PURPOSE: Platinum coordination complex (cisplatin) has been currently used as one of the most effective compound in the treatment of various solid tumors. However, its use has been limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program has been aimed at developing drugs capable of diminishing toxicity and selective cytotoxicity. MATERIALS AND METHODS: A new series of highly water soluble platinum (II) complexes Pt (II) [1,3-Bis (phenylthio) propane) (trans-l-1,2-diaminocyclohexane) (PC-1) and Pt (II) [1,3-Bis-(phenylthio) (propane)]-1,2-diaminocyclohexane (PC-2) were synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (.IR), ""C-nuclear magnetic resonance (NMR)]. In vitro antitumor activity and nephrotoxi -cities of new Pt (II) complexes were tested against MKN-45 human gastric cancer cell- lines and normal kidney cells using colorimetric MTT[3-(4,5-dimethyl thiazol-2-yl)-2,5- diphenyl tetrazolium bromide] assay for cell survival and proliferation. RESULTS: PC-1 showed activity against MKN-45/P and MKN-45/CDDP human gastric adenocarcinoma cells, and the antitumor activity of this compound was comparable or superior to that of PC-2 and cisplatin. The nephrotoxicity of PC-1 and PC-2 were found quite less than that of cisplatin using MTT, [H] thymidine uptake and glucose consumption tests in rabbit proximal tubule cells, human kidney cortical cells and human renal cortical tissues. CONCLUSION: Based on these results, this novel platinum (II) complex compound (PC-1) represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low nephrotoxicity.
Adenocarcinoma ; Cell Survival ; Cisplatin ; Drug Discovery ; Glucose ; Humans* ; Kidney* ; Platinum ; Stomach Neoplasms* ; Thymidine

Refractory status epilepticus (RSE) is defined as seizure activity that continues after treatment with conventional anticonvulsants. Mortality rates of range from 2% to 100%. RSE are associated with significant morbidity and high mortality as evidenced by older age of the patient, acute etiology for the seizure, no previous history of seizures, low initial Glasgow Coma Scale, and the significant duration of the RSE. An intravenous valproic acid (VPA) was suggested as a useful drug in controlling RSE. A continuous infusion VPA was an efficient method of rapidly achieving VPA concentrations in the upper region of the therapeutic range while minimizing adverse effects. A 10-year-old female suffered a generalized tonic clonic seizure that developed into refractory status epilepticus. Her Glasgow Coma Scale was deteriorated to 4. Status epilepticus was refractory to phenytoin, phenobarbital, midazolam, thiopental. After 4days of unsatisfactory control of seizure activity, high dose VPA was administered for 2 months. The clinical and electrolgraphic seizure improved and the patient has made an satisfactory neurologic recovery
Anticonvulsants ; Child ; Female ; Glasgow Coma Scale ; Humans ; Midazolam ; Phenobarbital ; Phenytoin ; Seizures ; Status Epilepticus ; Thiopental ; Valproic Acid

PURPOSE: Both headache and obesity are prevalent and chronic conditions among children. A well-known pathophysiology of migraine is that calcitonin gene-related peptide (CGRP) is an important postsynaptic mediator of trigemino-vascular inflammation. Plasma CGRP levels have been shown to increase in obese individuals during the headache phase of migraines. The purpose of this study was to assess the relationship between headache and plasma CGRP levels in obese children. METHODS: We prospectively studied plasma CGRP levels in 33 patients (20 overweight and obese subjects without headache, 13 overweight and obese subjects with headache) who visited Chosun University Hospital from March 2009 to September 2009. Blood samples were collected from cubital veins and plasma levels of CGRP were measured by radioimmunoassay. RESULTS: The mean age was 12.3+/-2.3 (range 6-15 years) and mean CGRP level was 19.1+/-2.5 pg/ml in the overweight and obese with headache group and 17.4+/-5.1 pg/mL in the overweight and obese without headache group. In the group CGRP levels lower than 19 pg/mL, mean headache frequency per month, mean severity, and mean disability were 17.0+/-18.4, 4.0+/-2.8 and 2.0+/-0.0, respectively. In the group with CGRP levels of 19 or greater pg/ml, levels were 11.0+/-9.8, 5.6+/-1.0, and 23.1+/-8.2, respectively. CONCLUSION: The mean CGRP level in overweight and obese children with headache was not significantly higher than in those without headache (P =0.202). Further, there was no significant correlation between CGRP level and frequency, severity of headache, and disability due to headache (P > 0.05). Further studies are needed to access the relationship of CGRP and pediatric headache in obese subjects.
Calcitonin ; Calcitonin Gene-Related Peptide ; Child ; Headache ; Humans ; Inflammation ; Migraine Disorders ; Obesity ; Overweight ; Plasma ; Prospective Studies ; Veins

