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PubMed2000

Cell surface-bound collagenase-1 and focal substrate degradation stimulate the rear release of motile vascular smooth muscle cells.

To migrate in the vessel wall, smooth muscle cells (SMCs) must contend with abundant type I collagen. We investigated the mechanisms used by human SMCs to efficiently migrate on type I collagen, following stimulation with fibroblast growth factor-2 (FGF-2). FGF-2-stimulated migration was inhibited by a hydroxamic acid inhibitor of matrix metalloproteinases and by a neutralizing anti-collagenase-1 antibody. Moreover, migration speed of SMCs plated on mutant collagenase-resistant type I collagen was not increased by FGF-2. Time-lapse video analysis of unstimulated SMCs migrating on collagen revealed discrete phases of leading edge membrane extension and rear retraction, the latter often after rupture of an elongated tail. FGF-2 stimulation yielded a more synchronous, gliding motion with a collagenase-1-mediated decrease in tail ripping. Surface labeling of SMCs with biotin followed by immunoprecipitation revealed that a proportion of active collagenase-1, expressed in response to FGF-2, was bound to the plasma membrane. Pericellular collagen substrate cleavage was verified by immunostaining for neoepitopes generated by collagenase-1 action and was localized to discrete zones beneath the cell tail and the leading edge. These results identify a novel mechanism by which SMC migration on collagen is enhanced, whereby rear release from the substrate is orchestrated by the localized actions of membrane-bound collagenase-1.

Animals↗
PubMed2005

A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin.

The zinc-dependent enzyme LpxC catalyzes the deacetylation of UDP-3-O-acyl-GlcNAc, the first committed step of lipid A biosynthesis. Lipid A is an essential component of the outer membranes of most Gram-negative bacteria, including Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa, making LpxC an attractive target for antibiotic design. The inhibition of LpxC by a novel N-aroyl-l-threonine hydroxamic acid (CHIR-090) from a recent patent application (International Patent WO 2004/062601 A2 to Chiron and the University of Washington) is reported here. CHIR-090 possesses remarkable antibiotic activity against both E. coli and P. aeruginosa, comparable to that of ciprofloxacin. The biological activity of CHIR-090 is explained by its inhibition of diverse LpxC orthologues at low nanomolar concentrations, including that of Aquifex aeolicus, for which structural information is available. The inhibition of A. aeolicus LpxC by CHIR-090 occurs in two steps. The first step is rapid and reversible, with a K(i) of 1.0-1.7 nM, depending upon the method of assay. The second step involves the conversion of the EI complex with a half-life of about a minute to a tightly bound form. The second step is functionally irreversible but does not result in the covalent modification of the enzyme, as judged by electrospray ionization mass spectrometry. CHIR-090 is the first example of a slow, tight-binding inhibitor for LpxC and may be the prototype for a new generation of LpxC inhibitors with therapeutic applicability.

Amidohydrolases↗
PubMed2005

Induction of polyploidy by histone deacetylase inhibitor: a pathway for antitumor effects.

Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21WAF1-/- or HCT116 p53-/- cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21WAF1 or p53 genes.

Antineoplastic Agents↗
PubMed2005

It's about time: scheduling alters effect of histone deacetylase inhibitors on camptothecin-treated cells.

Chemotherapeutic treatment with combinations of drugs is front-line therapy for many types of cancer. Combining drugs which target different signaling pathways often lessens adverse side effects while increasing the efficacy of treatment and reducing patient morbidity. A defined scheduling protocol is described by which histone deacetylase inhibitors (HDIs) facilitate the cytotoxic effectiveness of the topoisomerase I inhibitor camptothecin in the killing of tumor cells. Breast and lung cancer cell lines were treated with camptothecin and sodium butyrate (NaB) or suberoylanilide hydroxamic acid on the day of, the day before, or the day after camptothecin addition. Depending on the time of addition, NaB-treated cells displayed a spectrum of responses from protection to sensitization, indicating the critical nature of timing in the use of HDIs. The IC80 (72-hour assay) dose of 100 nmol/L camptothecin could be lowered to 15 nmol/L camptothecin while maintaining or surpassing cell killing of the single agent if combined with an HDI added 24 to 48 hours after camptothecin. Experiments determined that cells arrested in G2-M by camptothecin were most sensitive to subsequent HDI addition. Western blot analysis indicated that in camptothecin-arrested cells, NaB decreases cyclin B levels, as well as the levels of the antiapoptotic proteins XIAP and survivin. These findings suggest that reducing the levels of these critical antiapoptotic factors may increase the efficacy of topoisomerase I inhibitors in the clinical setting if given in a sequence that does not prevent or inhibit tumor cell progression through the S phase.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells.

