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At least 271 records · Page 15Linked to original sources
PubMed2006

Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate-sensitive or imatinib mesylate-resistant chronic myelogenous leukemia cells.

PURPOSE: We determined the effects of vorinostat [suberoylanilide hydroxamic acid (SAHA)] and/or dasatinib, a dual Abl/Src kinase (tyrosine kinase) inhibitor, on the cultured human (K562 and LAMA-84) or primary chronic myelogenous leukemia (CML) cells, as well as on the murine pro-B BaF3 cells with ectopic expression of the unmutated and kinase domain-mutant forms of Bcr-Abl. EXPERIMENTAL DESIGN: Following exposure to dasatinib and/or vorinostat, apoptosis, loss of clonogenic survival, as well as the activity and levels of Bcr-Abl and its downstream signaling proteins were determined. RESULTS: Treatment with dasatinib attenuated the levels of autophosphorylated Bcr-Abl, p-CrkL, phospho-signal transducer and activator of transcription 5 (p-STAT5), p-c-Src, and p-Lyn; inhibited the activity of Lyn and c-Src; and induced apoptosis of the cultured CML cells. Combined treatment of cultured human CML and BaF3 cells with vorinostat and dasatinib induced more apoptosis than either agent alone, as well as synergistically induced loss of clonogenic survival, which was associated with greater depletion of Bcr-Abl, p-CrkL, and p-STAT5 levels. Cotreatment with dasatinib and vorinostat also attenuated the levels of Bcr-AblE255K and Bcr-AblT315I and induced apoptosis of BaF3 cells with ectopic expression of the mutant forms of Bcr-Abl. Finally, cotreatment of the primary CML cells with vorinostat and dasatinib induced more loss of cell viability and depleted Bcr-Abl or Bcr-AblT315I, p-STAT5, and p-CrkL levels than either agent alone. CONCLUSIONS: As shown here, the preclinical in vitro activity of vorinostat and dasatinib against cultured and primary CML cells supports the in vivo testing of the combination in imatinib mesylate-sensitive and imatinib mesylate-resistant CML cells.

Animals↗
PubMedDate not supplied

Further studies on the protein conjugation of hydroxamic acid bifunctional chelating agents: group-specific conjugation at two different loci.

A procedure utilizing an activated ester approach for conjugation of unprotected hydroxamic acids to antibodies and peptides was recently reported. Here, an alternative method with advantages over the activated ester strategy is described. This protocol utilizes the hydrazone formation between a hydrazide derivative of the trihydroxamate ligand trisuccin and either a ketone derivative of antibody or the aldehyde groups, generated by oxidation of the carbohydrate residues. Thus, the trisuccin carboxylic acid (1) was derivatized with tert-butyl carbazate to the hydrazide 2, and the protecting groups were removed by catalytic hydrogenation and acidolysis with TFA to afford the hydroxamate hydrazide 4. Conjugation of 4 to monoclonal antibody CC49 was effected by two approaches: attachment through the amine (e.g., lysine) residues of the antibody or oxidation of the carbohydrate residues. The extent of conjugations were monitored by MALDI, through evaluation of the increases in molecular weights of the conjugates compared to the unconjugated antibody. The first approach utilizing a ketone linker (6-oxoheptanoic acid, OHA) which served as a hydrazide anchor, is being introduced in this report as a new technique for conjugation of hydrazide derivatives to proteins. The OHA approach proved to be a superior strategy over the aldehyde approach in the ease of the procedure and yield of protein recovery. It also had the advantage of yielding more control in adjusting the ligand-to-protein ratio and was therefore selected for protocol optimization. All conjugates resulting from both approaches were radiolabeled with 125I and screened for their immunoreactivity. Furthermore, the conjugates prepared through the optimized OHA protocol were radiolabeled with both 99mTc and 125I for which the radiolabeling yields and immunoreactivities are reported.

Antibodies, Monoclonal↗
PubMed2001

Synthesis and evaluation of steroidal hydroxamic acids as inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase).

