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Medical research on stelazine
Plant Physiol. 2008 Nov 14;
Chen T, Wu X, Chen Y, Li X, Huang M, Zheng M, Baluska F, Samaj J, Lin J
Ca(2+)-calmodulin (Ca(2+)-CaM) is a critical molecule that mediates cellular functions by interacting with various metabolic and signaling pathways. However, the protein expression patterns and accompanying serial cytological responses in Ca(2+)-CaM signaling deficiency remain enigmatic. Here, we provide a global analysis of the cytological responses and significant alterations in protein expression profiles after trifluoperazine treatment, which abrogates Ca(2+)-CaM signaling. Ninety-three differential displayed proteins were identified by comparative proteomics at different developing stages and were assigned to different functional categories closely related to tip growth machinery. The inhibition of Ca(2+)-CaM signaling rapidly induced an increase in extracellular Ca(2+) influx, resulting in dramatically increased cytosolic Ca(2+) concentrations and ultrastructural abnormalities in organelles as the primary responses. Secondary and tertiary alterations included actin filament depolymerization, disrupted patterns of endocytosis and exocytosis, and cell wall remodeling, ultimately resulting in perturbed pollen tube extension. In parallel with these cytological events, time-course experiments revealed that most differentially expressed proteins showed time-dependent quantitative changes, i.e., some signaling proteins and proteins involved in organelle functions and energy production changed first, followed by alterations in proteins related to cytoskeletal organization, secretory pathways and polysaccharide synthesis. Taken together, Ca(2+)-CaM dysfunction induced serial cytological responses and temporal changes in protein expression profiles, indicating the pivotal role of Ca(2+)-CaM in the regulation of tip growth machinery.
Melanoma Res. 2008 Dec; 18(6): 386-99
Vad NM, Yount G, Moridani MY
In the current work, we investigated the biochemical toxicity of acetylsalicylic acid (ASA; Aspirin) in human melanoma cell lines using tyrosinase enzyme as a molecular cancer therapeutic target. At 2 h, ASA was oxidized 88% by tyrosinase. Ascorbic acid and NADH, quinone reducing agents, were significantly depleted during the enzymatic oxidation of ASA by tyrosinase to quinone. The 50% inhibitory concentration (48 h) of ASA and salicylic acid toward SK-MEL-28 cells were 100 mumol/l and 5.2 mmol/l, respectively. ASA at 100 mumol/l was selectively toxic toward human melanocytic SK-MEL-28, MeWo, and SK-MEL-5 and murine melanocytic B16-F0 and B16-F10 melanoma cell lines. However, ASA was not significantly toxic to human amelanotic C32 melanoma cell line, which does not express tyrosinase enzyme, and human nonmelanoma BJ, SW-620, Saos, and PC-3 cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, increased ASA toxicity toward SK-MEL-28 cells indicating quinone formation and intracellular GSH depletion played important mechanistic roles in ASA-induced melanoma toxicity. Ascorbic acid, a quinone reducing agent, and GSH, an antioxidant and quinone trap substrate, prevented ASA cell toxicity. Trifluoperazine, inhibitor of permeability transition pore in mitochondria, prevented ASA toxicity. ASA led to significant intracellular GSH depletion in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ASA also led to significant reactive oxygen species (ROS) formation in melanocytic SK-MEL-28 melanoma cells but not in amelanotic C32 melanoma cells. ROS formation was exacerbated by dicoumarol and 1-bromoheptane in SK-MEL-28. Our investigation suggests that quinone species, intracellular GSH depletion, ROS formation, and mitochondrial toxicity significantly contributed toward ASA selective toxicity in melanocytic SK-MEL-28 melanoma cells.
Talanta. 1998 Nov; 47(3): 625-30
Patela YP, Dhorda UJ, Sundaresan M
A reproducible and selective method was developed for the analysis of three anti-pschycotics, i.e. haloperidol, trifluoperazine and trihexyphenidyl in bulk and dosage forms using packed column supercritical fluid chromatography (SFC). The analytes were resolved by elution with supercritical fluid carbon dioxide doped with 16.67% (v/v) methanol containing 0.8% isopropylamine. Parallel studies were performed by HPLC using ion pairing reagent and a comparison is discussed. The method was successfully used for the assay of three formulations containing a combination of: (1) haloperidol-trihexyphenidyl; (2) haloperidol-trifluoperazine; (3) trifluoperazine-trihexyphenidyl.
