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1.
Crit Rev Toxicol ; 49(4): 281-301, 2019 04.
Article in English | MEDLINE | ID: mdl-31106649

ABSTRACT

Phthalates are ubiquitous chemical compounds, and two-di-ethyl phthalate (DEP) and di-isobutyl phthalate (DiBP)-are not currently regulated by the U.S. Congress or the European Union. While many reviews of phthalates have been published, none have examined bone health, inflammation, or oxidative stress; anogenital distance was most recently reviewed in 2014. The objective of this paper is to determine if an association exists between mono-ethyl phthalate (MEP) or mono-isobutyl phthalate (MiBP), metabolites of DEP and DiBP, respectively, and the four outcomes indicated above. We conducted a literature search of PubMed through December 2017 and included 29 observational epidemiologic studies published in English that assessed MEP and/or MiBP in relation to one of the above four health outcomes in humans. Two authors rated each paper using a modified Downs and Black (DB) assessment tool; a third author settled score disagreements. A single author extracted information related to the study population, exposure and outcome assessment, covariates, and significant results from each article. Ten studies were identified on anogenital distance, four on bone health, five on inflammation, and thirteen on oxidative stress. Score percentages (total points given out of total possible points) were calculated for each study. The current research suggests a positive association between MiBP and two measures of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. MEP is potentially associated with 8-OHdG as well, although the evidence is limited by fewer high-quality studies. There does not appear to be an association between anogenital distance and MEP or MiBP, and it is unclear if relationships exist between these phthalate metabolites and bone health and inflammation. Given the role that oxidative stress plays in a number of diseases and the ubiquity of MEP and MiBP, it is important that individuals be aware of potential sources of exposure to these chemicals.


Subject(s)
Environmental Exposure , Environmental Pollutants , Phthalic Acids , Adult , Anal Canal/anatomy & histology , Bone Density , Female , Genitalia/anatomy & histology , Humans , Inflammation , Male , Oxidative Stress
2.
J Physiol Pharmacol ; 67(5): 769-775, 2016 Oct.
Article in English | MEDLINE | ID: mdl-28011957

ABSTRACT

The maintenance of protein homeostasis in the endoplasmic reticulum (ER) is crucial in cell life. Disruption of proteostasis results in ER stress that activates the unfolded protein response (UPR); a signalling network assigned to manage the accumulated misfolded or unfolded proteins. Prolonged or unresolved ER stress leads to apoptotic cell death that can be the basis of many serious diseases. Our aim was to study the effect of pulsed electromagnetic fields (PEMF), an alternative, non-invasive therapeutic method on ER stressed cell lines. First, the effect of PEMF treatment on the expression of ER stress markers was tested in three different cell lines. PEMF had no remarkable effect on ER stress protein levels in human embryonic kidney (HEK293T) and human liver carcinoma (HepG2) cell lines. However, the expression of BiP, Grp94 and CHOP were increased in HeLa cells upon PEMF exposure. Therefore, HepG2 cell line was selected for further experiments. Cells were stressed by tunicamycin and exposed to PEMF. Grp94, PDI, CHOP and PARP expression as markers of stress were monitored by Western blot and cell viability was also investigated. Tunicamycin treatment, as expected, increased the expression of Grp94, PDI, CHOP and inactivated PARP. Analysis of protein expression showed that PEMF was able to decrease the elevated level of ER chaperons Grp94, PDI and the apoptosis marker CHOP. The truncated, inactive form of PARP was also decreased. Accordingly, cell viability was also improved by PEMF exposure. These results indicate that PEMF is able to moderate ER stress induced by tunicamycin in HepG2 cells. However, our results clearly draw attention to that different cell lines may vary in the response to PEMF treatment.


Subject(s)
Electromagnetic Fields , Endoplasmic Reticulum Stress/drug effects , Tunicamycin/pharmacology , Apoptosis/drug effects , Cell Survival/drug effects , HEK293 Cells , HeLa Cells , Hep G2 Cells , Humans , Membrane Glycoproteins/metabolism , Poly(ADP-ribose) Polymerases/metabolism , Transcription Factor CHOP/metabolism
4.
Risk Anal ; 34(5): 865-78, 2014 May.
Article in English | MEDLINE | ID: mdl-24955469

ABSTRACT

The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.


