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Results for “Inhibitory Concentration 50”

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PubMed2001

In vitro hemolysis of human erythrocytes -- by plant extracts with antiplasmodial activity.

Human erythrocytes were exposed in a dose dependent manner to various ethanolic plant extracts, and fractions obtained from plant parts of Calotropis procera (Ait.) R. Br. and the gum--oleo resin of Commiphora wightii (Arnott.) Bhand. These have been screened for in vitro schizontocidal activity and graded with respect to their 50% inhibitory concentration (IC(50)) derived from the twofold serial dilution of the dose range 0.0625--2 mg/ml. An attempt had been made to relate their antiplasmodial activity with their cytotoxicity as represented by the in vitro rate of hemolysis. Intact erythrocytes were found to respond with a dose--time-integral and fitted to models of pseudo first-order reaction, Michaelis--Menten equation and Hill equation with k(1), k(2) and k(3) as their rate constants, respectively. Hemolysis isotherms of flower and root of C. procera and gum--oleo resin of C. wightii extracts were representative. Erythrocytic membrane instability is possibly a major factor as has been earlier reported with ethanol and chloroquine for the cytotoxicity of these plant extracts.

Erythrocytes↗

PubMed2003

Increased efficacy of acyclovir-loaded microparticles against herpes simplex virus type 1 in cell culture.

Acyclovir is one of the most effective and selective agents against viruses of the herpes group. In order to increase its antiviral activity, acyclovir loaded microparticles, prepared by an O/W solvent evaporation method were developed. Their antiviral activity against herpes simplex virus type 1 (HSV-1) and toxicity were evaluated on Vero cells and then compared with those presented by a drug solution. The 50% inhibitory concentration (IC(50)) values for acyclovir loaded microspheres determined by plaque reduction assays at 48 and 96 h, were found to be 1.06 +/- 0.01 microM and 0.15 +/- 0.03 microM, respectively, while the equivalent values obtained for an acyclovir solution were 1.28 +/- 0.04 microM at 48 h and 0.27 +/- 0.02 microM at 96 h. These results indicate that acyclovir shows a higher antiviral activity, against herpes simplex virus type 1, when this drug was loaded in microparticles rather than as a drug solution, especially after 96 h of incubation. The toxicity of these microparticles was determined by the MTT test at 48 and 96 h. At 48 h only a small toxicity was found (cell viability ranged from 72 to 82%, with the higher concentration tested) and it could not be attributed to the microparticles, since the acyclovir control solution showed similar toxicity values. However, after 96 h a higher toxicity was observed with acyclovir microparticles as well as with the unloaded ones (cell viability located between 60 and 70%). In summary, acyclovir-loaded microparticles have shown to be promising carriers for the effective delivery of acyclovir in the treatment of HSV-1 infections in cells so they can have a potential use in vivo.

Acyclovir↗

PubMedDate not supplied

Two technetium-99m-labeled cholecystokinin-8 (CCK8) peptides for scintigraphic imaging of CCK receptors.

