Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer

Martínez-Iglesias, Olaia; Ruiz, Lı́dia; Martínez, Rubén; García, Laura Pérez; Zambrano, Alberto; Aranda, Ana

doi:10.1007/s12094-008-0221-x

Cited by 102 publications

(66 citation statements)

References 29 publications

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“…BACH1 was previously shown to form a repressive complex containing p53, HDAC1, and the nuclear cofactor NcoR that regulates cellular senescence in mouse embryonic fibroblasts (21). To investigate the involvement of HDACs in BACH1 regulation of itself and RKIP, we tested two histone deacetylase inhibitors (HDACi) that inhibit class I and II deacetylases: trichostatin A (TSA), a natural compound with high cell toxicity, and vorinostat (SAHA), a synthetic derivative of hydroxamic acid that is the first HDACi approved by the Food and Drug Administration for clinical use in cancer patients (26). Because inhibition of HDACs causes acetylation of lysine residues on histones, and thus transcriptional activation of regulated genes, we anticipated a derepression of BACH1 transcription following HDACi treatment.…”

Section: Bach1 Negativelymentioning

confidence: 99%

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Lee

Farquhar

et al. 2014

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

134

166

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The sources and consequences of nongenetic variability in metastatic progression are largely unknown. To address these questions, we characterized a transcriptional regulatory network for the metastasis suppressor Raf kinase inhibitory protein (RKIP). We previously showed that the transcription factor BACH1 is negatively regulated by RKIP and promotes breast cancer metastasis. Here we demonstrate that BACH1 acts in a double-negative (overall positive) feedback loop to inhibit RKIP transcription in breast cancer cells. BACH1 also negatively regulates its own transcription. Analysis of the BACH1 network reveals the existence of an inverse relationship between BACH1 and RKIP involving both monostable and bistable transitions that can potentially give rise to nongenetic variability. Single-cell analysis confirmed monostable and bistablelike behavior. Treatment with histone deacetylase inhibitors or depletion of the polycomb repressor enhancer of zeste homolog 2 altered relative RKIP and BACH1 levels in a manner consistent with a prometastatic state. Together, our results suggest that the mutually repressive relationship between metastatic regulators such as RKIP and BACH1 can play a key role in determining metastatic progression in cancer.ancer progression is an evolutionary process of variant cells competing to expand first locally and then distally within the human body. Ultimately, tumor evolution generates metastatic lesions that account for over 90% of cancer deaths (1). Whereas the requirement of heritably variant cells for tumor progression is undisputed, how they emerge is much less clear. Traditionally, genetic mutations causing oncogene activation or tumor suppressor loss were considered essential (2). However, accumulating evidence for tumor-promoting epigenetic, microenvironmental, and stochastic forms of heritable variation is challenging the traditional view (3, 4). Genetically identical tumor cells show highly variable responses to apoptosis-inducing ligands (5) and chemotherapeutic drugs (6, 7) attributable to cell-cell differences in gene expression and pathway activity. Tumor cells diversify in vitro (8) and in vivo (9) showing different levels of stem cell marker expression. However, the molecular mechanisms and interactions controlling such nongenetic forms of diversity are not fully known (10, 11).Multiple studies have implicated positive feedback loops in amplifying and maintaining stochastic fluctuations, creating heritable diversity in genetically homogenous cell populations (12, 13). This heritable nongenetic diversity then generates random subpopulations that can survive during various forms of environmental stress (14, 15), enabling subsequent evolutionary adaptation (16). Understanding how feedback loops and other network structures may affect nongenetic heterogeneity and contribute to metastatic cancer progression will be crucial for combating the disease (3, 10). However, the regulation of metastasis-related genes is incompletely understood, and the role of regulatory network-mediated n...

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Section: Bach1 Negativelymentioning

confidence: 99%

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Lee

Farquhar

et al. 2014

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

134

166

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“…The ability of the secoiridoid-rich EVOO-PE 7 to functionally restore the p53 pathway in p53-deficient JIMT-1 cells (13) while efficiently activating the G2/M checkpoint might suggest that natural phenolic molecules from EVOO might unexpectedly function as regulators of histone deacetylase (HDAC) activity. Although future studies appear necessary to definitely elucidate these putative intriguing mechanisms, it should be noted that secoiridoid-rich EVOO-PE 7 appeared to recapitulate wellknown effects of HDAC inhibitors (30,(66)(67)(68). Supporting this notion, treatment with the secoiridoid-rich EVOO-PE 7 markedly induced the expression of acetylated H3 histone proteins.…”

