ArticleThe Journal of biological chemistry2012
Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
69 citing papers in PubMed, 100 citations in OpenAlex.
- Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling.Nature communications · 2025Trial
- 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer.Gynecologic oncology · 2019Trial
- A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2015Trial
- Targeting DNA Topoisomerase I for the Treatment of Cancer: Past, Present and Future.Journal of molecular biology · 2026Review
- Codon specific readthrough as a mechanism of BRCA2 restoration in acquired PARP inhibitor and chemotherapy resistance.Nucleic acids research · 2025Article
- Antitumor activity of rucaparib plus PLX038A in serous endometrial carcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Preclinical evaluation of a novel antibody-drug conjugate OBI-992 for Cancer therapy.Scientific reports · 2025Article
- First-In-Human Dose Finding Study of Venadaparib (IDX-1197), a Potent and Selective PARP Inhibitor, in Patients With Advanced Solid Tumors.Cancer medicine · 2025Article
- Synergistic antitumor effect of liposomal-based formulations of olaparib and topotecan in primary epithelial ovarian cancer cells.Cancer cell international · 2024Article
- Vector-Mediated Cancer Gene Therapy Reduces Toxicity and Inhibition of Lung Carcinoma Growth in Nude Mice.Applied biochemistry and biotechnology · 2024Article
- Targeting BRPF3 moderately reverses olaparib resistance in high grade serous ovarian carcinoma.Molecular carcinogenesis · 2023Article
- Alkylation of nucleobases by 2-chloro-NAR cancer · 2023Article
- A Phase I Study of a Combination of Liposomal Irinotecan and Veliparib in Solid Tumors.The oncologist · 2023Article
- Transcriptomic Analysis of CRISPR/Cas9-Mediated PARP1-Knockout Cells under the Influence of Topotecan and TDP1 Inhibitor.International journal of molecular sciences · 2023Article
- PLX038: A Long-Acting Topoisomerase I Inhibitor With Robust Antitumor Activity in ATM-Deficient Tumors and Potent Synergy With PARP Inhibitors.Molecular cancer therapeutics · 2022Article
- A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.Cancer chemotherapy and pharmacology · 2022Article
- The potential of PARP inhibitors in targeted cancer therapy and immunotherapy.Frontiers in molecular biosciences · 2022Review
- Review
- Serine-linked PARP1 auto-modification controls PARP inhibitor response.Nature communications · 2021Article
- AraC-FdUMP[10] Is a Next-Generation Fluoropyrimidine with Potent Antitumor Activity in PDAC and Synergy withMolecular cancer research : MCR · 2021Article
9 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Poly(ADP-ribose) polymerase-1 (PARP1) plays critical roles in the regulation of DNA repair. Accordingly, small molecule inhibitors of PARP are being developed as agents that could modulate the activity of genotoxic chemotherapy, such as topoisomerase I poisons. In this study we evaluated the ability of the PARP inhibitor veliparib to enhance the cytotoxicity of the topoisomerase I poisons topotecan and camptothecin (CPT). Veliparib increased the cell cycle and cytotoxic effects of topotecan in multiple cell line models. Importantly, this sensitization occurred at veliparib concentrations far below those required to substantially inhibit poly(ADP-ribose) polymer synthesis and at least an order of magnitude lower than those involved in selective killing of homologous recombination-deficient cells. Further studies demonstrated that veliparib enhanced the effects of CPT in wild-type mouse embryonic fibroblasts (MEFs) but not Parp1(-/-) MEFs, confirming that PARP1 is the critical target for this sensitization. Importantly, parental and Parp1(-/-) MEFs had indistinguishable CPT sensitivities, ruling out models in which PARP1 catalytic activity plays a role in protecting cells from topoisomerase I poisons. To the contrary, cells were sensitized to CPT in a veliparib-independent manner upon transfection with PARP1 E988K, which lacks catalytic activity, or the isolated PARP1 DNA binding domain. These results are consistent with a model in which small molecule inhibitors convert PARP1 into a protein that potentiates the effects of topoisomerase I poisons by binding to damaged DNA and preventing its normal repair.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.