A broad spectrum of radiolabeled peptides with high affinity for receptors expressed on tumor cells is currently under preclinical and clinical investigation for scintigraphic imaging and radionuclide therapy. The present paper evaluates two (99m)Tc-labeled forms of the C-terminal octapeptide of cholecystokinin (CCK8): sulfated (s)CCK8, with high affinity for CCK1 and CCK2 receptors, and nonsulfated (ns)CCK8, with high affinity for CCK2 receptors but low affinity for CCK1 receptors. Peptides were conjugated with the bifunctional chelator N-hydroxysuccinimidyl hydrazino niconitate (s-HYNIC). (99m)Tc-labeling, performed in the presence of nicotinic acid and tricine, was highly efficient (approximately 95%) and yielded products with a high specific activity (approximately 700 Ci/mmol) and good stability (approximately 5% release of radiolabel during 16 h incubation in phosphate buffered saline at 37 degrees C). Chinese hamster ovary cells stably expressing the CCK1 receptor (CHO-CCK1 cells) internalized approximately 3% of added (99m)Tc-sCCK8 per confluent well during 2 h at 37 degrees C. Internalization was effectively blocked by excess unlabeled sCCK8. CHO-CCK1 cells did not internalize (99m)Tc-nsCCK8. Displacement of (99m)Tc-sCCK8 and -nsCCK8 by unlabeled CCK-8 (performed at 0 degrees C to prevent internalization) revealed 50% inhibitory concentrations (IC(50)) of 8 nM and >1 microM, respectively. CHO-CCK2 cells internalized approximately 25% and approximately 5% of added (99m)Tc-sCCK8 and -nsCCK8, respectively. In both cases internalization was blocked by excess unlabeled peptide. IC(50) values for the displacement of (99m)Tc-sCCK8 and -nsCCK8 were 3 nM and 10 nM, respectively. CHO-CCK1 cell-derived tumors present in one flank of athymic mice accumulated 2.0% of injected (99m)Tc-sCCK8 per gram tissue at 1 h postinjection. This value decreased to 0.6% following coinjection with excess unlabeled peptide. Uptake of (99m)Tc-nsCCK8 was low (0.2%) and not did change by excess unlabeled peptide (0.3%). Accumulation of (99m)Tc-sCCK8 and -nsCCK8 by CHO-CCK2 cell-derived tumors (present in the other flank) amounted to 4.2% and 0.6%, respectively. In both cases uptake was significantly reduced by excess unlabeled peptide to 1.0% and 0.4% for sCCK8 and nsCCK8, respectively. Accumulation of (99m)Tc-sCCK8 was also high in pancreas (11.7%), stomach (2.0%), and kidney (2.1%), whereas uptake of (99m)Tc-nsCCK8 was high in stomach (0.7%) and kidney (1.4%). Both radiolabeled peptides showed a rapid blood clearance. In conclusion, these data show that CCK8 analogues can be efficiently labeled with (99m)Tc using s-HYNIC as chelator and nicotinic acid/tricine as coligand system without compromising receptor binding. Furthermore, the present study demonstrates that CCK1 tumors hardly accumulate (99m)Tc-nsCCK8, CCK2 tumors accumulate 2 times more (99m)Tc-sCCK8 than CCK1 tumors, and CCK2 tumors accumulate 15 times more (99m)Tc-sCCK8 than (99m)Tc-nsCCK8. Although accumulation in some nontarget organs was also higher with (99m)Tc-sCCK8, this may not reflect the human situation due to a different receptor expression pattern in humans as compared to mice. Therefore, further studies are warranted to investigate the possible use of (99m)Tc-sCCK8 for scintigraphic imaging of CCK receptor-positive tumors in humans.

Animals↗

PubMed2003

Antioxidative and antiplatelet effects of aqueous inflorescence Piper betle extract.

Piper betle, belonging to the Piperaceae family, is a tropical plant, and its leaf and inflorescence are popularly consumed by betel quid (BQ) chewers in Taiwan and many other South and Southeast Asian countries. However, little is known about the biochemical properties of inflorescence Piper betle (IPB) toward reactive oxygen species (ROS) and platelet functions. In the present work, aqueous IPB extract was shown to be a scavenger of H(2)O(2), superoxide radical, and hydroxyl radical with a 50% inhibitory concentration (IC(50)) of about 80, 28, and 73 microg/mL, respectively. IPB extract also prevented the hydroxyl radical induced PUC18 plasmid DNA breaks at concentrations higher than 40 microg/mL. Since ROS are crucial for platelet aggregation, we further found that IPB extract also inhibited the arachidonic acid (AA) induced and collagen-induced platelet aggregation, with an IC(50) of 207 and 335 microg/mL, respectively. IPB extract also inhibited the AA-, collagen- (>100 microg/mL of IPB), and thrombin (>250 microg/mL of IPB)-induced thromboxane B(2) (TXB(2)) production by more than 90%. However, IPB extract showed little effect on thrombin-induced aggregation. These results indicated that aqueous components of IPB are potential ROS scavengers and may prevent the platelet aggregation possibly via scavenging ROS or inhibition of TXB(2) production.

Animals↗

PubMed2004

Pigments in green tea leaves (Camellia sinensis) suppress transformation of the aryl hydrocarbon receptor induced by dioxin.