PURPOSE: To establish a new therapeutic strategy for proliferative vitreoretinopathhy (PVR), we examined the effect of combined treatment with HDAC inhibitor SAHA and proteasome inhibitor lactacystin in human retinal pigment epithelial (RPE) cells, ARPE-19. METHODS: Viability was determined by trypan blue exclusion assay. Mitochondrial membrane potential (MMP) was measured by flow cytometry. Proteasome activity was measured by fluorophotometry. The expression and degradation of apoptosis-related proteins were assesssed by Western blotting. Subcellular location of apoptosis-related factors was monitored by confocal miscroscopy. RESULTS: A single treatment with 5 micro M SAHA or 10 micro M lactacystin did not reduce cell viability. However, combination treatment with 5 micro M SAHA and 10 micro M lactacystin substantially reduced the viability, because the mixture induced the reduction of MMP and nuclear condensation or fragmentation. Moreover, the combination treatment triggered the activation of caspase-3 and the production of PARP cleavage products. These data indicate that the combination treatment efficiently induces apoptosis in ARPE-19 cells. However, co-treatment of SAHA did not augment the proteasome inhibitory activity of lactacystin, nor did co-treatment of lactacystin augment acetylation of histones. It is notable that while p53 and CAD were observed in the mitochondria of cells treated with SAHA, they were translocated into the nucleus after the combination treatment. CONCLUSIONS: These results suggest that the combination treatment of SAHA and lactacystin effectively induced apoptosis in ARPE-19 cells. Further work is warranted to develop this combination therapy as a novel therapeutic strategy for PVR.
Acetylation ; Apoptosis* ; Blotting, Western ; Caspase 3 ; Cell Survival ; Flow Cytometry ; Fluorophotometry ; Histones ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria ; Proteasome Endopeptidase Complex ; Proteasome Inhibitors ; Retinaldehyde ; Trypan Blue

No abstract available.
Fetus* ; Humans ; Male* ; Mesothelioma*

Suppressor of Variegation 3–9 Homolog 2 (SUV39H2) methylates the lysine 9 residue of histone H3 and induces heterochromatin formation, resulting in transcriptional repression or silencing of target genes. SUV39H1 and SUV39H2 have a role in embryonic development, and SUV39H1 was shown to suppress cell cycle progression associated with Rb. However, the function of human SUV39H2 has not been extensively studied. We observed that forced expression of SUV39H2 decreased cell proliferation by inducing G1 cell cycle arrest. In addition, SUV39H2 was degraded through the ubiquitin-proteasomal pathway. Using yeast two-hybrid screening to address the degradation mechanism and function of SUV39H2, we identified translationally controlled tumor protein (TCTP) as an SUV39H2-interacting molecule. Mapping of the interacting regions indicated that the N-terminal 60 amino acids (aa) of full-length SUV39H2 and the C-terminus of TCTP (120–172 aa) were critical for binding. The interaction of SUV39H2 and TCTP was further confirmed by co-immunoprecipitation and immunofluorescence staining for colocalization. Moreover, depletion of TCTP by RNAi led to up-regulation of SUV39H2 protein, while TCTP overexpression reduced SUV39H2 protein level. The half-life of SUV39H2 protein was significantly extended upon TCTP depletion. These results clearly indicate that TCTP negatively regulates the expression of SUV39H2 post-translationally. Furthermore, SUV39H2 induced apoptotic cell death in TCTP-knockdown cells. Taken together, we identified SUV39H2, as a novel target protein of TCTP and demonstrated that SUV39H2 regulates cell proliferation of lung cancer cells.
Amino Acids ; Apoptosis ; Carrier Proteins ; Cell Cycle ; Cell Death ; Cell Proliferation ; Embryonic Development ; Female ; Fluorescent Antibody Technique ; G1 Phase Cell Cycle Checkpoints ; Half-Life ; Heterochromatin ; Histones ; Humans ; Immunoprecipitation ; Lung Neoplasms ; Lysine ; Mass Screening ; Pregnancy ; Repression, Psychology ; RNA Interference ; Up-Regulation ; Yeasts