Subject(s)
Aldrin/adverse effects , Dieldrin/adverse effects , Insecticides/adverse effects , Neoplasms/chemically induced , Dose-Response Relationship, Drug , Humans
5.
Curr Med Chem ; 21(17): 1938-55, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24606495

ABSTRACT

The extensively investigated serine/threonine kinase, B-RAF, is a member of the RAS/RAF/MEK/ERK pathway. It plays important role in the regulation of cell growth, differentiation and survival. The mutation of B-RAF occurs frequently in melanomas and colon tumors; therefore, it is considered as an outstanding therapeutic target. In recent years a great number of B-RAF inhibitors have been reported and this number is expected to increase. The aim of our work was to compare the structures and binding mode of the published B-RAF inhibitors, and then to apply the correlations found for the explanation of our experimental results. In the first part of this paper we describe the main pharmacophore features of the co-crysallized B-RAF inhibitors published in the literature, focusing on the binding modes and common structural elements. In the second part we present and characterize our recently developed B-RAF inhibitor family by application of in silico methods and in vitro kinetic profiling. The inhibitory activity of these compounds was determined in biochemical kinase- and cell-based assays. The docking and assay results support our conclusion that the presented compound family belongs to the type I 1/2 subgroup, they inhibit B-RAF and B-RAF(V600E) mutant in a sub-micromolar range and most of them show selectivity towards B-RAF(V600E) mutant expressing cell lines with equal or even better IC50 values than sorafenib.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Animals , Cell Line, Tumor , Humans , Molecular Docking Simulation , Mutation , Protein Binding , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism
6.
Curr Med Chem ; 20(10): 1203-17, 2013.
Article in English | MEDLINE | ID: mdl-23409720

ABSTRACT

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 µM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.


Subject(s)
Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/chemistry , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Antineoplastic Agents/metabolism , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Humans , Molecular Docking Simulation , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/toxicity , Protein Structure, Tertiary , Receptor, Fibroblast Growth Factor, Type 1/chemistry , Receptor, Fibroblast Growth Factor, Type 4/metabolism
7.
Int J Biol Macromol ; 50(3): 788-95, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22142793

ABSTRACT

Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.


Subject(s)
Orosomucoid/metabolism , Piperazines/metabolism , Protein Kinase Inhibitors/metabolism , Pyrimidines/metabolism , Benzamides , Humans , Imatinib Mesylate , Models, Molecular , Orosomucoid/chemistry , Piperazines/chemistry , Protein Binding , Protein Conformation , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Spectrum Analysis
8.
Integr Biol (Camb) ; 3(6): 603-31, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21541433

ABSTRACT

We review novel, in vivo and tissue-based imaging technologies that monitor and optimize cancer therapeutics. Recent advances in cancer treatment centre around the development of targeted therapies and personalisation of treatment regimes to individual tumour characteristics. However, clinical outcomes have not improved as expected. Further development of the use of molecular imaging to predict or assess treatment response must address spatial heterogeneity of cancer within the body. A combination of different imaging modalities should be used to relate the effect of the drug to dosing regimen or effective drug concentration at the local site of action. Molecular imaging provides a functional and dynamic read-out of cancer therapeutics, from nanometre to whole body scale. At the whole body scale, an increase in the sensitivity and specificity of the imaging probe is required to localise (micro)metastatic foci and/or residual disease that are currently below the limit of detection. The use of image-guided endoscopic biopsy can produce tumour cells or tissues for nanoscopic analysis in a relatively patient-compliant manner, thereby linking clinical imaging to a more precise assessment of molecular mechanisms. This multimodality imaging approach (in combination with genetics/genomic information) could be used to bridge the gap between our knowledge of mechanisms underlying the processes of metastasis, tumour dormancy and routine clinical practice. Treatment regimes could therefore be individually tailored both at diagnosis and throughout treatment, through monitoring of drug pharmacodynamics providing an early read-out of response or resistance.


Subject(s)
Biomarkers, Tumor/analysis , Molecular Imaging/methods , Neoplasm Proteins/analysis , Neoplasms/diagnosis , Neoplasms/therapy , Humans , Neoplasms/metabolism , Systems Integration
9.
Curr Med Chem ; 18(3): 342-58, 2011.
Article in English | MEDLINE | ID: mdl-21143121

ABSTRACT

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-to-date review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC(50) < 100 nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.