With the aim of developing new inhibitors of 17 alpha-hydroxylase/C17,20-lyase (P450 17, CYP 17), two steroidal hydroxamic acids (compounds 2 and 3) were synthesized and evaluated as inhibitors of CYP 17. The synthesis was performed using carboxylic acids as starting material to give acid chlorides which were reacted with N,N,O-tris(trimethylsilyl) hydroxylamine. Using microsomal fractions of human and rat testes and progesterone as a substrate, both compounds moderately inhibited the human and rat enzyme.

Animals↗
PubMed2005

High turbulence liquid chromatography online extraction and tandem mass spectrometry for the simultaneous determination of suberoylanilide hydroxamic acid and its two metabolites in human serum.

A reliable and sensitive method incorporating high turbulence liquid chromatography (HTLC) online extraction with tandem mass spectrometry (MS/MS), for simultaneous determination of suberoylanilide hydroxamic acid (SAHA) and its two metabolites, SAHA-glucuronide (M1) and 4-anilino-4-oxobutanoic acid (M2), in human serum, has been developed to support clinical studies. The HTLC technology significantly reduces the time required for sample clean-up since sample extraction and analysis are performed online. Clinical samples, internal standards (IS) and buffer are transferred into 96-well plates using a robotic liquid handling system. A 20 microL aliquot of prepared sample is directly injected into the HTLC/LC-MS/MS system where the matrix is rapidly washed away to waste and the analytes are retained on the narrow-bore extraction column (0.5 x 50 mm), using an aqueous mobile phase at 1.5 mL/min. Analytes are then eluted from the extraction column and transferred to the analytical column using a gradient mobile phase prior to detection by MS/MS. Interference with determination of SAHA from in-source dissociation of M1 is eliminated by the chromatographic separation. The resolution of SAHA and M1 did not change for more than 1500 serum sample injections by applying an acid wash (15% acetic acid) on the extraction column. The linear calibration ranges for SAHA, M1, and M2 are 2-500, 5-2000, and 10-2000 ng/mL, respectively. Assay intraday validation was conducted using five calibration curves prepared in five lots of human control serum. The precision expressed as relative standard deviation (RSD) is less than 6.8% and accuracy is 94.6-102.9% of nominal values for all three analytes. Assay specificity, freeze/thaw stability, storage stability, and matrix effects were also assessed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Microsome- and hepatocyte-mediated mutagenicity of hydroxyurea and related aliphatic hydroxamic acids in V79 Chinese hamster cells.

The potential of N-hydroxyurea to induce gene mutations in V79 Chinese hamster cells was investigated. Upon metabolic activation by liver microsomes from phenobarbital-treated rats or by isolated rat hepatocytes co-cultured with the V79 cells, hydroxyurea caused a concentration-dependent increase in the frequency of HGPRT-deficient mutants. Hydroxyurea was not mutagenic in the absence of metabolic activation. Addition of catalase inhibited microsome-mediated mutagenicity, indicating that hydrogen peroxide was involved in the formation of the mutagenic DNA lesion. Acetohydroxamic acid and N-hydroxyurethane also induced hepatocyte-mediated mutagenicity, suggesting that the potential to elicit metabolism-dependent mutagenicity may be a common property of aliphatic hydroxamic acids.

Animals↗
PubMed2005

Suberoylanilide hydroxamic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing nuclear factor-kappaB activation.

Because of its ability to suppress tumor cell proliferation, angiogenesis, and inflammation, the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials. How SAHA mediates its effects is poorly understood. We found that in several human cancer cell lines, SAHA potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents and inhibited TNF-induced invasion and receptor activator of NF-kappaB ligand-induced osteoclastogenesis, all of which are known to require NF-kappaB activation. These observations corresponded with the down-regulation of the expression of anti-apoptotic (IAP1, IAP2, X chromosome-linked IAP, Bcl-2, Bcl-x(L), TRAF1, FLIP, and survivin), proliferative (cyclin D1, cyclooxygenase 2, and c-Myc), and angiogenic (ICAM-1, matrix metalloproteinase-9, and vascular endothelial growth factor) gene products. Because several of these genes are regulated by NF-kappaB, we postulated that SAHA mediates its effects by modulating NF-kappaB and found that SAHA suppressed NF-kappaB activation induced by TNF, IL-1beta, okadaic acid, doxorubicin, lipopolysaccharide, H(2)O(2), phorbol myristate acetate, and cigarette smoke; the suppression was not cell type-specific because both inducible and constitutive NF-kappaB activation was inhibited. We also found that SAHA had no effect on direct binding of NF-kappaB to the DNA but inhibited sequentially the TNF-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha ubiquitination, IkappaBalpha degradation, p65 phosphorylation, and p65 nuclear translocation. Furthermore, SAHA inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NF-kappaB-inducing kinase, IkappaBalpha kinase, and the p65 subunit of NF-kappaB. Overall, our results indicated that NF-kappaB and NF-kappaB-regulated gene expression inhibited by SAHA can enhance apoptosis and inhibit invasion and osteoclastogenesis.

