Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer

Feng, Jinhong; Fang, Hao; Wang, Xuejian; Jia, Yuping; Zhang, Lei; Jiao, Jie; Zhang, Jian; Gu, Lichuan; Xu, Wenfang

doi:10.4161/cbt.11.5.14529

Cited by 14 publications

(6 citation statements)

References 25 publications

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“…26,27 HDAC inhibitors (HDACi) induce cell growth arrest, differentiation and apoptosis and play crucial roles in a wide range of biological processes, mainly through their repressive influence on transcription, and thus, become very influential and powerful targets for many diseases. 28 Unlike HDAC1, HDAC3 is required for cell growth and is involved in transcriptional regulation of genes important for cell cycle progression and development. HDAC3 has been implicated to play roles in governing cell proliferation via the inhibition of cell cycle genes.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Zheng

Zhang

et al. 2012

Epigenetics

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Maternal exposure to environmental agents throughout pregnancy and lactation may affect offspring's mammary gland growth and alter the epigenome. This may predispose the offspring's mammary glands to be more susceptible to carcinogenesis. The purpose of this study was to examine the effect of a maternal high-fat diet on the regulation of p16 (INK4a) gene expression in the mammary gland of rat offspring. Timed-pregnant Sprague-Dawley rats were fed one of the two diets, a control (C, 16% of fat) or a high fat (HF, 45% of fat) diet, throughout gestation and lactation and sacrificed at 12 weeks of age. Compared with C, HF offspring showed a decrease of p16 (INK4a) gene expression in the mammary gland at both mRNA and protein levels. Chromatin immunoprecipitation (ChIP) assay demonstrated that the downregulation of p16 (INK4a) transcription in HF offspring was associated with reduced acetylation of histone H4 and increased recruitment of histone deacetylase 3 (HDAC3) within the p16 (INK4a) promoter region, but was not associated with acetylation of histone H3 or HDAC1. Methylated DNA immunoprecipitation (MeDIP) did not detect differences in methylation at different regions of the p16 (INK4a) gene between C and HF offspring. We conclude that maternal high fat exposure represses p16 (INK4a) gene expression in the mammary gland of offspring through changes of histone modifications and HDAC3 binding activity within the regulatory regions of the p16 (INK4a) gene.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Zheng

Zhang

et al. 2012

Epigenetics

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“…TRAIL alone and combined TRAIL and SAHA treatment also induced DR5 expression in both MDA-MB-231 and MCF-7 cell lines. A number of studies have demonstrated that both SAHA4148516061 and TRAIL626364 were able to activate Caspase-3 in breast cancer cell lines. We found that SAHA alone significantly induced Caspase-3 expression in MDA-MB-231 but not in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells

Zhou

Feng

Han

et al. 2016

Sci Rep

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Previous studies showed that either histone deacetylase (HDAC) inhibitors or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in tumor cells including breast cancer. However, the underling mechanisms of combining HDAC inhibitors with TRAIL in the treatment of breast cancer are poorly understood. In this study, we determined the ability of SAHA and TRAIL as single agents or in combination to inhibit the growth and survival of MCF-7 and MDA-MB-231 breast cancer cells. Our results demonstrate that the distinct effects of SAHA or TRAIL individually and in combination on the proliferation, cell viability, apoptosis, cell cycle distribution, and morphological changes of MDA-MB-231 and MCF-7 cells. We further determined the different effects of SAHA or TRAIL alone and combining SAHA with TRAIL on the expression of a number of apoptosis-related molecules, cell cycle, growth factors and their receptors in cancer cells. Our results demonstrated that the combinatorial treatment of SAHA and TRAIL may target multiple pathways and serve as an effective therapeutic strategy against breast cancer. An improved understanding of the molecular mechanisms may facilitate either SAHA or TRAIL targeted use and the selection of suitable combinations.

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“…For Western blot analysis of acetylated tubulin, acetylated histone H3, H4, and p21, total protein extracts were separated on a polyacrylamide gel, transferred onto polyvinylidene difluoride membranes and blotted as previously described . Protein immunoblots were shown for acetylated tubulin (Sigma, Shanghai, China), acetylated histone H3 (Sigma), acetylated histone H4 (Sigma), and p21 (Cell Signaling, Shanghai, China) using β‐Actin (Sigma) as a loading control.…”

Section: Methodsmentioning

confidence: 99%

Design and Synthesis of a Tetrahydroisoquinoline‐Based Hydroxamate Derivative (ZYJ‐34v), An Oral Active Histone Deacetylase Inhibitor with Potent Antitumor Activity

et al. 2013

Self Cite

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In our previous study we developed a novel series of tetrahydroisoquinoline-based hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors (Bioorg. Med. Chem., 2010, 18, 1761–1772., J. Med. Chem., 2011, 54, 2823–2838.), among which compound ZYJ-34c (1) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency (J. Med. Chem., 2011, 54, 5532–5539.). Herein further modification of 1 afforded another oral active analogue ZYJ-34v (2) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against HDAC1, 2, 3 and 6, which was confirmed by western blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved HDAC inhibitor SAHA.

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Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer

Cited by 14 publications

References 25 publications

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells

Design and Synthesis of a Tetrahydroisoquinoline‐Based Hydroxamate Derivative (ZYJ‐34v), An Oral Active Histone Deacetylase Inhibitor with Potent Antitumor Activity

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Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer

Cited by 14 publications

References 25 publications

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Synergistic effects of combined treatment with histone deacetylase inhibitor suberoylanilide hydroxamic acid and TRAIL on human breast cancer cells

Design and Synthesis of a Tetrahydroisoquinoline‐Based Hydroxamate Derivative (ZYJ‐34v), An Oral Active Histone Deacetylase Inhibitor with Potent Antitumor Activity

Contact Info

Product

Resources

About

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet

Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of thep16^INK4agene in mammary gland of the female rat offspring exposed to an early-life high-fat diet