Treatment with LAQ824 (Novartis Pharmaceutical, Inc.), a cinnamyl hydroxamic acid analogue inhibitor of histone deacetylases, depleted the mRNA and protein expression of Bcr-Abl in human chronic myeloid leukemia blast crisis (CML-BC) cells. Exposure to LAQ824 induced the expression of the cell cycle-dependent kinase inhibitors p21 and p27 and caused cell cycle G(1)-phase accumulation and apoptosis of CML-BC cells. LAQ824 also induced acetylation of heat shock protein 90. This inhibited the chaperone association of Bcr-Abl with heat shock protein 90, thereby promoting the proteasomal degradation of Bcr-Abl. Cotreatment with LAQ824 increased imatinib mesylate-induced apoptosis of CML-BC cells. Additionally, LAQ824 down-regulated the levels of mutant Bcr-Abl possessing the T315I point mutation, as well as induced apoptosis of imatinib-refractory primary CML-BC cells. Therefore, LAQ824 may be a promising therapeutic agent in the treatment of imatinib-sensitive or -refractory human leukemia.

Acetylation↗
PubMed2002

One-step SFE-plus-C(18) selective extraction of low-polarity compounds, with lipid removal, from smoked fish and bovine milk.

Co-extraction of lipid materials is the major source of interference in determinations of low-polarity compounds in many biological matrixes. "SFE-plus-C(18)", a recently developed supercritical fluid extraction method employing C(18) adsorbent in the extraction chamber, can enable selective extraction of low-polarity compounds in lipid-rich biological matrixes without a cleanup step. This study reports the application of the SFE-plus-C(18) method to the quantification of: 1. polycyclic aromatic hydrocarbons (PAH) in commercially purchased smoked fish; and 2. anti-cancer agents cyclophosphamide (CP) and suberoylanilide hydroxamic acid (SAHA) spiked into homogenized whole bovine milk. Over the course of SFE-plus-C(18)extraction, indigenous lipids are preferentially retained on the C(18) adsorbent. Compared with the conventional method, only 8-15% of the lipids in the smoked fish sample, and only 6-18% of the lipids in the milk sample, were co-extracted by SFE-plus-C(18). This reduction in the quantity of background lipids significantly improved chromatographic separations, retarded deterioration of the column, and dramatically improved the ability to quantify PAH present at trace levels in smoked fish by GC-MS. Using the SFE-plus-C(18) method, ten targeted PAH were detected in the range 9.5-13.5 ng g(-1) in the smoked fish sample. Compared with these levels, PAH extractions by use of conventional SFE gave values that were lower by 38-86%. Recoveries of CP and SAHA spiked into milk were close to 100% in both SFE-plus-C(18)and conventional SFE, where the lipid background during the chromatographic elution of CP and SAHA was not so severe.

Animals↗
PubMed2006

SAHA-sensitized prostate cancer cells to TNFalpha-related apoptosis-inducing ligand (TRAIL): mechanisms leading to synergistic apoptosis.

Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFalpha-Related Apoptosis-Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined even with the lowest dose of SAHA. Treatment with caspase inhibitor confirmed that SAHA-induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKalpha, IKKbeta and IKKgamma, suggesting that SAHA treatment may reduce the activity of NFkappaB. However, assay for NFkappaB luciferase reporter activity showed highly significant increase in SAHA-treated cells, supporting earlier suggestions that HDACi promotes NFkappaB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFkappaB activity at several regulatory steps.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Combined histone deacetylase and NF-kappaB inhibition sensitizes non-small cell lung cancer to cell death.

