ArticleProceedings of the National Academy of Sciences of the United States of America2008
Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed.
- Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2009Trial
- Pharmacological Inhibition of cFLIP Targets Breast Cancer Stem Cells.Journal of cancer treatment & diagnosis · 2025Article
- TRAIL induces cytokine production via the NFkB2 pathway promoting neutrophil chemotaxis and neutrophil-mediated immune-suppression in triple negative breast cancer cells.Cancer letters · 2025Article
- Brain Tumors: Development, Drug Resistance, and Sensitization - An Epigenetic Approach.Epigenetics · 2023Review
- Primary cilia: a novel research approach to overcome anticancer drug resistance.Frontiers in molecular biosciences · 2023Review
- Indomethacin-induced oxidative stress enhances death receptor 5 signaling and sensitizes tumor cells to adoptive T-cell therapy.Journal for immunotherapy of cancer · 2022Article
- The paradigm of drug resistance in cancer: an epigenetic perspective.Bioscience reports · 2022Review
- Kaempferol sensitizes tumor necrosis factor-related apoptosis-inducing ligand-resistance chronic myelogenous leukemia cells to apoptosis.Molecular biology reports · 2022Article
- Combination treatment with VPA and MSCs‑TRAIL could increase anti‑tumor effects against intracranial glioma.Oncology reports · 2021Article
- Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach.International journal of molecular sciences · 2020Review
- Suppression of histone deacetylases by SAHA relieves bone cancer pain in rats via inhibiting activation of glial cells in spinal dorsal horn and dorsal root ganglia.Journal of neuroinflammation · 2020Article
- Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer.Frontiers in oncology · 2020Review
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- New findings showing how DNA methylation influences diseases.World journal of biological chemistry · 2019Article
- Review
- Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFCancers · 2018Review
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- Review
1 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.
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