Talanta. 1998 Aug; 46(6): 1433-8
Kitamura K, Goto T, Kitade T
The absorption spectra of six phenothiazine derivatives, chlorpromazine, triflupromazine, promazine, promethazine, trifluoperazine and prochlorperazine, measured in the solutions containing various amounts of human erythrocyte ghosts (HEG) showed bathocromic shifts according to the amount of HEG. Due to the strong background signals caused by HEG, the baseline compensation was incomplete, even though the sample and the reference solutions contained the same amount of HEG, hence further spectral information could not be obtained. The second derivative spectra of these absorption spectra clearly showed the derivative isosbestic points, indicating that the residual background signal effects were entirely eliminated. The derivative intensity differences of the phenothiazines (DeltaD values) before and after the addition of HEG were measured at a specific wavelength. Using the DeltaD values, the partition coefficients (K(p)) of these drugs were calculated and obtained with R.S.D. of below 10 %. The fractions of partitioned phenothiazines calculated from the K(p) values agreed well with the experimental values. The results indicate that the derivative method can be applicable to the determination of partition coefficients of drugs to HEG without any separation procedures.
Effects of psychotropic drugs on the thrombin-induced liberation of arachidonate in human platelets.
Saudi Med J. 2008 Oct; 29(10): 1397-407
Oruch R, Pryme IF, Holmsen H
OBJECTIVE: To compare the effects of chlorpromazine (CPZ), prochlorperazine (PCP), trifluoperazine (TFP), clozapine (CLO), haloperidol (HPD), quetiapine (QTP), pimozide (PMZ), and olanzapine (OLP) as well as the tricyclic antidepressants amitriptyline AMI, imipramine IMI, and nortriptyline NTP on thrombin-induced liberation of arachidonic acid AA in platelets. METHODS: This work was carried out at the Department of Biomedicine, University of Bergen, Norway in 2006-2007. Human platelets pre labelled with [3H] arachidonate were incubated with thrombin in the absence and presence of the drugs, and the amount of free [3H] arachidonate liberated was determined. Myosin light chain (MLC) phosphorylation was determined in [32P] phosphate-labelled platelets after sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of the drugs on the molecular area and surface pressure of phospholipid monolayers were determined in the Langmuir apparatus. RESULTS: All drugs reduced arachidonate liberation with the ranking order of increasing potency: OLP
Induction of autophagic cell death by a novel molecule is increased by hypoxia.
Autophagy. 2008 Nov 16; 4(8): 1042-53
Tafani M, Schito L, Anwar T, Indelicato M, Sale P, Di Vito M, Morgante E, Beraldi R, Makovec F, Letari O, Caselli G, Spadafora C, Pucci B, Russo MA
Adaptation to hypoxia through activation of the hypoxia inducible factor-1 (HIF-1) is crucial for tumor cells survival. Here we describe the antitumoral effects of the new molecule CR 3294 on tumor cells in the presence of hypoxia. Treatment of the breast carcinoma cell line MDA-MB-231 with CR 3294 in 1% O(2) resulted in an in vivo and in vitro inhibition of tumor growth. CR 3294 induced accumulation of autophagosomes in hypoxic MDA-MB-231 cells as assessed by both transmission electron microscopy (TEM) and the autophagic marker LC3-II. TEM analysis revealed the presence of invaginations of the cytoplasm into the nucleus. Autophagosomes were present in such invaginations. Moreover, CR 3294 inhibited both the DNA binding of HIF-1alpha and VEGF mRNA synthesis. Immunoprecipitation and immunofluorescence studies showed an interaction between LC3 and HIF-1alpha. We next detailed the effect of inhibitors and activators of autophagy on both HIF-1alpha and LC3. In particular, 3 methyladenine (3MA) and wortmannin, two macroautophagic inhibitors, prevented both the decrease of HIF-1alpha protein levels and LC3 processing in cells treated with CR 3294. Bafilomycin and leupeptin, inhibitors of lysosomes, prevented HIF-1alpha decrease without affecting LC3 processing. By contrast, treating hypoxic MDA-MB-231 cells with trifluoperazine (TFP) or serum withdrawal (SW), two activators of autophagy, diminished HIF-1alpha levels and stimulated LC3 processing. These results indicate that activation of the autophagic pathway in hypoxic cells by the new molecule CR 3294, as well as by TFP or SW, can have potentially important implications for cancer treatment.
Calmodulin binds to maize lipid transfer protein and modulates its lipids binding ability.
