h-89 has been researched along with Neoplasms* in 8 studies
8 other study(ies) available for h-89 and Neoplasms
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Design, synthesis, biological evaluation, and molecular docking of novel benzopyran and phenylpyrazole derivatives as Akt inhibitors.
By inspiration of good Akt1 inhibitory and cytotoxic activity of our previously screened hits 1 and 2, a series of novel benzopyrans 3a-c, 4 and phenylpyrazoles 5a-c, 6a-b, and 7 were designed, synthesized, and biologically evaluated for their in vitro Akt1 inhibitory and cytotoxic activity. The results revealed that all of these compounds showed moderate-to-excellent antiproliferative effects against the tested cancer cell lines (i.e. HL-60, OVCAR, PC-3, and HepG2). Among them, compounds 3a and 3c exhibited preferable Akt1 inhibitory activities (IC(50) of 3a and 3c are 6.18 and 5.28 μm, respectively), while compounds 4, 5a-c, 6a-b, and 7 only showed weak Akt1 inhibitory activities. Consequently, we used molecular docking and dynamic simulation to propose a mode of binding between Akt1 and the 3c compound. Topics: Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Models, Molecular; Neoplasms; Proto-Oncogene Proteins c-akt; Pyrazoles | 2015 |
PKA/CREB regulates the constitutive promoter activity of the USP22 gene.
The human ubiquitin-specific processing enzyme 22 (USP22) plays a crucial role in regulating cell cycle processes and its overexpression has been linked to tumor progression. However, the mechanisms leading to USP22 transcriptional activation in human cancer cells are still unclear. Previously, we characterized the 5'-flanking sequence of the human USP22 gene and found a potential CREB/ATF binding site within the basic promoter region. The present study found that this site was required for constitutive USP22 transcriptional activity in HeLa and HepG2 cells. Chromatin immunoprecipitation assay confirmed that CREB interacted with this site. siRNA knockdown of CREB decreased USP22 transcriptional activation and endogenous expression, whereas CREB overexpression did not affect transcriptional levels. Furthermore, USP22 promoter activity and expression were decreased by inhibiting PKA with H-89, but were not responsive to forskolin induction. All of these results demonstrate that PKA/CREB is involved in the regulation of constitutive promoter activity of the USP22 gene. Topics: Binding Sites; Cell Line, Tumor; Chromatin Immunoprecipitation; Colforsin; Cyclic AMP Response Element-Binding Protein; HeLa Cells; Hep G2 Cells; Humans; Isoquinolines; Mutation; Neoplasms; Promoter Regions, Genetic; Protein Kinase Inhibitors; RNA Interference; RNA, Small Interfering; Sulfonamides; Thiolester Hydrolases; Transcriptional Activation; Ubiquitin Thiolesterase | 2015 |
H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway.
High doses of the organic nitrate glyceryl trinitrate (GTN), a nitric oxide (NO) donor, are known to trigger apoptosis in human cancer cells. Here, we show that such a cytotoxic effect can be obtained with subtoxic concentrations of GTN when combined with H89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide.2HCl. This synergistic effect requires the generation of reactive oxygen species (ROS) from H89 and NO from GTN treatment that causes cGMP production and PKG activation. Furthermore, the GTN/H89 synergy was attenuated by inhibition of P2-purinergic receptors with suramin and competition with ATP/UDP. By down-regulating genes with antisense oligonucleotides, P2-purinergic receptors P2X3, P2Y1, and P2Y6 were found to have a role in creating this cytotoxic effect. Thus, H89 likely acts as an ATP mimetic synergizing with GTN to trigger apoptosis in aggressive cancer cells. Topics: Adenosine Triphosphate; Animals; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Gene Expression Profiling; Humans; Isoquinolines; Membrane Potential, Mitochondrial; Mice; Neoplasms; Nitric Oxide; Nitroglycerin; Oligonucleotides, Antisense; Protein Kinase Inhibitors; Reactive Oxygen Species; Receptors, Purinergic; Receptors, Purinergic P2; Receptors, Purinergic P2X3; Receptors, Purinergic P2Y1; Signal Transduction; Sulfonamides; Transfection | 2015 |
Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: toward the discovery of novel Akt1 inhibitors.
A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain(2) = 0.948, Rtest(2) = 0.907 and Qcv(2) = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a-d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors. Topics: Cell Line, Tumor; Cell Proliferation; Drug Discovery; Humans; Molecular Docking Simulation; Neoplasms; Proto-Oncogene Proteins c-akt; Pyrimidines; Quantitative Structure-Activity Relationship | 2014 |
PP2A inactivation is a crucial step in triggering apoptin-induced tumor-selective cell killing.