Environmental contaminants such as dioxins enter the body mainly through diet and cause various toxicities through transformation of the aryl hydrocarbon receptor (AhR). We previously reported that certain natural flavonoids at the dietary level suppress the AhR transformation induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we identified lutein and chlorophyll a and b from green tea leaves as the novel antagonists for AhR. These active compounds suppressed AhR transformation dose-dependently with the 50% inhibitory concentration (IC(50)) values against 0.1 nM TCDD-induced AhR transformation at 3.2, 5.0, and 5.9 microM, respectively. (-)-Epigallocatechin gallate, which is the most abundant flavonoid in green tea leaves, also showed stronger suppressive effects than did other major tea components, with the IC(50) value of 1.7 microM. Thus, these pigments of green tea leaves have the potential to protect from dioxin toxicity through the suppression of AhR transformation.

Camellia sinensis↗

PubMed1998

Polyanion inhibitors of HIV and other viruses. 7. Polyanionic compounds and polyzwitterionic compounds derived from cyclodextrins as inhibitors of HIV transmission.

New polyanionic compounds were obtained from radical addition of thiomalic acid and mercaptopropionic acid onto perallylated cyclodextrins (CDs) under UV irradiation with a catalytic amount of alpha,alpha'-azobis(isobutyronitrile). All these polyanions, bearing 18-48 carboxylate groups, inhibited human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-4 cells at a 50% inhibitory concentration (IC50) of 0.1-2.9 microM, while not being toxic to the host cells at concentrations up to 62 microM. These compounds were also active against a clinical HIV-1 isolate (HE) at >/=4-fold higher concentrations. Only some compounds showed activity against the two HIV-2 strains (ROD and EHO) but at higher concentrations than those required to inhibit HIV-1 (IIIB and HE) replication. In addition, these compounds were not active against the M-tropic HIV-1 strain BaL but were active against simian immunodeficiency virus [SIV (MAC251)]. These compounds were also inhibitory to the replication of human cytomegalovirus at an IC50 of 1-10 microM, but not herpes simplex virus (type 1 and type 2) or other (picorna-, toga-, reo-, orthomyxo-, paramyxo-, bunya-, rhabdo-, and poxvirus) viruses. Radical addition on perallylated CDs of a protected cysteine gave polyzwitterionic compounds. None of these last compounds proved inhibitory to the replication of HIV-1, HIV-2, or any of the other viruses tested.

Animals↗

PubMed2000

Inhibitory effects on HIV-1 protease of constituents from the wood of Xanthoceras sorbifolia.

From a methanolic extract of the wood of Xanthoceras sorbifolia, two new compounds, 29-hydroxy-3-oxotirucalla-7,24-dien-21-oic acid (3, xanthocerasic acid) and epigallocatechin-(4beta-->8, 2beta-->O-7)-epicatechin (6), were isolated, together with 11 known compounds. Of the isolated compounds, 3-oxotirucalla-7, 24-dien-21-oic acid (2), oleanolic acid (4), and 6 were found to be inhibitory substances against human immunodeficiency virus (HIV-1) protease, with their 50% inhibitory concentrations (IC(50)) being 20, 10, and 70 microg/mL, respectively. Condensed tannins of high molecular weights with epicatechin and epiafzelechin as the main extender units were found to be the most active principles of this plant (IC(50) values ca. 6.0 microg/mL).

Anthocyanins↗

PubMed2002

Antioxidant effects and anti-elastase activity of the calcium antagonist nicardipine on activated human and rabbit neutrophils--a potential antiatherosclerotic property of calcium antagonists?

Activated neutrophils which produce certain proteases, such as elastase and reactive oxygen species (ROS) are involved in oxidative stress and inflammation. In the present study, we have shown that nicardipine, a calcium channel blocker, affects the release of elastase and superoxide anion radicals (O(2-)) in vitro during human and rabbit neutrophil respiratory bursts. The drug inhibited the release of elastase and O(2-) by fMLP (N-formyl-methionylleucin-phenylalaninin), calcium ionophore (A23187) and PMA (phorbol-myristate-acetate)-stimulated human and rabbit neutrophils. Besides the release of elastase, strongly inhibited in the fMLP and A23187 stimulated systems, nicardipine affected elastase and O(2-) in a dose-dependent manner. The corresponding 50% inhibitory concentration (IC(50)) of nicardipine for elastase, released in PMA-stimulated human and rabbit neutrophils, was 15.95 +/- 0.17 microM and 18.06 +/- 0.08 microM, respectively, whereas for O(2-), the IC(50) of nicardipine in PMA, fMLP and A23187-stimulated human and rabbit neutrophils was 55.41 +/- 0.09 microM and 58.43 +/- 0.03 microM, 45.21 +/- 0.13 microM and 37.19 +/- 0.53 microM, 33.54 +/- 0.09 microM and 30.54 +/- 0.29, respectively. The mechanisms underlying the inhibition of elastase and superoxide anion radicals by nicardipine appear related to an inhibiting effect on the mobilisation of cytosolic calcium and on activation of protein kinase C (PKC). These antioxidant and anti-elastasic activities contribute to the properties of nicardipine, as positive side effects of its antihypertensive activity and may be useful to prevent inflammatory disorders (tissue damage, oxidative injury) involved in the pathogenesis of hypertension.