Subject(s)
Anti-HIV Agents/chemistry , Cyclin-Dependent Kinase 9/antagonists & inhibitors , HIV Infections/drug therapy , Protein Kinase Inhibitors/chemistry , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/toxicity , Binding Sites , Catalytic Domain , Cell Line , Computer Simulation , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 2/physiology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 4/physiology , Cyclin-Dependent Kinase 9/metabolism , Cyclin-Dependent Kinase 9/physiology , HIV/drug effects , Humans , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/toxicity , Pyrimidines/chemistry , Virus Replication/drug effects
10.
Curr Med Chem ; 17(4): 321-33, 2010.
Article in English | MEDLINE | ID: mdl-20015044

ABSTRACT

Compound lipophilicity connected to ADME(T)(a) has great importance in drug development and it has to be evaluated by the generally used drug developmental process. In addition to the importance of lipophilicity in ADMET, recently it has been reported that lipophilicity of small molecules correlates with their antiproliferative activity because of certain specific hydrophobic and lipophilic interactions. Due to the complexity of ADME(T) parameters an efficient and fast method is needed to characterize the many promising candidate lead molecules as a preselection in order not to be rejected from the latter phase of drug development. In the present paper we provide an overview of the importance of lipophilicity of drug candidates for biological action and for ADME(T) and describe a novel approach for drug-likeness characterization of a molecular library using correlation study between lipophilicity and biological activity. Lipophilicity and molecular characteristics have been measured, predicted and optimized for a diverse library from which the best members have been selected to describe their biological, chemical and drug-likeness properties. Molecules were selected from the family of alpha,beta-unsaturated ketones and thorough HPLC characterization for lipophilicity and morphological, antiproliferative and flow cytometric studies were carried out on them. Based on the results 17 member isochromanone library including E and Z geometric isomers were selected for further characterization. In this focused library linear correlation has been found between the calculated and measured lipophilicity and significant parabolic correlation was found between the antiproliferative effect and lipophilicity. Using our efficient and fast method, from a diverse library, we identified an outstandingly effective inhibitor of A431 tumour cell growth via a PARP(a) cleavage dependent apoptosis. In summary the optimized HPLC analyses of lipophilicity combined with the cell-culture assay, introduced above, resulted in the determination of an optimal lipophilicity range. This optimized lipophilicity range should be used in designing novel antiproliferative compounds.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Chromones/chemistry , Chromones/pharmacology , Hydrophobic and Hydrophilic Interactions , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Drug Discovery , Flow Cytometry , Humans , Immunoblotting , Inhibitory Concentration 50 , Microscopy
11.
Br J Pharmacol ; 158(4): 1153-64, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19785662

ABSTRACT

BACKGROUND AND PURPOSE: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. EXPERIMENTAL APPROACH: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. KEY RESULTS: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters. CONCLUSIONS AND IMPLICATIONS: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/metabolism , Aniline Compounds/metabolism , Neoplasm Proteins/metabolism , Nitriles/metabolism , Pyrimidines/metabolism , Quinolines/metabolism , Thiazoles/metabolism , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/antagonists & inhibitors , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cyclosporins/pharmacology , Dasatinib , Dose-Response Relationship, Drug , Drug Resistance, Multiple/drug effects , Fusion Proteins, bcr-abl/metabolism , Humans , Indoles/pharmacology , K562 Cells , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Nitriles/pharmacology , Nitriles/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Pyrimidines/pharmacology , Pyrimidines/therapeutic use , Quinolines/pharmacology , Quinolines/therapeutic use , Substrate Specificity , Thiazoles/pharmacology , Thiazoles/therapeutic use
12.
Anticancer Res ; 28(5A): 2769-74, 2008.
Article in English | MEDLINE | ID: mdl-19035308