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,3-dichloropropane (DCP) as a leaving group. A new series of (Pt(cis-DACH)(DCP))(PC) was evaluated for its cytotoxic: activity on MKN-45 human gastric adenocarcinoma cells and normal primary cultured kidney cells. The new platinum complex has demonstrated high efficacy in the cytotoxicity against MKN-45/P, MKN-45/ADM and MKN-45/CDDP cell-lines. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined by MTT assay, the (3H)-thymidine uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new, clinically available anticancer chemotherapeutic agents.
Adenocarcinoma ; Cisplatin ; Glucose ; Humans ; Kidney ; Platinum

Cisplatin is often effective in cancer treatment, but its clinical use is limited because of its nephrotoxicity. We have synthesized new platinum (II) coordination complexes (PC-1 & PC-2) containing trans-l and cis-1, 2-diaminocyclohexane (DACH) as carrier ligands and L-3 -phenyllactic acid (PLA) as a leaving group with the aim of reducing nephrotoxicity but maintaining its anticancer activity. In this study, new platinum (II) complex compounds were evaluated for selective cytotoxicity on cancer cell-lines and normal kidney cells. The new platinum complexes have demonstrated high efficacy in the cytotoxicity against human bladder carcinoma cell-lines (T-24/HT-1376). The cytotoxicity of these compounds against rabbit proximal renal tubular cells and human renal cortical tissues, was determined by MTT assay, the [3H]-thymidine uptake and glucose consumption test, and found to be quite less than those of cisplatin. Based on our results, these novel platinum compounds appear to be valuable lead compounds with high efficacy and low nephrotoxicity.
Cisplatin ; Coordination Complexes* ; Glucose ; Humans* ; Kidney* ; Ligands ; Platinum Compounds ; Platinum* ; Urinary Bladder Neoplasms* ; Urinary Bladder*

We have synthesized a novel platinum(II) coordination complex containing cis-1,2-diaminocyclohexane (DACH) as a carrier ligand and 1,2-dichloroethane (DCE) as a leaving group. In addition, nitrate was added to improve the water-solubility. A new series of (Pt(cis-DACH)(DCE)) cntdot 2NO3(PC) was evaluated for its cytotoxic activity on T-24 and J-82 human bladder carcinoma cells and normal primary cultured kidney cells. PC has demonstrated high levels of cytotoxicity against T-24 and J-82 cells. The cytotoxicity of PC against rabbit proximal renal tubular cells, human renal cortical cells and human renal cortical tissues, determined using the MTT assaying technique, the (3H)-thymidine uptake and glucose consumption tests, was found to be quite less than those of cisplatin. Based on these results, this novel platinum(II) coordination complex appears to be better for improving antitumor activities with low nephrotoxicity and is a valuable lead in the development of new clinically available anticancer chemotherapeutic agents.
Cell Line* ; Cisplatin ; Glucose ; Humans* ; Kidney* ; Urinary Bladder Neoplasms* ; Urinary Bladder*

Expression of matrix metalloproteinase-9 (MMP-9) is associated with airway remodeling and tissue injury in asthma. However, little is known about how MMP-9 is up-regulated in airway epithelial cells. In this study, we show that phorbol myristate acetate (PMA) induces MMP-9 expression via a protein kinase Calpha(PKCalpha)-dependent signaling cascade in BEAS-2B human lung epithelial cells. Pretreatment with either GF109203X, a general PKC inhibitor, or Go6976, a PKCalpha/beta isozyme inhibitor, inhibited PMA-induced activation of the MMP-9 promoter, as did transient transfection with PKCalpha antisense oligonuclotides. PMA activated NF-kappaB by phosphorylating IkappaB in these cells and this was also inhibited by GF109203X and Go6976, suggesting that PKCalpha acts as an upstream regulator of NF-kappaB in PMA-induced MMP-9 induction. Our results indicate that a "PKCalpha-NF-kappaB"-dependent cascade is involved in the signaling leading to PMA-induced MMP-9 expression in the lung epithelium.
Up-Regulation/*drug effects ; Tetradecanoylphorbol Acetate/*pharmacology ; Protein Kinase C-alpha/*metabolism ; NF-kappa B/*metabolism ; Matrix Metalloproteinase 9/*metabolism ; Lung/drug effects/*metabolism ; Humans ; Epithelial Cells/drug effects/metabolism ; Cell Line