Apoptin (apoptosis-inducing protein) harbors tumor-selective characteristics making it a potential safe and effective anticancer agent. Apoptin becomes phosphorylated and induces apoptosis in a large panel of human tumor but not normal cells. Here, we used an in vitro oncogenic transformation assay to explore minimal cellular factors required for the activation of apoptin. Flag-apoptin was introduced into normal fibroblasts together with the transforming SV40 large T antigen (SV40 LT) and SV40 small t antigen (SV40 ST) antigens. We found that nuclear expression of SV40 ST in normal cells was sufficient to induce phosphorylation of apoptin. Mutational analysis showed that mutations disrupting the binding of ST to protein phosphatase 2A (PP2A) counteracted this effect. Knockdown of the ST-interacting PP2A-B56γ subunit in normal fibroblasts mimicked the effect of nuclear ST expression, resulting in induction of apoptin phosphorylation. The same effect was observed upon downregulation of the PP2A-B56δ subunit, which is targeted by protein kinase A (PKA). Apoptin interacts with the PKA-associating protein BCA3/AKIP1, and inhibition of PKA in tumor cells by treatment with H89 increased the phosphorylation of apoptin, whereas the PKA activator cAMP partially reduced it. We infer that inactivation of PP2A, in particular, of the B56γ and B56δ subunits is a crucial step in triggering apoptin-induced tumor-selective cell death. Topics: Adaptor Proteins, Signal Transducing; Antigens, Polyomavirus Transforming; Apoptosis; Apoptosis Regulatory Proteins; Cell Line; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Fibroblasts; HeLa Cells; Humans; Isoquinolines; Neoplasms; Nuclear Proteins; Phosphorylation; Point Mutation; Protein Binding; Protein Phosphatase 2; Protein Subunits; RNA Interference; RNA, Small Interfering; Sulfonamides | 2012 |
Pharmacophore identification, virtual screening and biological evaluation of prenylated flavonoids derivatives as PKB/Akt1 inhibitors.
A total of 24 well-defined PKB/Akt1 inhibitors were used to generate pharmacophore models applying Catalyst/HypoGen program. The best ranked model (Hypo_1) was then validated by cost analysis, prediction capability, Cat-Scramble and receiver operating characteristic (ROC) studies. Then, pharmacophore-based virtual screening combined with docking study was performed to search an in-house compound database. Nine preferable hits 75-80, HTS-02143, BTB-14740 and HTS-08006 were prepared and biologically evaluated. Several compounds were identified as good PKB/Akt1 inhibitors, suggesting that Hypo_1 would be reliable and useful in virtual screening. Flow cytometric and western blotting analysis on compounds 79 and 80 further demonstrated that the inhibition of phosphorylation of PKB/Akt1 and its substrates (such as GSK3β) was responsible for their cytotoxic activities. Topics: 3-Phosphoinositide-Dependent Protein Kinases; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Design; Flavonoids; Humans; Models, Molecular; Neoplasms; Prenylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt | 2011 |
Homotypic gap junctional communication associated with metastasis suppression increases with PKA activity and is unaffected by PI3K inhibition.
Loss of gap junctional intercellular communication (GJIC) between cancer cells is a common characteristic of malignant transformation. This communication is mediated by connexin proteins that make up the functional units of gap junctions. Connexins are highly regulated at the protein level and phosphorylation events play a key role in their trafficking and degradation. The metastasis suppressor breast cancer metastasis suppressor 1 (BRMS1) upregulates GJIC and decreases phosphoinositide-3-kinase (PI3K) signaling. On the basis of these observations, we set out to determine whether there was a link between PI3K and GJIC in tumorigenic and metastatic cell lines. Treatment of cells with the well-known PI3K inhibitor LY294002, and its structural analogue LY303511, which does not inhibit PI3K, increased homotypic GJIC; however, we found the effect to be independent of PI3K/AKT inhibition. We show in multiple cancer cell lines of varying metastatic capability that GJIC can be restored without enforced expression of a connexin gene. In addition, while levels of connexin 43 remained unchanged, its relocalization from the cytosol to the plasma membrane was observed. Both LY294002 and LY303511 increased the activity of protein kinase A (PKA). Moreover, PKA blockade by the small molecule inhibitor H89 decreased the LY294002/LY303511-mediated increase in GJIC. Collectively, our findings show a connection between PKA activity and GJIC mediated by PI3K-independent mechanisms of LY294002 and LY303511. Manipulation of these signaling pathways could prove useful for antimetastatic therapy. Topics: Androstadienes; Cell Communication; Cell Line, Tumor; Cell Membrane; Chromones; Connexin 43; Cyclic AMP-Dependent Protein Kinases; Cytosol; Enzyme Activation; Enzyme Inhibitors; Fluoresceins; Fluorescent Antibody Technique; Gap Junctions; Humans; Immunoblotting; Isoquinolines; Morpholines; Neoplasm Metastasis; Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Signal Transduction; Sulfonamides; Wortmannin | 2010 |
Modulation of choline kinase activity in human cancer cells observed by dynamic 31P NMR.
Choline metabolites are widely studied in cancer research as biomarkers of malignancy and as indicators of therapeutic response. However, endogenous phosphocholine levels are determined by a number of processes that confound the interpretation of these measurements, including membrane transport rates and a series of enzyme catalysed reactions in the Kennedy pathway. Employing a dynamic (31)P NMR assay that is specific to choline kinase (ChoK) we have measured the rates of this enzyme reaction in cell lysates of MDA-MB-231 breast, PC-3 prostate and HeLa cervical cancer cells and in solutions of purified human ChoK. The rates are sensitive to inhibition by hemicholinium-3 (HC-3), a competitive ChoK inhibitor, and to N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulphonamide (H-89), an agent commercialized as a specific cyclic-AMP-dependent protein kinase A (PKA) inhibitor. Topics: Cell Line, Tumor; Choline Kinase; Humans; Isoquinolines; Magnetic Resonance Spectroscopy; Neoplasms; Phosphorus Isotopes; Phosphorylation; Sulfonamides; Time Factors | 2009 |