ArticleOncotarget2018
Combination of a hypomethylating agent and inhibitors of PARP and HDAC traps PARP1 and DNMT1 to chromatin, acetylates DNA repair proteins, down-regulates NuRD and induces apoptosis in human leukemia and lymphoma cells.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 45 citations in OpenAlex.
- Sensitizing Colorectal Cancer to PARP Inhibitors: Biomarkers, Mechanisms, and Combination Strategies.International journal of molecular sciences · 2026Review
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- Impact of CaInternational journal of molecular sciences · 2026Review
- PARP inhibitors across different malignancies: clinical applications, resistance mechanisms, and strategies to enhance efficacy through combination therapies.Frontiers in cell and developmental biology · 2026Review
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- Poly (ADP-Ribose) Polymerase 1 and 2 in B-Cell Lymphoma: Pathogenic Roles and Therapeutic Implications.The American journal of pathology · 2025Review
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- Getting the right combination to break the epigenetic code.Nature reviews. Clinical oncology · 2025Review
- Roles ofClinical Medicine Insights. Oncology · 2024Article
- Therapeutic targeting of PARP with immunotherapy in acute myeloid leukemia.Frontiers in pharmacology · 2024Review
- Advances in the pathogenesis and therapeutic strategies of angioimmunoblastic T-cell lymphoma.Clinical and experimental medicine · 2023Review
- Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.Cellular oncology (Dordrecht, Netherlands) · 2023Article
- Mutual Regulation of ncRNAs and Chromatin Remodeling Complexes in Normal and Pathological Conditions.International journal of molecular sciences · 2023Review
- Multifaceted Influence of Histone Deacetylases on DNA Damage Repair: Implications for Hepatocellular Carcinoma.Journal of clinical and translational hepatology · 2023Review
- HDAC-an important target for improving tumor radiotherapy resistance.Frontiers in oncology · 2023Review
- TargetingCancers · 2022Review
- Article
- PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.Expert opinion on investigational drugs · 2022Review
- Pharmacologic Induction of BRCAness inCancers · 2022Review
- Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.Journal of hematology & oncology · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis. Addition of the DNA alkylating agents busulfan (Bu) and/or melphalan enhanced the anti-proliferative/cytotoxic effects of the triple-drug combination. [Npb+DAC+Rom] significantly increased the level of chromatin-bound PARP1 and DNMT1 and caused acetylation of DNA repair proteins, including Ku70, Ku80, PARP1, DDB1, ERCC1 and XPF/ERCC4. This three-drug combination down-regulated the components of the nucleosome-remodeling deacetylase (NuRD) complex, which is involved in DNA-damage repair. Addition of Bu to this combination further enhanced these effects on NuRD. The trapping of PARP1 and DNMT1 to chromatin, acetylation of DNA repair proteins, and down-regulation of NuRD may all have increased double-strand DNA break (DSB) formation as suggested by activation of the DNA-damage response, concomitantly resulting in tumor cell death. Similar synergistic cytotoxicity was observed in blood mononuclear cells isolated from patients with AML and lymphoma. Our results provide a rationale for the development of [Npb+DAC+Rom/Pano] combination therapies for leukemia and lymphoma patients.
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