BACKGROUND: Non-small cell lung cancer (NSCLC) remains resistant to traditional and novel chemotherapeutic agents, relating, in part, to the activation of the antiapoptotic transcription factor NF-kappaB. We hypothesize that inhibition of NF-kappaB using BAY-11-7085 will sensitize NSCLC cells to death, induced by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). METHODS: Five tumorigenic NSCLC cell lines (A549, H157, H358, H460, H1299) were treated with nothing, SAHA, BAY-11-7085, or both compounds. Cell death was determined by crystal violet staining. p65 nuclear translocation was determined by Western blot analysis. NF-kappaB activity was determined by reporter-gene assays and by reverse transcriptase-polymerase chain reaction of the endogenous NF-kappaB-dependent gene interleukin 8. Apoptosis was determined by DNA fragmentation. Clonogenic cell survival assays were also performed. Data was analyzed with the Student t test when appropriate. RESULTS: SAHA alone resulted in no meaningful NSCLC cell death. SAHA induced nuclear translocation of p65, which was inhibited by BAY-11-7085. SAHA significantly induced NF-kappaB-dependent transcription which was ameliorated after treatment with BAY-11-7085 (P = .01). Combined SAHA and BAY-11-7085 induced significantly more apoptosis and cell death than either drug alone (P = .002). CONCLUSIONS: Combined HDI and NF-kappaB inhibition using BAY-11-7085 sensitizes NSCLC cells to cell death and appears promising as a novel treatment strategy for this disease.

Active Transport, Cell Nucleus↗
PubMed2005

Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes.

Despite advances in understanding the role of histone deacetylases (HDACs) in tumorigenesis, the mechanism by which HDAC inhibitors mediate antineoplastic effects remains elusive. Modifications of the histone code alone are not sufficient to account for the antitumor effect of HDAC inhibitors. The present study demonstrates a novel histone acetylation-independent mechanism by which HDAC inhibitors cause Akt dephosphorylation in U87MG glioblastoma and PC-3 prostate cancer cells by disrupting HDAC-protein phosphatase 1 (PP1) complexes. Of four HDAC inhibitors examined, trichostatin A (TSA) and HDAC42 exhibit the highest activity in down-regulating phospho-Akt, followed by suberoylanilide hydroxamic acid, whereas MS-275 shows only a marginal effect at 5 microm. This differential potency parallels the respective activities in inducing tubulin acetylation, a non-histone substrate for HDAC6. Evidence indicates that this Akt dephosphorylation is not mediated through deactivation of upstream kinases or activation of downstream phosphatases. However, the effect of TSA on phospho-Akt can be rescued by PP1 inhibition but not that of protein phosphatase 2A. Immunochemical analyses reveal that TSA blocks specific interactions of PP1 with HDACs 1 and 6, resulting in increased PP1-Akt association. Moreover, we used isozyme-specific small interfering RNAs to confirm the role of HDACs 1 and 6 as key mediators in facilitating Akt dephosphorylation. The selective action of HDAC inhibitors on HDAC-PP1 complexes represents the first example of modulating specific PP1 interactions by small molecule agents. From a clinical perspective, identification of this PP1-facilitated dephosphorylation mechanism underscores the potential use of HDAC inhibitors in lowering the apoptosis threshold for other therapeutic agents through Akt down-regulation.

Apoptosis↗
PubMed1997

A metalloprotease-inhibitor reduces pain associated behavior in mice with experimental neuropathy.

Tumor necrosis factor-alpha (TNF) is involved in the generation of inflammatory and neuropathic pain. The synthetic hydroxamic acid based metalloprotease inhibitor TAPI blocks cleavage of cell surface TNF and thus reduces levels of the mature 17-kDa TNF polypeptide in activated macrophages and T-cells. We have previously shown that pharmacologic inhibition of TNF production reduces pain related behaviors in mice with chronic constriction injury (CCI). Here we investigated whether blockage of TNF shedding by administration of TAPI would diminish hyperalgesia in animals with partial nerve injury. We injected 0.5 mg of the inhibitor epineurially once daily to mice with CCI for 7 days. The animals were tested for withdrawal thresholds to heat to test for thermal hyperalgesia and to von Frey hairs to assess mechanical allodynia. Mice with CCI developed thermal hyperalgesia and mechanical allodynia by day 3 after the injury. In mice treated with TAPI, a reduction of thermal hyperalgesia and mechanical allodynia of up to 50% occurred. Endoneurial TNF-immunoreactivity was reduced, but not immunoreactivity for IL-1alpha or IL-1beta. The numbers of degenerating axons and endoneurial macrophages were not affected by the treatment as compared to controls. We conclude that the metalloprotease inhibitor TAPI specifically reduces endoneurial TNF-levels after nerve injury and thereby may diminish neuropathic pain in the CCI-model.