Animals↗
PubMed2005

Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo.

Current treatment modalities for malignant gliomas do not allow long-term survival. Here, we identify suberoylanilide hydroxamic acid (SAHA), an inhibitor of histone deacetylases (HDAC), as an effective experimental anti-glioma agent. Administration of SAHA to various glioma cell lines obtained from human, rat and mouse inhibited tumour cell growth in a range of 1-10 microm. This anti-glioma property is associated with up-regulation of the cell cycle control protein p21/WAF, as well as the induction of apoptosis. A novel tumour invasion model using slice cultures of rat brain corroborated the anti-glioma properties of SAHA in the organotypic brain environment. In this model, glioma invasion compromised adjacent brain parenchyma, and this tumour-associated cytotoxicity could be inhibited by SAHA. In addition, a 10-fold dose escalation experiment did not challenge the viability of cultured brain slices. In vivo, a single intratumoural injection of SAHA 7 days after orthotopic implantation of glioma cells in syngeneic rats doubled their survival time. These observations identify chromatin-modifying enzymes as possible and promising targets for the pharmacotherapy of malignant gliomas.

Acetylation↗
PubMed2001

Hydroxamic acids as weak base indicators: protonation in strong acid media.

The protonation equilibria of N-phenylbenzohydroxamic, benzohydroxamic, salicylhydroxamic, and N-p-tolylcinnamohydroxamic acids have been studied at 25 degrees C in concentrated sulfuric, hydrochloric, and perchloric acid media; the UV-vis spectral measurements were analyzed using the Hammett equation and the Bunnett-Olsen and excess acidity methods. The medium effects observed in the UV spectral curves were corrected with the Cox-Yates and vector analysis methods. The H(A) acidity function based on benzamides provided the best results. The range of variation of the solvation coefficient m is similar to that of amides, this indicating similar solvation requirements for amides and hydroxamic acids. For the same substrate, the observed variations of pK(BH)(+) with the mineral acid used was justified by formation of solvent-separated ion pairs; for the same mineral acid, the observed changes in pK(BH)(+) can be explained by the solvation of BH(+). The change of the pK(BH)(+) values was in reasonably good agreement with the sequence of the catalytic efficiency of the mineral acids used, HCl > H(2)SO(4) > HClO(4).

Acid-Base Equilibrium↗
PubMed1999

Analysis of the binding of hydroxamic acid and carboxylic acid inhibitors to the stromelysin-1 (matrix metalloproteinase-3) catalytic domain by isothermal titration calorimetry.

Matrix metalloproteinases (MMPs) are implicated in diseases such as arthritis and cancer. Among these enzymes, stromelysin-1 can also activate the proenzymes of other MMPs, making it an attractive target for pharmaceutical design. Isothermal titration calorimetry (ITC) was used to analyze the binding of three inhibitors to the stromelysin catalytic domain (SCD). One inhibitor (Galardin) uses a hydroxamic acid group (pK(a) congruent with 8.7) to bind the active site zinc; the others (PD180557 and PD166793) use a carboxylic acid group (pK(a) congruent with 4.7). Binding affinity increased dramatically as the pH was decreased over the range 5.5-7.5. Experiments carried out at pH 6.7 in several different buffers revealed that approximately one and two protons are transferred to the enzyme-inhibitor complexes for the hydroxamic and carboxylic acid inhibitors, respectively. This suggests that both classes of inhibitors bind in the protonated state, and that one amino acid residue of the enzyme also becomes protonated upon binding. Similar experiments carried out with the H224N mutant gave strong evidence that this residue is histidine 224. DeltaG, DeltaH, DeltaS, and DeltaC(p) were determined for the three inhibitors at pH 6.7, and DeltaC(p) was used to obtain estimates of the solvational, translational, and conformational components of the entropy term. The results suggest that: (1) a polar group at the P1 position can contribute a large favorable enthalpy, (2) a hydrophobic group at P2' can contribute a favorable entropy of desolvation, and (3) P1' substituents of certain sizes may trigger an entropically unfavorable conformational change in the enzyme upon binding. These findings illustrate the value of complete thermodynamic profiles generated by ITC in discovering binding interactions that might go undetected when relying on binding affinities alone.