ABSTRACT

BACKGROUND: The somatostatin structural derivative, TT-232, has a special 5-residue ring structure (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) and very different characteristics from the known growth hormone (GH) active somatostatin analogs. This somatostatin structural derivative has no GH release inhibitory or antisecretory activity and does not bind to rat pituitary or the cortex, where all the known somatostatin receptor subtypes are expressed. TT-232 had previously been shown to inhibit the proliferation of a large number of cancer cell lines in vitro and reduce the size of different tumors in animal models in vivo. MATERIALS AND METHODS: The therapeutic efficacy of TT-232 was evaluated in different long-term administration routes: the traditional injection (i.p. or s.c.) versus infusion treatment via s.c.- or i.v.-inserted Alzet osmotic minipump, and on different types of transplantable rodent (S-180 sarcoma, P-388sc lymphoid leukemia, Colon-26 adenocarcinoma, MXT breast carcinoma, B-16 melanoma) and human tumor models (HT-18 lymphoid melanoma, T-47/D breast carcinoma, A-431 epidermoid carcinoma). On the basis of our previous experiments the optimum injected dose of TT-232 was found to be 15 microg/kg twice a day. This dose is equivalent to 0.6 dg/day by infusion therapy. RESULTS: In our experiments, the best results were achieved when TT-232 was applied as an infused treatment. In the S-180 sarcoma and P-388sc lymphoid leukemia rodent tumor models the infusion treatment with TT-232 resulted in 61%-100% tumor growth inhibition and in 20%-60% of the mice being long-term and tumor-free survivors. In the aggressive Colon-26 adenocarcinoma and MXT breast carcinoma models, the infusion treatment resulted in 52%-75% tumor growth inhibition. In the B-16 melanoma model, the infusion treatments resulted in 47% -63% growth inhibition. The tumor growth inhibitory effect of infusion treatment with TT-232 on HT-18 human lymphoid melanoma tumor proved to be significant, resulting in 69%-79% decreases in tumor volume. In the T-47/D human breast carcinoma, the infusion treatment resulted in 48%-53% tumor growth inhibition. The tumor growth inhibitory effect of infusion treatment on A-431 human epidermoid carcinoma tumor resulted in 70%-74% decreases in tumor volume. CONCLUSION: The antitumor efficacy of TT-232 was seen in almost all the tumors investigated. In our study, the route of infusion was shown to increase drug efficacy relative to conventional delivery methods (injection). The results obtained from this study suggest that TT-232 is a promising new antitumor agent in cancer chemotherapy and a good candidate for delivery by continuous (infusion) therapy.


Subject(s)
Neoplasms, Experimental/drug therapy , Peptides, Cyclic/administration & dosage , Animals , Humans , Infusion Pumps, Implantable , Infusions, Subcutaneous , Mice , Somatostatin/analogs & derivatives
13.
Curr Med Chem ; 15(26): 2760-70, 2008.
Article in English | MEDLINE | ID: mdl-18991635

ABSTRACT

Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.


Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/metabolism , Signal Transduction/drug effects , Tuberculosis/drug therapy , Tuberculosis/metabolism , Anti-Bacterial Agents/toxicity , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/toxicity , Humans , Macrophages/drug effects , Macrophages/enzymology
14.
Curr Med Chem ; 13(3): 277-87, 2006.
Article in English | MEDLINE | ID: mdl-16475937

ABSTRACT

Epidermal Growth Factor Receptor (EGFR) is a high priority target in anticancer drug research. Thousands of very effective EGFR inhibitors have been developed in the last decade. The known inhibitors are originated from a very diverse chemical space but--without exception--all of them act at the Adenosine TriPhosphate (ATP) binding site of the enzyme. We have collected all of the diverse inhibitor structures and the relevant biological data obtained from comparable assays and built prediction oriented Quantitative Structure-Activity Relationship (QSAR) which models the ATP binding pocket's interactive surface from the ligand side. We describe a QSAR method with automatic Variable Subset Selection (VSS) by Genetic Algorithm (GA) and goodness-of-prediction driven QSAR model building, resulting an externally validated EGFR inhibitory model built from pIC50 values of a diverse structural set of 623 EGFR inhibitors. Repeated Trainings/Evaluations (RTE) were used to obtain model fitness values and the effectiveness of VSS is amplified by using predictive ability scores of descriptors. Numerous models were generated by different methods and viable models were collected. Then, intensive RTE were applied to identify ultimate models for external validations. Finally, suitable models were validated by statistical tests. Since we use calculated molecular descriptors in the modeling, these models are suitable for virtual screening for obtaining novel potential EGFR inhibitors.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Quantitative Structure-Activity Relationship
16.
Br J Cancer ; 88(1): 132-6, 2003 Jan 13.
Article in English | MEDLINE | ID: mdl-12556972