Animals↗

PubMed2003

BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells.

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC(50) : 30-40 microM) compared with MCF-7 (IC(50) : 60-70 microM) and MDA-MB231 (IC(50) : 90-100 microM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC(50) : 45-50 microM) compared with MCF-7 (IC(50) : 1-5 microM) and MDA-MB231 (IC(50) : 5-10 microM) (P<0.02), as well as to paclitaxel (Tax) (IC(50) : >2 microM for HCC1937, 0.1-0.2 microM for MCF-7 and 0.01-0.02 microM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.

Antineoplastic Agents↗

PubMed2002

Effects of the selective inhibition of platelet thromboxane synthesis on the platelet-subendothelium interaction.

1. Drugs that inhibit TxA(2) synthesis are used to reduce platelet aggregation. The aim of this study was to compare the effects of a cyclo-oxygenase (COX) inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor (dazoxiben) and a dual TxS inhibitor and TxA(2) receptor blocker (DT-TX 30) on platelet aggregation and the platelet-subendothelium interaction in flow conditions. 2. The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B(2) and prostaglandin E(2) production and leucocyte production of 6-keto-PGF(1alpha). The platelet-subendothelium interaction was evaluated in rabbit aorta subendothelium preparations exposed to flowing blood at a shear stress of 800 s(-1). Morphometric methods were used to calculate the percentage of subendothelium occupied by platelets. 3. The 50% inhibitory concentration (IC(50)) of DT-TX 30 in whole blood was in the range of 10(-7) micro M (induced with collagen or arachidonic acid) to 10(-5) micro M (induced with thrombin) or 10(-4) (induced with ADP). IC(50) values under all experimental conditions were lower with DT-TX 30 than with ASA. For thromboxane B(2) the IC(50) were: ASA 0.84+/-0.05 micro M, dazoxiben 765+/-54 micro M, DT-TX 30 8.54+/-0.60 micro M. Prostaglandin E(2) was inhibited only by ASA (IC(50) 1.21+/-0.08 micro M). Leucocyte 6-keto-PGF(1alpha) was inhibited by ASA (IC(50) 6.58+/-0.76 micro M) and increased by dazoxiben and DT-TX 30. The greatest reduction in percentage subendothelial surface occupied by platelets after blood perfusion was seen after treatment with DT-TX 30 in the range of concentrations that inhibited collagen-induced platelet aggregation (control group: 31.20+/-3.8%, DT-TX 30 at 0.1 micro M: 10.71+/-0.55%, at 1.0 micro M: 6.53+/-0.44%, at 5.0 micro M; 1.48+/-0.07%). All three drugs reduced thrombus formation, although ASA (unlike dazoxiben or DT-TX 30) increased the percentage surface occupied by adhesions. 4. In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA(2) can surpass the effect of ASA in inhibiting the platelet-subendothelium interaction in flow conditions.

6-Ketoprostaglandin F1 alpha↗

PubMed2003

Comparison of HSV-1 thymidine kinase-dependent and -independent inhibition of replication-competent adenoviral vectors by a panel of drugs.

