Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells

Qiao, Zhixin; Ren, Suping; Li, Weijing; Wang, Xuanlin; He, Min; Guo, Yingjie; Sun, Liwei; He, Yuezhong; Ge, Yubin; Yu, Qun

doi:10.1016/j.bbrc.2013.03.059

Cited by 66 publications

(46 citation statements)

References 21 publications

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“…A number of different classes exist and the development of new derivatives is intensively investigated aimed at designing inhibitors that exhibit decreased toxicity, high potency, blood-brain barrier permeability, and improved selectivity. [55][56][57][58] An overview of HDACi highlighting mechanisms of action, blood-brain barrier permeability, clinical assessment, and safety information can be found in Table 1.…”

Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

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Section: Dna Methylationmentioning

confidence: 99%

Epigenetic Mechanisms in Cerebral Ischemia

Schweizer

Meisel

Märschenz

2013

J Cereb Blood Flow Metab

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“…Our previous study demonstrates that chidamide, in combination with gemcitabine. causes growth inhibition of pancreatic cancer cells by inducing p21 expression and cell cycle arrest, and down-regulates the expression of Mcl-1[16]. In this study, we clarify the mechanism of Mcl-1 degradation, investigate the metabolic role of Mcl-1 and propose one of the underlying molecular mechanisms of chidamide in pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Chidamide Inhibits Aerobic Metabolism to Induce Pancreatic Cancer Cell Growth Arrest by Promoting Mcl-1 Degradation

Qiao

Wang

et al. 2016

PLoS ONE

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Pancreatic cancer is a fatal malignancy worldwide and urgently requires valid therapies. Previous research showed that the HDAC inhibitor chidamide is a promising anti-cancer agent in pancreatic cancer cell lines. In this study, we elucidate a probable underlying anti-cancer mechanism of chidamide involving the degradation of Mcl-1. Mcl-1 is frequently upregulated in human cancers, which has been demonstrated to participate in oxidative phosphorylation, in addition to its anti-apoptotic actions as a Bcl-2 family member. The pancreatic cancer cell lines BxPC-3 and PANC-1 were treated with chidamide, resulting in Mcl-1 degradation accompanied by induction of Mcl-1 ubiquitination. Treatment with MG132, a proteasome inhibitor reduced Mcl-1 degradation stimulated by chidamide. Chidamide decreased O2 consumption and ATP production to inhibit aerobic metabolism in both pancreatic cancer cell lines and primary cells, similar to knockdown of Mcl-1, while overexpression of Mcl-1 in pancreatic cancer cells could restore the aerobic metabolism inhibited by chidamide. Furthermore, chidamide treatment or Mcl-1 knockdown significantly induced cell growth arrest in pancreatic cancer cell lines and primary cells, and Mcl-1 overexpression could reduce this cell growth inhibition. In conclusion, our results suggest that chidamide promotes Mcl-1 degradation through the ubiquitin-proteasome pathway, suppressing the maintenance of mitochondrial aerobic respiration by Mcl-1, and resulting in inhibition of pancreatic cancer cell proliferation. Our work supports the claim that chidamide has therapeutic potential for pancreatic cancer treatment.

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“…HDACs are often overexpressed in various types of cancer, resulting in increased proliferation and dedifferentiation [6], [7], and their pharmacologic inhibition has been shown to have potent anticancer effects, including growth arrest, differentiation and apoptosis, in multiple types of human cancer cells [7], [8], including pancreatic cancer. For example, trichostatin A [9] and suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza) have been shown to inhibit the growth of various pancreatic cell lines alone and in combination with gemcitabine [10], [11], and in vitro synergism was reported for the combination of chidamide, a novel benzamide HDAC inhibitor, and gemcitabine in inducing cell growth arrest and apoptosis in pancreatic cancer cell lines [12].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42

Henderson

Ding

et al. 2016

Neoplasia

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PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC. EXPERIMENTAL DESIGN: The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). AsPC-1 subcutaneous xenograft and transgenic KPfl/flC (LSL-KrasG12D;Trp53flox/flox;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. RESULTS: Growth suppression in AR-42–treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, AR-42 as a single agent preserved muscle size and increased grip strength in KPfl/flC mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. CONCLUSIONS: These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer.

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Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells

Cited by 66 publications

References 21 publications

Epigenetic Mechanisms in Cerebral Ischemia

Epigenetic Mechanisms in Cerebral Ischemia

Chidamide Inhibits Aerobic Metabolism to Induce Pancreatic Cancer Cell Growth Arrest by Promoting Mcl-1 Degradation

Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42

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