PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma

Sholler, Giselle L. Saulnier; Currier, Erika A.; Dutta, Akshita; Slavik, Marni A; Illenye, Sharon; Mendonça, Maria C.; Dragon, Julie; Roberts, Stephen S.; Bond, Jeffrey P.

doi:10.7243/2049-7962-2-21

Cited by 24 publications

(11 citation statements)

References 45 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased production of ROS upon treatment with HDAC inhibitors can lead to oxidative stress which may induce apoptosis in many cancer cells . In line with this, we observed that the SAHA greatly increased intracellular ROS levels and induced apoptosis in lung cancer cells.…”

Section: Discussionsupporting

confidence: 85%

Suberoylanilide hydroxamic acid induces thioredoxin1‐mediated apoptosis in lung cancer cells via up‐regulation of miR‐129‐5p

You

Park

2017

Molecular Carcinogenesis

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors, especially suberoylanilide hydroxamic acid (SAHA) induce apoptosis in various cancer cells. Here, we investigated the effect of SAHA on apoptosis in lung cancer cells and addressed the role of reactive oxygen species (ROS), glutathione (GSH), and thioredoxin1 (Trx1) levels in this process. We also identified the miRNAs that down-regulate Trx1 expression at RNA level and thereby influence apoptotic cell death of SAHA increased intracellular ROS levels and promoted apoptotic cell death in cancerous cells but not in non-cancerous normal lung cells. Likewise, SAHA induced GSH depletion specifically in cancerous cells. While N-acetyl cysteine (NAC) reduced ROS level and reversed the effect of SAHA on cell death, L-buthionine sulfoximine (BSO) further enhanced GSH depletion, and promoted cell death. SAHA decreased the mRNA and protein levels of Trx1 in lung cancer cells. Knockdown/suppression of Trx1 intensified apoptosis in SAHA-treated lung cancer cells whereas overexpression of Trx1 prevented the cell death in these cells. SAHA up-regulated the level of miR-129-5p, which binds to 3' untranslated region (3'UTR) of Trx1 and down-regulates Trx1 expression. Down-regulation of Trx1 led to activation of apoptosis-signal regulating kinase (ASK), which induced apoptotic cell death by triggering ASK-JNK or ASK-p38 kinase pathway. In conclusion, changes in ROS and GSH levels in SAHA-treated lung cancer cells partially co-related with cell death. SAHA induced apoptosis via the down-regulation of Trx1, which was regulated by miR-129-5p.

show abstract

Section: Discussionsupporting

confidence: 85%

Suberoylanilide hydroxamic acid induces thioredoxin1‐mediated apoptosis in lung cancer cells via up‐regulation of miR‐129‐5p

You

Park

2017

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…Abexinostat-induced cell death occurred through caspase-8 and the Fas-associated death domain, and was associated with a prominent increase in reactive oxygen species (8). Similar apoptotic responses were observed in neuroblastoma and soft tissue sarcoma models (9)(10)(11). Abexinostat also affects recombination by reducing RAD51, a recA homolog that binds single-stranded DNA-forming nucleoprotein filaments essential for recombination repair (12,13).…”

Section: Introductionsupporting

confidence: 48%

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

Evens

Balasubramanian

Vose

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N ¼ 55) with single-agent abexinostat in relapsed/refractory lymphoma.Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m 2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/ refractory follicular lymphoma or mantle cell lymphoma.Results: The recommended phase II dose was 45 mg/m 2 twice daily (90 mg/m 2 total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigatorassessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3þ). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with !10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths.Conclusions: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

show abstract

“…Not surprisingly, multiple end points for HDAC-inhibitor activity have been reported, including gene expression, cell-cycle arrest, cell differentiation, antiangiogenesis, cell death, and autophagy. 81 In addition, HDAC inhibitors have been reported to generate ROS and modulate redox levels in cells, [82][83][84][85][86][87] resulting in DNA damage and activation of the DDR. 88,89 Others have shown that key DNA-repair molecules including Ku70/Ku80, DNA-PK, RAD50, RAD51, BRCA1/2, and MRE11 are downregulated by vorinostat and other HDAC inhibitors in combination with radiotherapy, leading to RIF persistence.…”

Section: Chromatin Structure and Targetingmentioning

confidence: 99%

Opportunities and challenges of radiotherapy for treating cancer

2015

View full text Add to dashboard Cite

The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.

show abstract

PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma

Cited by 24 publications

References 45 publications

Suberoylanilide hydroxamic acid induces thioredoxin1‐mediated apoptosis in lung cancer cells via up‐regulation of miR‐129‐5p

Suberoylanilide hydroxamic acid induces thioredoxin1‐mediated apoptosis in lung cancer cells via up‐regulation of miR‐129‐5p

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

Opportunities and challenges of radiotherapy for treating cancer

Contact Info

Product

Resources

About