Binding Sites↗
PubMed2005

Effects of suberoylanilide hydroxamic acid and trichostatin A on induction of cytochrome P450 enzymes and benzo[a]pyrene DNA adduct formation in human cells.

In this study, we investigated the effects of histone deacetylase (HDAC) inhibitors suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) on the metabolism of polycyclic aromatic hydrocarbons (PAH) in human mammary carcinoma derived MCF-7 cells in culture. Benzo[a]pyrene (B[a]P) induces cytochrome P450 (CYP) 1A1, CYP1B1 and other xenobiotic metabolizing enzymes. Results from our study indicated a significant increase in CYP activity in comparison to vehicle control in cells treated with SAHA or TSA as measured by ethoxyresorufin-O-deethylase assay. However, co-treatment with 1.0 microM SAHA and BP, reduced the mRNA levels of CYP1B1 relative to B[a]P alone. When co-treated with 1.0 microM TSA and BP, a reduction in the mRNA levels of both CYP1A1 and CYP1B1 was observed relative to BP alone. We further investigated to ascertain if the differential expression and activity of CYP1A1 and CYP1B1 influenced levels of B[a]P DNA adduct formation. MCF-7 cells co-treated with B[a]P and SAHA or TSA formed DNA adducts, although no significant differences in levels of DNA binding were revealed. These results suggest that while CYP enzyme activity and gene expression were affected by the HDAC inhibitors SAHA and TSA, they had no apparent influence on B[a]P DNA binding.

Antineoplastic Agents↗
PubMed2005

A new simple and high-yield synthesis of suberoylanilide hydroxamic acid and its inhibitory effect alone or in combination with retinoids on proliferation of human prostate cancer cells.

We have developed a procedure for the synthesis of N-hydroxy-N(1)-phenyloctanediamide (suberoylanilide hydroxamic acid (SAHA)), providing the product in 79.8% yield. SAHA is a potent inhibitor of histone deacetylase, induces differentiation and/or apoptosis in certain transformed cells in culture, and suppressed the growth of human prostate cancer LNCaP and PC-3 cell lines. The combination of SAHA with other compounds inhibited cell proliferation of LNCaP cells in additive fashion and resulted in synergistic growth inhibition.

Antineoplastic Agents↗
PubMed2005

Suberoylanilide hydroxamic acid combined with gemcitabine enhances apoptosis in non-small cell lung cancer.

BACKGROUND: We have shown that non-small cell lung cancer (NSCLC) is resistant to the histone deacetylase inhibitor (HDI) suberoylanilide hydroxamic acid (SAHA) through upregulation of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB). HDIs also promote chromatin remodeling, potentially making the DNA more accessible to chemotherapy. We hypothesize that combined SAHA and gemcitabine sensitizes NSCLC to apoptosis. METHODS: Three NSCLC cell lines (A549, H358, H460) were untreated, or treated with SAHA, gemcitabine, or both agents. NF-kappaB-dependent transcription was determined by reporter gene assays, reverse transcriptase-polymerase chain reaction RT-PCR, and Western blot analysis for the NF-kappaB-regulated antiapoptotic gene MnSOD. Survival of NSCLC cells overexpressing Bfl/A1, Bcl-X(L), or MnSOD and treated with SAHA and gemcitabine was determined in the presence or absence of NF-kappaB. Survival of treated cells overexpressing HDAC-1, 2, 3 or p/CAF was determined. Apoptosis was determined by fluorescence-activated cell sorter analysis, DNA fragmentation, and caspase-3 activity. Colony formation assays were performed on cells treated concurrently and sequentially with SAHA and gemcitabine. Assays were performed in triplicate, and the Student t test was applied as appropriate. RESULTS: SAHA-activated NF-kappaB (P <or= .05) and gemcitabine inhibited these effects (P <or= .01). Increased cell survival was observed after overexpression of antiapoptotic genes, as well as in cells overexpressing HDAC-1, -2, and -3. Fluorescence-activated cell sorter analysis, DNA fragmentation, and caspase-3 assays all showed enhanced apoptosis with combined therapy, compared with single-agent therapy (P <or= .01). Sequential treatment offered no improvement over concurrent treatment. CONCLUSIONS: Combined SAHA and gemcitabine sensitized NSCLC cells to apoptosis. Potential "proapoptotic" mechanisms for this finding include gemcitabine inhibition of SAHA-induced NF-kappaB activation and chromatin remodeling mediated by the inhibition of histone deacetylases.