ABSTRACT

A novel somatostatin analogue, TT-232 (which inhibits the proliferation of various cell cultures and transplantable mouse tumours), was examined regarding its effect on human melanoma and lymphoma xenografts as a single treatment or in combination with DTIC (dacarbazine) and etoposide. TT-232 inhibited the growth of HT-18 melanoma xenografts, a dose of 5 mg kg(-1) being the most effective. Combination of 1 mg kg(-1) TT-232 with 30 or 60 mg kg(-1) DTIC (administered daily) resulted in a stronger inhibitory effect compared to TT-232 or DTIC as a single modality. Antimetastatic effect of TT-232 treatment combined with DTIC was studied using the B16 mouse melanoma muscle - lung metastasis model. The number of lung metastases of B16 melanoma could be decreased by the daily administration of 1 mg kg(-1) TT-232 or 60 mg kg(-1), but not of 30 mg kg(-1) DTIC. TT-232, combined with 30 or 60 mg kg(-1) DTIC decreased the lung metastasis number significantly lower than the control. Nearly 50% growth inhibition of HT-58 lymphoma was achieved by daily treatment with 1 mg kg(-1) TT-232. 5 mg kg(-1) etoposide, administered daily, resulted in a similar effect. The combination of 1 mg kg(-1) TT-232 and 5 mg kg(-1) etoposide was significantly more effective than TT-232 or etoposide as a single treatment. The very strong tumour growth inhibitory effect of 10 mg kg(-1) etoposide could even be increased by combination with TT-232. These experimental data suggest that TT-232 may be an effective new tool in the combination chemotherapy of malignant tumours like melanoma and lymphoma.


Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma, Experimental/drug therapy , Neoplasms, Experimental/drug therapy , Somatostatin/therapeutic use , Animals , Dacarbazine/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Etoposide/therapeutic use , Humans , Lymphoma/drug therapy , Male , Mice , Mice, Inbred CBA , Neoplasm Metastasis , Neoplasm Transplantation , Peptides, Cyclic/therapeutic use , Somatostatin/analogs & derivatives , Xenograft Model Antitumor Assays
17.
Ann N Y Acad Sci ; 1010: 109-12, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15033704

ABSTRACT

Selective inhibition of the "false" proliferative signals via targeting tyrosine kinases resulting in the induction of apoptosis by depletion of the "survival factors" is one of the most studied and widely accepted concepts of modern chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors and tested these compounds for apoptosis induction. Some of the tyrosine kinase inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various tumor cell cultures. The somatostatin analogue oligopeptide TT-232, which indirectly inhibits tyrosine kinases, exerted a dose-dependent apoptosis-inducing effect. The tumor growth-inhibitory effect of TT-232 and some tyrosine kinase inhibitors has also been proven by in vivo experiments, using human tumor xenografts. On the other hand, a dose-dependent pro- or anti-apoptotic activity of (-)-deprenyl has been shown in melanoma cell cultures, the lower doses inhibiting and the higher doses inducing apoptosis. Various metabolites of (-)-deprenyl are responsible for these actions. The effect of (-)-deprenyl is connected with depolarization of mitochondrial membranes. The kinase inhibitors act on the growth factor receptor signaling pathways (survival factor pathways) and initiate the caspase cascade. The key enzyme for the action of both pro-apoptotic and anti-apoptotic compounds is caspase 3.


Subject(s)
Apoptosis/drug effects , Enzyme Inhibitors/pharmacology , Peptides, Cyclic/pharmacology , Protein Kinase Inhibitors , Signal Transduction/physiology , Tyrphostins/pharmacology , Animals , Apoptosis/physiology , Cell Division/drug effects , Male , Mice , Mice, Inbred CBA , Selegiline/pharmacology , Signal Transduction/drug effects , Somatostatin/analogs & derivatives
18.
Org Lett ; 3(23): 3723-5, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11700122

ABSTRACT

[carbohydrate structure--see text] Resistance to chemotherapy has become a major problem in cancer therapy. The new sugar amino acid (SAA) containing somatostatin analogues presented possess antiproliferative and apoptotic activity against both multidrug-resistant and drug-sensitive hepatoma carcinoma cells. Synthesis, design, and biological evaluation of the cyclic analogues and of the furanoid SAA used will be discussed. Four analogues have IC(50) values in the low microM range, making them promising leads for chemotherapeutic drugs against multidrug-resistant carcinoma.


Subject(s)
Amino Acids/chemistry , Antineoplastic Agents/pharmacology , Apoptosis , Hormone Antagonists/pharmacology , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Sugar Acids/chemistry , Algorithms , Animals , Antineoplastic Agents/chemical synthesis , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Hormone Antagonists/chemical synthesis , Rats , Somatostatin/chemical synthesis , Structure-Activity Relationship , Tumor Cells, Cultured
19.
Br J Pharmacol ; 134(7): 1571-9, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11724765