FEBS J. 2008 Nov; 275(21): 5298-308
Li C, Xie W, Bai W, Li Z, Zhao Y, Liu H
Although plant non-specific lipid transfer proteins (ns-LTPs) are characterized by their ability to bind and transfer a broad range of hydrophobic ligands in vitro, their biological functions in vivo remain unclear. Recently, it has been proposed that ns-LTPs may play a key role in plant defense mechanisms, particularly during the induction of systemic acquired resistance, however, very little is known about the regulation in this process. We report that the binding of maize non-specific lipid transfer protein (Zm-LTP) to calmodulin (CaM) is in a calcium-independent manner. To better understand the interaction mechanism between Zm-LTP and CaM, the CaM-binding site of Zm-LTP was mapped to the region of amino acids 46-60. Point mutations indicate that four amino acid residues, R46, R47, K54 and R58, in this region are crucial for binding. Furthermore, we tested the effects of CaM on the lipid-binding activity of Zm-LTP in the presence of Ca(2+), EGTA, N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide and trifluoperazine respectively. We also investigated the structural features of CaM-binding motifs in LTPs from different species and strong differences were observed. Taken together, our results suggest that the interaction with CaM could be a common feature of plant LTPs. The identification and characterization of CaM-binding domain of LTPs should provide new insights into the mechanism by which the physiological functions of LTPs are regulated.
Med Mycol. 2008 Sep 16; 1-5
Galgoczy L, Papp T, Kovacs L, Ordogh L, Vagvolgyi C
The in vitro antifungal activities of two phenothiazine (PTZ) compounds, trifluoperazine (TFP) and chlorpromazine (CPZ) separately and in combination with amphotericin B (AMB) were tested against eight fungal isolates known to be possible agents of rhinocerebral zygomycosis. While both PTZs individually had antifungal effects against these filamentous fungi, only the antifungal activity of TFP increased in presence of AMB. TFP and AMB acted synergistically and caused full inhibition of all strains tested except for Absidia glauca. In contrast, CPZ was found to act antagonistically with AMB with all of studied isolates.
Biochemical mechanism of acetaminophen (APAP) induced toxicity in melanoma cell lines.
J Pharm Sci. 2008 Aug 29;
Vad NM, Yount G, Moore D, Weidanz J, Moridani MY
In this work, we investigated the biochemical mechanism of acetaminophen (APAP) induced toxicity in SK-MEL-28 melanoma cells using tyrosinase enzyme as a molecular cancer therapeutic target. Our results showed that APAP was metabolized 87% by tyrosinase at 2 h incubation. AA and NADH, quinone reducing agents, were significantly depleted during APAP oxidation by tyrosinase. The IC(50) (48 h) of APAP towards SK-MEL-28, MeWo, SK-MEL-5, B16-F0, and B16-F10 melanoma cells was 100 microM whereas it showed no significant toxicity towards BJ, Saos-2, SW-620, and PC-3 nonmelanoma cells, demonstrating selective toxicity towards melanoma cells. Dicoumarol, a diaphorase inhibitor, and 1-bromoheptane, a GSH depleting agent, enhanced APAP toxicity towards SK-MEL-28 cells. AA and GSH were effective in preventing APAP induced melanoma cell toxicity. Trifluoperazine and cyclosporin A, inhibitors of permeability transition pore in mitochondria, significantly prevented APAP melanoma cell toxicity. APAP caused time and dose-dependent decline in intracellular GSH content in SK-MEL-28, which preceded cell toxicity. APAP led to ROS formation in SK-MEL-28 cells which was exacerbated by dicoumarol and 1-bromoheptane whereas cyslosporin A and trifluoperazine prevented it. Our investigation suggests that APAP is a tyrosinase substrate, and that intracellular GSH depletion, ROS formation and induced mitochondrial toxicity contributed towards APAP's selective toxicity in SK-MEL-28 cells. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci.
Sci China C Life Sci. 1998 Feb; 41(1): 64-70
Li C, Xiang Z, Ling Q, Shang K
Light-induced phosphorylation of endogenous thylakoid membrane protein can be inhibited markedly by a novel inhibitor CaMBP-10 which is discovered and isolated from plant. The inhibitory effect of BP-10 can be eliminated by addition of CaM. At the same time, the phosphorylation can also be inhibited by EGTA or CaM antagonists, such as TFP (trifluoperazine) and W-7 (N-(6-aminohexyl)-5-chloro-l-naphthalene sulfonamide). This result implies that (i) Ca(2+) and CaM most likely participate in and regulate plant photosynthesis; (ii) the kinase that catalyzes thylakoid membrane protein phosphorylation can be regulated by Ca(2+) and CaM. However, the further experiments indicate that BP-10 has no effect on dephosphorylation of thylakoid phosphoproteins.