Acetylation↗
PubMed2004

Pectin hydroxamic acids exhibit antioxidant activities in vitro.

Commercial pectins with different degrees of esterification (DE) were reacted with equal volumes of 2 M alkaline hydroxylamine (pH 12.0) at room temperature for 4 h to prepare pectin hydroxamic acids (PHAs; DE94T4, DE65T4, and DE25T4) according to a previously reported method (Hou et al., J. Agric. Food Chem. 2003, 51, 6362-6366) and were used to test the antioxidant and antiradical activities in comparison with those of DE94, DE65, and DE25 pectins. The half-inhibition concentrations, IC(50), of scavenging activity against DPPH were 1.51, 5.43, and 5.63 mg/mL for DE94T4, DE65T4, and DE25T4, respectively, and were much lower than those of corresponding DE pectins under the same concentrations. The scavenging activities of PHAs for DPPH radicals were positively correlated with original DE values of pectin. The optimal pH of DE94T4 for scavenging DPPH radicals was 7.9 or 8.0. Using electron spin resonance (ESR) for scavenging hydroxyl radicals, under the same concentrations of 125 microg/mL, DE94T4, DE65T4, and DE25T4, respectively, exhibited 73.53, 69.01, and 55.17% antiradical activities. PHAs also exhibited protection against hydroxyl radical-mediated DNA damage and anti-human low-density lipoprotein peroxidation tests.

Animals↗
PubMed2006

Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.

Animals↗
PubMed1989

Identification and evaluation of O-alkyl substituted hydroxamic acids as potent in vitro inhibitors of the hepatic glycine cleavage system and investigation of their action on in vivo central nervous system glycine concentration.

The identification and evaluation of an extensive series of O-alkyl substituted hydroxamic acids as potent in vitro inhibitors of the hepatic glycine cleavage system is described. An investigation of the action of selected examples on the in vitro brain glycine cleavage system and their influence on in vivo plasma and central nervous system glycine concentrations following systemic administration is also reported.

Animals↗
PubMed2005

Immobilized zinc affinity chromatography of pectin hydroxamic acids for purification of trypsin inhibitors from soybean and sweet potato.

Commercial pectin (with a 94% degree of esterification, DE94) suspended in methanol was reacted with methanolic alkaline hydroxylamine at room temperature for 20 h to prepare pectin hydroxamic acids (PHAs). The prepared PHA was coupled to the epoxy-activated Sepharose 6B gel to get immobilized PHA resins. The immobilized PHA resin was then balanced in column with 2 mM ZnCl2 in 50 mM Tris-HCl buffer (pH 7.9) to test the immobilized Zn-PHA gel as solid phase for immobilized metal affinity chromatography for the purification of trypsin inhibitors (TIs) from soybean and sweet potato. Using TI activity staining, it was found that purified TIs from the commercial soybean and sweet potato after trypsin affinity column purification could be adsorbed onto an immobilized Zn-PHA affinity column and eluted by 100 mM EDTA in 10 mM Tris-HCl buffer (pH 7.9). The immobilized Zn-PHA affinity column was used for TI purifications from crude extracts of sweet potato. The recovery of TI activity for one step was 90%, with 19.74-fold purification increase.

Chromatography, Affinity↗