Animals↗
PubMed2004

Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter-associated proteins, including HDAC1.

Histone deacetylase (HDAC) inhibitors (HDACi) cause cancer cell growth arrest and/or apoptosis in vivo and in vitro. The HDACi suberoylanilide hydroxamic acid (SAHA) is in phase I/II clinical trials showing significant anticancer activity. Despite wide distribution of HDACs in chromatin, SAHA alters the expression of few genes in transformed cells. p21(WAF1) is one of the most commonly induced. SAHA does not alter the expression of p27(KIPI), an actively transcribed gene, or globin, a silent gene, in ARP-1 cells. Here we studied SAHA-induced changes in the p21(WAF1) promoter of ARP-1 cells to better understand the mechanism of HDACi gene activation. Within 1 h, SAHA caused modifications in acetylation and methylation of core histones and increased DNase I sensitivity and restriction enzyme accessibility in the p21(WAF1) promoter. These changes did not occur in the p27(KIPI) or epsilon-globin gene-related histones. The HDACi caused a marked decrease in HDAC1 and Myc and an increase in RNA polymerase II in proteins bound to the p21(WAF1) promoter. Thus, this study identifies effects of SAHA on p21(WAF1)-associated proteins that explain, at least in part, the selective effect of HDACi in altering gene expression.

Acetylation↗
PubMed2003

NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma.

Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM.

Acetylation↗
PubMed2006

Apoptosis signal-regulating kinase 1 is a direct target of E2F1 and contributes to histone deacetylase inhibitor-induced apoptosis through positive feedback regulation of E2F1 apoptotic activity.

The oncogenic retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis as a fail-safe mechanism to protect aberrant oncogenic transformation. We have previously shown that histone deacetylase inhibitors (HDACIs) activate the E2F1-Bim apoptotic pathway, leading to efficient cell killing in cancer cells with deregulated E2F1 activity. To identify additional gene cassettes that might contribute HDACI-induced apoptosis upon E2F1 activation, we investigated the apoptotic transcriptional network affected by HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in cancer cells with inducible E2F1. Data analysis focusing on 220 apoptosis-related genes identified apoptosis signal-regulating kinase 1 (ASK1) as one of a few genes in addition to Bim that are substantially up-regulated by SAHA upon E2F1 activation. We show that ASK1 is directly regulated by E2F1 and that prevention of ASK1 induction by RNA interference decreases SAHA-induced apoptosis. We further show that the role of ASK1 in the SAHA apoptotic response is not associated with its downstream effectors p38 or JNK. Instead, ASK1 knockdown results in reduced E2F1 transcriptional activity, leading to decreased Bim induction by SAHA. Moreover, ASK1 expression reverses the negative effect of Rb on E2F1 activity. These results indicate that ASK1 induction by E2F1 provides positive feedback regulation of E2F1 activity via Rb inhibition, which allows an efficient E2F1-Bim activation. Thus, the concomitant induction of E2F1 targets ASK1 and Bim by HDACIs warrants an effective activation of E2F1-dependent apoptosis in response to SAHA.

Adenoviridae↗
PubMed1999

Direct determination of stability of protease inhibitors in plasma by HPLC with automated column-switching.