Replication-competent adenoviral vectors hold the promise to be more efficient gene delivery vehicles than their replication-deficient counterparts, but they are also associated with a higher risk for adverse effects, especially in light of the fact that there is no established effective therapy for serious, disseminated adenovirus infection. To assess whether the therapeutic options to inhibit adenoviral replication can be enhanced by expressing a suicide gene, we examined the antiadenoviral effects of 15 drugs against wild-type adenovirus type 5 (Ad5) and an Ad5-based replication-competent vector expressing herpes simplex virus-1 thymidine kinase (HSV-tk) (Ad.OW34) using a real-time polymerase chain reaction -based assay and flow cytometry. Ad5 and Ad.OW34 were highly susceptible to the fluorinated pyrimidine analogs 5-fluoro-2'-deoxyuridine (FUdR), 5-fluorouridine (FUR), and trifluorothymidine (TFT), with a mean 50% inhibitory concentration (IC(50)) ranging from 0.12 to 0.32 microM. The mean IC(50) of ribavirin and cidofovir (CDV) for Ad5, the most frequently used drugs to treat adenovirus disease, was 6.87 and 3.19 microM, respectively. In contrast to Ad5, the Ad.OW34 vector was susceptible to (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU, IC(50) 0.09 microM), ganciclovir (GCV, IC(50) 0.19 microM), and acyclovir (ACV, IC(50) 32.04 microM). Additionally, we demonstrated in an animal model that Ad.OW34 vector replication can be inhibited significantly by GCV, CDV, and TFT by 35.2, 7.7, and 3.7-fold, respectively, compared to untreated animals. The observed antiadenoviral effects were primarily not through cell killing, since the in vitro 50% cytotoxic concentrations (CC(50)) were more than 1000 times higher than the antiadenoviral IC(50) of the drugs examined, even in cells stably expressing HSV-tk. Since for HSV-tk-dependent inhibition of adenoviral vectors, stability of HSV-tk expression is crucial, we examined Ad.OW34 vector stability, by passaging the vector 10 times serially in the presence of 10 microM GCV. The HSV-tk/GCV system neither changed the susceptibility of Ad.OW34 to GCV significantly nor detectable vector rearrangements occurred, suggesting that the system might be suitable as a fail-safe mechanism to stop adenoviral vector replication.

Adenoviridae↗

PubMed2003

FR901228 induces tumor regression associated with induction of Fas ligand and activation of Fas signaling in human osteosarcoma cells.

We investigated the antitumor effects of FR901228, a HDAC inhibitor, on human osteosarcoma cells, in vitro and in vivo to explore its possible utility in the treatment of pediatric bone cancers. FR901228 caused marked growth inhibition with a 50% inhibitory concentration of 1.2-7.3 nM and induction of apoptosis in all eight osteosarcoma cell lines tested. These effects of FR901228 were also observed in vivo xenograft models on BALB/c nude mice, and treatment with 5.6 mg/kg/day resulting in a >70% reduction in the mean final tumor volume compared with the mean initial tumor volume. TUNEL assays demonstrated extensive apoptosis in tumor sections of mice treated with FR901228. Induction of apoptosis was preceded by increased expression of Fas ligand (FasL) mRNA, resulting in expression of membrane-bound FasL, which was followed by sequential activation of caspase-8 and -3. The level of apoptosis induction was reduced using a neutralizing anti-FasL antibody and overexpression of either the dominant-negative FADD or the viral FLICE inhibitory protein. Furthermore, treatment with a suboptimal dose of FR901228 greatly sensitized osteosarcoma cells to agonistic anti-Fas antibody-mediated apoptosis. These findings suggest that FR901228 is a highly promising antitumor agent against osteosarcoma, inducing apoptosis by the activation of the Fas/FasL system.

Animals↗

PubMed2002

Synergistic interactions of the two classes of ligand, sialyl-Lewis(a/x) fuco-oligosaccharides and short sulpho-motifs, with the P- and L-selectins: implications for therapeutic inhibitor designs.

The E-, L- and P-selectins are carbohydrate-recognizing cell-adhesion molecules mediating selective leucocyte recruitment in inflammation. The 3'-sialyl- and 3'-sulpho-oligosaccharides of Lewis(x) (Le(x)) and Lewis(a) (Le(a)) series are bound by them, but for high-avidity binding of P- and L-selectins to the glycoprotein counter-receptor known as P-selectin glycoprotein ligand, PSGL-1, there is a requirement for sulpho-tyrosines neighbouring a sialyl-Le(x) glycan. The two selectins can also bind 3-O- or 6-O-sulphated galacto-lipids (sulphatides). Here we compare some features of the interactions of P- and L-selectins with a novel lipid-linked sulpho-tyrosine probe, and with the sulphatides and neoglycolipids of sialyl- and sulpho-Le(x)/Le(a) fuco-oligosaccharides. The sulpho-tyrosine probe is bound by both selectins. There are close similarities in the interactions of the two selectins with sulpho-tyrosine and the sulphatides; the binding is relatively resistant to chelation of calcium ions, in contrast to the absolute requirement of calcium ions with the long fuco-oligosaccharides, including 6-sulpho-sialyl-Le(x). With both selectins, there is striking synergy in binding signals elicited by the two ligand types when presented as equimolar mixtures on a matrix. Thus, there are two operationally distinct binding sites on both L- and P-selectin; and the binding sites for sulphate groups in the two ligand types are probably distinct. When sulpho-tyrosine and sialyl-Le(x) are presented on liposomes, a potent inhibitory activity is generated toward the binding of P-selectin to HL60 cells, with 50% inhibitory concentration (IC(50)) values in the nanomolar range. These features of the lipid-linked ligand analogues, and the simple approach for their display on liposomes, may have applications in designs and screening of selectin inhibitors as anti-inflammatory compounds.