ABSTRACT

1. Somatostatin (6.11 nmol kg(-1) i.p.) inhibited neurogenic plasma extravasation evoked by 1% mustard oil and non-neurogenic oedema induced by 5% dextran in the rat skin. 2. Cyclic synthetic octapeptide (TT-248 and TT-250) and heptapeptide (TT-232) somatostatin analogues proved to be more effective in reducing neurogenic and non-neurogenic inflammatory reactions but octreotide had no influence on either neurogenic or non-neurogenic inflammation. 3. TT-232 administered i.p. or i.v. (1.06 - 42.40 nmol kg(-1)) inhibited in a dose-dependent manner the plasma extravasation evoked by mustard oil in the rat's paw. Neither diclofenac (15.78 - 315.60 micromol kg(-1)) nor the selective COX-2 inhibitor meloxicam (2.95 - 569.38 micromol kg(-1)) attenuated the mustard oil-induced neurogenic plasma extravasation. 4. TT-232, diclofenac and meloxicam dose-dependently diminished non-neurogenic dextran-oedema of the paw the ED(35) values were 1.73 nmol kg(-1) for TT-232 and 34.37 micromol kg(-1) for diclofenac. 5. TT-232 inhibited in the dose range of 1.06 - 21.21 nmol kg(-1) the bradykinin-induced plasma extravasation in the skin of the chronically denervated paw. 6. Mustard oil-induced cutaneous plasma extravasation was dose-dependently diminished by s.c. TT-232 1, 2, 4, 6 or 16 h after the treatment. TT-232 (2 x 106, 2 x 212 and 2 x 530 nmol kg(-1) per day s.c. for 18 days) caused dose-dependent inhibition of chronic Freund adjuvant-induced arthritis during the experimental period. 7. TT-232 (200 and 500 nM) inhibited the release of SP, CGRP and somatostatin from the rat isolated trachea induced by electrical field stimulation (40 V, 0.1 ms, 10 Hz, 120 s) or by capsaicin (10(-7) M), but did not influence the basal, non-stimulated peptide release. 8. It is concluded that somatostatin analogues without endocrine functions as TT-232 are promising compounds with a novel site of action for inhibition of non-neurogenic and neurogenic inflammatory processes.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Somatostatin/pharmacology , Animals , Arthritis, Experimental/pathology , Arthritis, Experimental/prevention & control , Bradykinin/administration & dosage , Capillary Permeability/drug effects , Dextrans/administration & dosage , Diclofenac/pharmacology , Dose-Response Relationship, Drug , Evans Blue/metabolism , Female , Hindlimb/drug effects , Hindlimb/innervation , Hindlimb/pathology , In Vitro Techniques , Inflammation/chemically induced , Inflammation/prevention & control , Injections, Intraperitoneal , Meloxicam , Neuropeptides/drug effects , Neuropeptides/metabolism , Peptides, Cyclic/pharmacology , Rats , Rats, Wistar , Somatostatin/analogs & derivatives , Thiazines/pharmacology , Thiazoles/pharmacology , Time Factors , Trachea/drug effects , Trachea/metabolism , Treatment Outcome
20.
Biochem Biophys Res Commun ; 288(3): 564-72, 2001 Nov 02.
Article in English | MEDLINE | ID: mdl-11676480

ABSTRACT

The somatostatin analogue, TT-232 inhibits cell proliferation and induces apoptosis in a variety of tumor cells both in vivo and in vitro. While the early transient activation of Erk/MAPK was found to be important for the induction of cell cycle arrest, the signaling pathway leading to the activation of Erk/MAPK had not been fully established. Here we present evidence that activation of the Erk/MAPK pathway by TT-232 involves PI 3-kinase, PKCdelta and the protein tyrosine phosphatase alpha (PTPalpha). We show a physical interaction of PI 3-kinase and PKCdelta with PTPalpha and show that the tyrosine phosphatase plays a role in the activation of MAPK. In this process, PTPalpha Ser-180 and Ser-204 phosphorylation is critical for the induction of phosphatase activity, which is required for dephosphorylation of pp60(c-src). Taken together, we demonstrate the physical and functional association between PI 3-kinase, PKCdelta and PTPalpha in a signaling complex that mediates the antitumor activity of the somatostatin analogue TT-232.


Subject(s)
Heterogeneous-Nuclear Ribonucleoprotein Group F-H , Isoenzymes/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase C/metabolism , Protein Tyrosine Phosphatases/metabolism , Animals , Antineoplastic Agents/pharmacology , COS Cells , Cells, Cultured , Enzyme Activation , GTP-Binding Proteins/physiology , Genes, src/physiology , Humans , Mitogen-Activated Protein Kinases/metabolism , Peptides, Cyclic/pharmacology , Phosphorylation , Protein Kinase C-delta , RNA-Binding Proteins , Serine/metabolism , Signal Transduction/drug effects , Somatostatin , Virulence Factors, Bordetella/pharmacology
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