Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells

Miller, Claudia P.; Rudra, Sharmistha; Keating, Michael J.; Wierda, William G.; Palladino, Michael A.; Chandra, Joya

doi:10.1182/blood-2008-08-174797

Cited by 64 publications

(56 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, we show that the combination of HDACi with a proteasome inhibitor has a much higher efficacy, with respect to the treatment with HDACi alone, inducing the death of cell lines deriving from ATCs. In agreement with our findings, the synergism of proteasome inhibitors with HDACis has recently been reported in glioma, in cervical cancer and in leukemia (Miller et al, 2007(Miller et al, , 2009Dai et al, 2008;Yu et al, 2008;Lin et al, 2009), strongly supporting our molecular model and suggesting the application of this combined treatment in other types of cancers.…”

Section: Discussionsupporting

confidence: 81%

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

et al. 2009

View full text Add to dashboard Cite

Anaplastic thyroid carcinoma (ATC) is considered one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemotherapy and radiotherapy. Alteration in histone deacetylase (HDAC) activity has been reported in cancer, thus encouraging the development of HDAC inhibitors, whose antitumor action has been shown in both solid and hematological malignancies. However, the molecular basis for their tumor selectivity is unknown. To find an innovative therapy for the treatment of ATCs, we studied the effects of deacetylase inhibitors on thyroid tumorigenesis models. We show that HDACs 1 and 2 are overexpressed in ATCs compared with normal cells or benign tumors and that HDAC inhibitors induce apoptosis selectively in the fully transformed thyroid cells. Our results indicate that these phenomena are mediated by a novel action of HDAC inhibitors that reduces tumor necrosis factor-related apoptosis-inducing ligand protein degradation by affecting the ubiquitin-dependent pathway. Indeed, the combined treatment with HDAC and proteasome inhibitors results in synergistic apoptosis. These results strongly encourage the preclinical application of the combination deacetylaseproteasome inhibitors for the treatment of ATC.

show abstract

Section: Discussionsupporting

confidence: 81%

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Furthermore, the histone acetylation was ROS-and caspase-8-dependent as both NAC-and caspase-8-specific inhibitor, Z-IETD-FMK, could markedly reduce the acetylation of the histones. The results were similar to the induction of caspase-8-dependent histone acetylation by combination of HDAC and proteasome inhibitors in leukemic cells (21). One of the major effects mediated by histone hyperacetylation is upregulation of tumor suppressor genes (9).…”

Section: Discussionsupporting

confidence: 71%

“…Bortezomib/SAHA triggers apoptosis through caspase activation (14,(16)(17)(18) and ROS generation (13)(14)(15)(16)19) in various types of cancers. Other cellular effects of combined proteasome and HDAC inhibitors in various cancer types include histone acetylation (20,21), aggresome disruption (22), NF-kB inactivation (13,14,16,17,19), p53 and p21 upregulation (13,15,16,18), c-Jun NH 2 -terminal kinase activation (13,17), and mitochondrial membrane dysfunction (13,(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

Hui

Lam

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein-Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G 1 , Annexin V-positive, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8-dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/ SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. Mol Cancer Ther; 12(5); 747-58. Ó2013 AACR.

show abstract

“…In this respect, the outcome of the combined treatment of HDAC inhibitor and proteasome inhibitor resulted in increased inhibitory effects on proteasome activity in a fashion that reflected levels of HR23B. From the clinical perspective, HDAC inhibitors have been studied in combination with an increasing array of anticancer agents (6,8,16), and clinical studies in which HDAC inhibitors were combined with proteasome inhibitors yielded results that suggest additive effects (7,16,20,21). For example, the combined treatment of SAHA/vorinostat with bortezomib produced encouraging clinical effects in patients with relapsed and refractory multiple myeloma (20).…”

Section: Hr23bmentioning

confidence: 99%

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

Khan

Fotheringham

Wood

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

138

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors are emergent cancer drugs. HR23B is a candidate cancer biomarker identified in a genome-wide loss-of-function screen which influences sensitivity to HDAC inhibitors. Because HDAC inhibitors have found clinical utility in cutaneous T-cell lymphoma (CTCL), we evaluated the role of HR23B in CTCL cells. Our results show that HR23B governs the sensitivity of CTCL cells to HDAC inhibitors. Furthermore, proteasome activity is deregulated in HDAC inhibitor-treated CTCL cells through a mechanism dependent upon HR23B, and HDAC inhibitors sensitize CTCL cells to the effects of proteasome inhibitors. The predictive power of HR23B for clinical response to HDAC inhibitors was investigated through an analysis of a unique collection of CTCL biopsies taken from a phase II clinical trial, where there was a frequent coincidence between HR23B expression and clinical response to HDAC inhibitor. Our study supports the personalized medicine approach for treating cancer and the increasing drive to translate laboratory-based findings into clinical utility.cancer | histone deacetylase inhibitor | biomarker | proteasome | clinical trial I t is widely recognized that one of the most significant hurdles to developing new and efficacious cancer drugs is the absence of proven strategies that enable responsive tumors to be identified and treated with the most effective drug. Predictive biomarkers that inform on the clinical response to cancer therapies will not only assist in planning focused and hypothesis-driven clinical development programs but, once approved, provide a companion biomarker that enables patients to be stratified and aligned with an appropriate therapeutic regime (1).Aberrant epigenetic control is an early event in the onset of tumor progression, and there have been intense efforts to develop drugs that modulate epigenesis in cancer (2). One of the most promising approaches has been seen in the development of inhibitors of histone deacetylase (HDAC). HDAC is a family of enzymes that regulate the acetylation level of chromatin, together with a variety of nonhistone proteins (3). Proteins that are involved with tumor progression, including the cell cycle, apoptosis, angiogenesis, and cell invasion, are influenced by acetylation (4).HDAC inhibitors are potent antiproliferative agents in cellbased studies, where they exhibit striking effects on tumor cell proliferation (5-7). Consequently, there has been great interest in developing HDAC inhibitors as new anticancer agents, and an extensive number of clinical trials are underway in which HDAC inhibitors either alone or in combination with other agents are being evaluated (8). To date, SAHA (also known as Vorinostat and Zolinza) and more recently romidepsin (also known as depsipeptide, FK228, and Istodax) are the only HDAC inhibitorbased therapies that have achieved regulatory approval, being marketed for the treatment of advanced and refractory cutaneous T-cell lymphoma (CTCL) (9-11) (http://istodax.com) . Other than CTCL, tumor types that ha...

show abstract

Caspase-8 dependent histone acetylation by a novel proteasome inhibitor, NPI-0052: a mechanism for synergy in leukemia cells

Cited by 64 publications

References 37 publications

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy

Contact Info

Product

Resources

About