyungpook National University, Daegu 41944, Republic of Korea.
  • 2 Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
  • 3 Department of Radiation Oncology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
  • 4 Department of Obstetrics and Gynecology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
  • 5 Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 6 Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu 42472, Republic of Korea.
PMID: 40243501 DOI: 10.3390/ijms26072921
Abstract

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.

Keywords

homologous recombination deficiency; ovarian carcinoma; poly (ADP-ribose) polymerase inhibitor; synthetic lethality; trabectedin.

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