Binding Sites↗

PubMed1999

Antiproliferative properties of the lazaroids U-83836E and U-74389G on glioma cells in vitro.

The 21-aminosteroids (lazaroids) are a new family of steroid compounds that inhibit lipid peroxidation reactions. They are novel antioxidant agents, which have been shown to have antiproliferative properties on cancer cells and also are thought to prevent free radical-mediated blood-brain barrier damage. In order to understand the effect of lazaroids on glioma, we tested U-83836E and U-74389G at doses ranging between 0.1 100 m mM on primary cultures of glioblastoma multiforme from three patients, rat C6 glioma cell line, and 5 th subculture established from one of the patients. The effects of both compounds on cell proliferation were determined using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. U-83836E in the primary cultures was found to have 50% inhibitory concentrations (IC50 ) of 6.30, 6.75 and 6.50 m mM, respectively. The IC50 value of U-74389G was calculated as 91 m mM in only one of the patients. On C6 glioma cells, while the IC50 of U-83836E was 45 m mM, U-74389G showed no cytotoxic effect. On the 5 th subculture, U-83836E had an IC50 of 37.5 m mM, but the cytotoxic effects of U-74389G was less than in that of the primary culture. In conclusion, these compounds were found to be more cytotoxic in primary culture than the cell lines and there were also differences between their members in the inhibition of cell survival.

Animals↗

PubMed2001

Inhibition of protein farnesylation enhances the chemotherapeutic efficacy of the novel geranylgeranyltransferase inhibitor BAL9611 in human colon cancer cells.

Proteins belonging to the ras superfamily are involved in cell proliferation of normal and neoplastic tissues. To be biologically active, they require post-translational isoprenylation by farnesyl-transferase and geranylgeranyl-transferase. Enzyme inhibition by drugs may thus represent a promising approach to the treatment of cancer. Therefore, the combined effect of BAL9611, a novel inhibitor of geranylgeranylation, and manumycin, a farnesyl-transferase inhibitor, was evaluated on the SW620 human colon cancer cell line which harbours a mutated K-ras gene. BAL9611 and manumycin dose-dependently inhibited SW620 cell growth with 50% inhibitory concentration (IC(50)) of 0.47 +/- 0.03 and 5.24 +/- 1.41 microM (mean +/- SE), respectively. The isobologram analysis performed at the IC(50)level revealed that the combined treatment was highly synergistic with respect to cell growth inhibition. BAL9611 and manumycin were able to inhibit the geranylgeranylation of p21rhoA and farnesylation of p21ras; both drugs inhibited p42ERK2/MAPK phosphorylation, but their combination was more effective than either drug alone. Moreover, the enhanced inhibition of cell growth in vitro by the BAL9611-manumycin combination was also observed in vivo in CD nu/nu female mice xenografted with SW620 tumours. Finally, both drugs were able to induce cell death by apoptosis in vitro and in vivo, as demonstrated by perinuclear chromatin condensation, cytoplasm budding and nuclear fragmentation, and interoligonucleosomal DNA digestion. In conclusion, the inhibition of protein farnesylation enhances the chemotherapeutic effect of BAL9611 in vitro and in vivo in a synergistic fashion, as a result of the impairment of post-translational isoprenylation of proteins and phosphorylation of p42ERK2/MAPK, whose activation is associated with post-translational geranylgeranylation and farnesylation of p21rhoA and p21ras.

Alkyl and Aryl Transferases↗

PubMed2003

Angiotensin converting enzyme (ACE) inhibitory alkaloids from Fritillaria ussuriensis.