Section: Discussionmentioning

confidence: 75%

Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3

Menéndez¹

2011

Int J Oncol

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Abstract.Characterization of the molecular function of complex phenols naturally present in extra virgin olive oil (EVOO) against the HER2-gene amplified JIMT-1 cell line, a unique breast cancer model that inherently exhibits cross-resistance to multiple HER1/2-targeted drugs including trastuzumab, gefitinib, erlotinib and lapatinib, may underscore innovative cancer molecules with novel therapeutic targets because they should efficiently circumvent de novo resistance to HER1/2 inhibitors in order to elicit tumoricidal effects. We identified pivotal signaling pathways associated with the efficacy of crude phenolic extracts (PEs) obtained from 14 monovarietals of Spanish EVOOs. i) MTT-based cell viability and HPLC coupled to time-of-flight (TOF) mass spectrometry assays revealed that anti-cancer activity of EVOO PEs positively correlated with the phenolic index (i.e., total content of phenolics) and with a higher presence of the complex polyphenols secoiridoids instead of lignans. ii) Genome-wide analyses using 44 K Agilent's whole human arrays followed by Gene Set Enrichment Analysis (GSEA)-based screening of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database revealed a differential modulation of the JIMT-1 transcriptome at the level of the cell cycle and p53 pathways. EVOO PEs differentially impacted the expression status of stress-sensing, G2-M checkpoint-related GADD45 genes and of p53-related CDKN1A, CDKN1C and PMAIP-1 genes. iii) Cell cycle and fluorescence microscopy analyses confirmed that secoiridoid-rich EVOO PE inhibited mitosis to promote G2-M cell cycle arrest. This was accompanied with the appearance of diffuse, even DNA staining with γH2AX and pan-nuclear hyperacetylation of Histone H3 at Lysine 18. iv) Semi-quantitative Signaling Node Multi-Target ELISAs determined that secoiridoid-rich EVOO PE drastically activated the mitogen-activated protein kinases MEK1 and p38 MAPK, a GADD45-related kinase involved in Histone H3 acetylation. Secoiridoids, a family of complex polyphenols characteristic of Oleaceae plants, appear to permit histones to remain in hyperacetylated states and through the resulting alterations in gene regulation to reduce mitotic viability and metabolic competence of breast cancer cells inherently refractory to HER-targeting therapies ab initio. Oleaceae secoiridoids could provide a valuable phytochemical platform for the design of more pharmacologically active secondgeneration phytopharmaceutical anti-breast cancer molecules with a unique mode of action.

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“…However, the link between hydroxycapsaicin-induced hyperacetylation and induction of cell-cycle arrest and apoptosis in both HT29 and HCT116 cells (Figures 2 and 3) remains to be investigated. There are 11 family members of zinc-dependent HDACs (Martinez-Iglesias et al, 2008;Mark and Xu, 2009), which commonly have a narrow pocket and zinc (Zn 2+ ) ion in the catalytic site. The general structural characteristics of TSA and SAHA that strongly inhibit zinc-dependent HDAC isozymes include a zincbinding moiety, an opposite capping group, and a straightchain alkyl linker connecting the zinc-binding moiety and the capping group (Finnin et al, 1999;Mark and Xu, 2009).…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitory activity of hydroxycapsaicin, a synthetic derivative of capsaicin, and its cytotoxic effects against human colon cancer cell lines

Senawong¹,

Wongphakham²,

Saiwichai³

et al. 2015

Turk J Biol

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Capsaicin possesses cytotoxic/anticancer activity and shares some common structural features, including a benzene ring and a long hydrophobic carbon tail, with the histone deacetylase (HDAC) inhibitors trichostatin A and suberoylanilide hydroxamic acid. The aims of this study were to investigate HDAC inhibitory and cytotoxic activities of a synthetic derivative of capsaicin, hydroxycapsaicin (6-hydroxy-N-(4-hydroxy-3-methoxybenzyl)-8-methylnonenamide), in colon cancer cell lines. Hydroxycapsaicin inhibited HDAC activity in vitro (IC 50 = 72 µM) much more effectively than the prototype capsaicin (IC 50 > 13.1 mM) and also exhibited HDAC inhibitory activity in human cells (HeLa cells). MTT assay demonstrated that hydroxycapsaicin was less toxic than capsaicin against both cancer and noncancer cells; however, hydroxycapsaicin, with greater HDAC inhibitory activity, was more effective than capsaicin at inducing apoptosis in colon cancer cell lines, especially in HCT116 cells. Hydroxycapsaicin appeared to induce less apoptotic cell death than capsaicin in Vero cells. Moreover, only hydroxycapsaicin induced S-phase cell-cycle arrest in both HT29 and HCT116 cells. The current study demonstrates that hydroxycapsaicin can act as a novel HDAC inhibitor, which would lead to a promising strategy for the development of safe and effective chemotherapeutic drugs from the abundant natural capsaicin of chili pepper.

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Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer

Cited by 102 publications

References 29 publications

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Network of mutually repressive metastasis regulators can promote cell heterogeneity and metastatic transitions

Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3

Histone deacetylase inhibitory activity of hydroxycapsaicin, a synthetic derivative of capsaicin, and its cytotoxic effects against human colon cancer cell lines

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