Automated column-switching HPLC methods were developed and utilized for the direct analyses of three hydroxamic acid based metalloprotease inhibitors in rat plasma. These column-switching methods involved the use of a restricted-access media (RAM) precolumn and a column-switching valve, allowing the complete automation of sample preparation and HPLC. The plasma samples were directly injected onto a precolumn packed with SPS/ODS stationary phase and then backflushed onto an ODS analytical column using a 6-port column-switching device. The drug stability in rat plasma was determined using both the automated and traditional HPLC methods. The results obtained from the automated column-switching methods were in good agreement with those from traditional methods that involve sequential protein precipitation, liquid extraction, solvent evaporation, and sample reconstitution. In addition to the elimination of labor-intensive and time-consuming sample preparation procedures, the column-switching methods allowed on-line analyte enrichment and accurate determination of drug stability in plasma with detection limits in the range of 10-20 ng/ml(-1). This work represents, for the first time, a drug stability study in plasma by automated column-switching HPLC technique with the use of a RAM column. Our column-switching methods can be readily adapted to any existing HPLC system with minimal hardware modification.

Animals↗
PubMed2006

Concentration of benzoxazinoids in roots of field-grown wheat (Triticum aestivum L.) varieties.

Benzoxazinones are naturally occurring secondary metabolites of some Gramineae plants, responsible for their resistance to some pathogenic fungi and for their allelopathic action. Six varieties of winter wheat grown in fields under organic or conventional systems and 11 old accessions were tested for two consecutive seasons and three plant development stages for the concentration in their roots of cyclic hydroxamic acids and their degradation products. This is the first report of six benzoxazinones analyzed in plants grown in the field. An analytical technique employing LC-DAD was used for determination. It was shown that 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one, its degradation product 6-methoxybenzoxazolin-2-one, and the lactam 2-hydroxy-7-methoxy-1,4-benzoxazin-2-one were predominant compounds in all tested samples. Their concentrations significantly differed with plant development stage and season, but no significant differences were found between varieties and between plant cultivation systems. The concentrations of 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) and its degradation product benzoxazolin-2-one (BOA) were much lower, ranging from 60 to 430 mg/kg of dry matter, depending on accession, stage of development, and season. There was no significant difference found between plants grown in different cultivation systems, but there were significant differences between old and new varieties; concentrations of DIBOA and its derivatives were significantly lower in old accessions. It was concluded that the concentrations of DIBOA and BOA, which are precursors of highly fungicidal 2-aminophenol, 2-amino-3H-phenoxazin-3-one, and 2-acetylamino-3H-phenoxazin-3-one, are theoretically high enough to protect plants against some soilborne pathogens.

Benzoxazines↗
PubMed2002

The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin.

Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-up-regulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.

Apoptosis↗
PubMed2002

Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling.

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.

Angiogenesis Inhibitors↗
PubMed2005

Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation.

NF-kappaB activation is reciprocally regulated by RelA/p65 acetylation and deacetylation, which are mediated by histone acetyltransferases (HATs) and deacetylases (HDACs). Here we demonstrate that in leukemia cells, NF-kappaB activation by the HDAC inhibitors (HDACIs) MS-275 and suberoylanilide hydroxamic acid was associated with hyperacetylation and nuclear translocation of RelA/p65. The latter events, as well as the association of RelA/p65 with IkappaBalpha, were strikingly diminished by either coadministration of the IkappaBalpha phosphorylation inhibitor Bay 11-7082 (Bay) or transfection with an IkappaBalpha superrepressor. Inhibition of NF-kappaB by pharmacological inhibitors or genetic strategies markedly potentiated apoptosis induced by HDACIs, and this was accompanied by enhanced reactive oxygen species (ROS) generation, downregulation of Mn-superoxide dismutase and XIAP, and c-Jun N-terminal kinase 1 (JNK1) activation. Conversely, N-acetyl L-cysteine blocked apoptosis induced by Bay/HDACIs by abrogating ROS generation. Inhibition of JNK1 activation attenuated Bay/HDACI lethality without affecting NF-kappaB inactivation and ROS generation. Finally, XIAP overexpression dramatically protected cells against the Bay/HDACI regimen but failed to prevent ROS production and JNK1 activation. Together, these data suggest that HDACIs promote the accumulation of acetylated RelA/p65 in the nucleus, leading to NF-kappaB activation. Moreover, interference with these events by either pharmacological or genetic means leads to a dramatic increase in HDACI-mediated lethality through enhanced oxidative damage, downregulation of NF-kappaB-dependent antiapoptotic proteins, and stress-related JNK1 activation.

Acetylation↗