Bioassay-guided fractionation of the BuOH-soluble extract of Fritillaria ussuriensis afforded verticinone ( 1), verticine ( 2), and peimisine ( 3). Purification of these compounds was achieved with the use of various chromatographic methods. The structures of the compounds were identified on the basis of MS and NMR data analysis. Compounds 1 - 3 inhibited angiotensin I converting enzyme activity in a dose-dependent manner, displaying 50 % inhibitory concentration values of 165.0 microM, 312.8 microM, 526.5 microM, respectively. The presence of these active substances may be responsible, at least in part, for the antihypertensive action of the bulbs of Fritillaria ussuriensis.

Alkaloids↗

PubMed2006

Antiviral effect of aqueous extracts from species of the Lamiaceae family against Herpes simplex virus type 1 and type 2 in vitro.

Aqueous extracts from species of the Lamiaceae family were examined for their antiviral activity against Herpes simplex virus (HSV). Extracts from lemon balm (Melissa officinalis), peppermint (Mentha x piperita), prunella (Prunella vulgaris), rosemary (Rosmarinus officinalis), sage (Salvia officinalis) and thyme (Thymus vulgaris) were screened. Their inhibitory activity against Herpes simplex virus type 1 (HSV-1), type 2 (HSV-2) and an acyclovir-resistant strain of HSV-1 (ACV (res)) was tested in vitro on RC-37 cells in a plaque reduction assay. The 50% inhibitory concentrations (IC (50)) of the extracts for HSV plaque formation were determined in dose-response studies. All test compounds showed a high antiviral activity against HSV-1, HSV-2 and ACV (res). In order to identify the mode of antiviral action, the extracts were added to the cells or viruses at different stages of infection. Both types of Herpes virus including ACV (res) were considerably neutralized after treatment with the extracts prior to infection. At maximum non-cytotoxic concentrations of the extracts, plaque formation was significantly reduced by > 90% for HSV-1 and HSV-2 and > 85% for ACV (res). In time-response studies over a period of 2 hours, a clearly time-dependent activity was demonstrated. These results indicate that the extracts affect HSV before adsorption, but have no effect on the intracellular virus replication. Therefore, the extracts exert their antiviral effect on free HSV and offer a chance to use them for topical therapeutic application against recurrent HERPES infections.

Antiviral Agents↗

PubMed2002

Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine.

OBJECTIVES: Our objective was to examine the effect of different fruits and their constituents on P-glycoprotein and organic anion transporting polypeptide (OATP) activities in vitro and on drug disposition in humans. METHODS: P-glycoprotein-mediated digoxin or vinblastine efflux was determined in polarized epithelial cell monolayers. OATP-mediated fexofenadine uptake was measured in a transfected cell line. The oral pharmacokinetics of 120 mg fexofenadine was assessed with water, 25%-strength grapefruit juice, or normal-strength grapefruit, orange, or apple juices (1.2 L over 3 hours) in a randomized 5-way crossover study in 10 healthy subjects. RESULTS: Grapefruit juice and segments and apple juice at 5% of normal strength did not alter P-glycoprotein activity. Grapefruit extract reduced transport. 6',7'-Dihydroxybergamottin had modest inhibitory activity (50% inhibitory concentration [IC(50)], 33 micromol/L). In contrast, grapefruit, orange, and apple juices at 5% of normal strength markedly reduced human OATP and rat oatp activity. 6',7'-Dihydroxybergamottin potently inhibited rat oatp3 and oatp1 (IC(50), 0.28 micromol/L). Other furanocoumarins and bioflavonoids also reduced rat oatp3 activity. Grapefruit, orange, and apple juices decreased the fexofenadine area under the plasma concentration-time curve (AUC), the peak plasma drug concentration (C(max)), and the urinary excretion values to 30% to 40% of those with water, with no change in the time to reach C(max), elimination half-life, renal clearance, or urine volume in humans. Change in fexofenadine AUC with juice was variable among individuals and inversely dependent on value with water. CONCLUSIONS: Fruit juices and constituents are more potent inhibitors of OATPs than P-glycoprotein activities, which can reduce oral drug bioavailability. Results support a new model of intestinal drug absorption and mechanism of food-drug interaction.

ATP Binding Cassette Transporter, Subfamily B↗