Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1-11) and NAD ؉ -dependent enzymes (sirtuins 1-7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases ␣-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H2O2 reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to highmolecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.acetylation ͉ hydrogen peroxide ͉ histone deacetylase inhibitors
Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.anticancer agents | epigenetics-based chemotherapy | drug discovery H istone deacetylase 6 (HDAC6) is unique among the eleven zinc-dependent HDACs in humans. HDAC6 is located in the cytoplasm, and it has two catalytic domains and an ubiquitinbinding domain at the C-terminal region (1-3). This study focused on the development of a HDAC6-selective inhibitor and its biological effects. The substrates of HDAC6 include nonhistone proteins such as α-tubulin, peroxiredoxin (PRX), cortactin, and heat shock protein 90 (Hsp90) but not histones (4-7). HDAC6 plays a key role in the regulation of microtubule dynamics including cell migration and cell-cell interactions. The reversible acetylation of Hsp90, a substrate of HDAC6, modulates its chaperone activity and, accordingly, the stability of survival and antiapoptotic factors, including epidermal growth factor receptor (EGFR), protein kinase AKT, proto-oncogene C-RAF, survivin, and other factors. HDAC6, through its ubiquitin-binding activity and interaction with other partner proteins, plays a role in the degradation of misfolded proteins by binding polyubiquitinated proteins and delivering them to the dynein and motor proteins for transport into aggresomes which are degraded by lysosomes (8-10). Thus, HDAC6 has multiple biological functions through deacetylasedependent and -independent mechanisms modulating many cellular pathways relevant to normal and tumor cell growth, migration, and death. HDAC6 is an attractive target for potential cancer treatment.There are several previous reports on the development of HDAC6-selective inhibitors (11)(12)(13)(14)(15). The most extensively studied is tubacin (16,17). Tubacin has non-drug-like qualities, high lipophilicity, and difficult synthesis and has proved to be more useful as a research tool rather than as a potential drug (18). We and others (12)(13)(14)(15)19) have developed HDAC6-selective inhibitors whose pharmacokinetics, toxicity, and efficacy make them potentially more useful than tubacin as therapeutic agents. ACY-1215, 2-(Diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide, a HDAC6-selective inhibitor, is currently being evaluated in clinical trial...
We report the development of a potent, selective histone deacetylase 6 (HDAC6) inhibitor. This HDAC6 inhibitor blocks growth of normal and transformed cells but does not induce death of normal cells. The HDAC6 inhibitor alone is as effective as paclitaxel in anticancer activity in tumor-bearing mice.
Hexamethylenebisacetamide (HMBA), a potent inducer of differentiation of transformed cells such as murine erythroleukemia cells, causes a prolongation of the G, phase of the cell cycle during which commitment to terminal differentiation is first detected. Removal of HMBA prior to the G1 phase aborts commitment. To further derme the relationship between the G1 phase and commitment to differentiation, we used two inhibitors of cell cycle progression: aphidicolin, which blocks cells at the G1/S interphase, and deferoxamine, which blocks cells at an earlier stage during G1. HMBAinduced prolongation of G1 is associated with the accumulation of underphosphorylated retinoblastoma protein, decrease in cyclin A protein levels, and commitment to differentiation. G1 armst of murine erythroleukemia cells induced by aphidicolin or deferoxamine is not associated with accumulation of underphosphorylated retinoblastoma protein, suppression of cycll A protein, or commitment of cells to terminal differentiation. Neither of the cell cycle inhibitors alters the effect of HMBA in inducing the Gl-associated changes or commitment to differentiation. Taken together, the present fmdings indicate that the site of action of HMBA which leads to commitment is in a stage of the G1 phase prior to the point of cell cycle block caused by deferoxamine or aphidicolin. HMBA appears to cause cell differentiation with suppression of ceUl cycle progression by an action that affects events required for cell progression through G1, including accumulation of underphosphorylated retinoblastoma protein and changes in regulation of cyclin levels.Several studies indicate that the retinoblastoma-susceptibility gene product, the RB protein, is an important regulator of cell cycle progression (1-6). RB is a nuclear protein whose phosphorylation is regulated during progression of cells through the cell division cycle. The phosphorylation of RB appears necessary for the transition from G, to S phase and the underphosphorylated form ofRB is associated with arrest of cells in G1. It has been suggested that RB regulates transcription of growth-regulatory genes through its interaction with transcription factor E2F and possibly other factors (7-9). Recent evidence suggests that RB is a substrate of cyclin-dependent kinases (10)(11)(12). A series of steps must occur during the G1 phase for mammalian cells irreversibly to enter the S phase, including expression of various cyclins (e.g., cyclins D, E, and A) which associate with one or another of the cyclin-dependent kinases (10,11,(13)(14)(15). Regulation of expression of these cyclins and RB phosphorylation by extrinsic signals, such as growth factors (16) or chemical inducers of differentiation (6,17), are involved in the pathway determining cell proliferation or differentiation.
Histone deacetylase inhibitors (HDACi) are a new group of anticancer drugs with tumor selective toxicity. Normal cells are relatively resistant to HDACi-induced cell death compared with cancer cells. Previously, we found that vorinostat induces DNA breaks in normal and transformed cells, which normal but not cancer cells can repair. In this study, we found that checkpoint kinase 1 (Chk1), a component of the G2 DNA damage checkpoint, is important in the resistance of normal cells to HDACi in vitro and in vivo. Inhibition of Chk1 activity with Chk1 inhibitor (UCN-01, AZD7762, or CHIR-124) in normal cells increases their sensitivity to HDACi (vorinostat, romidepsin, or entinostat) induced cell death, associated with extensive mitotic disruption. Mitotic abnormalities included loss of sister chromatid cohesion and chromosomal disruption. Inhibition of Chk1 did increase HDACi-induced cell death of transformed cells. Thus, Chk1 is an important factor in the resistance of normal cells, and some transformed cells, to HDACi-induced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.