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The effect of salinomycin on ovarian cancer stem-like cells
( Hyewon Chung ),( Yu-hwan Kim ),( Myoung Kwon ),( So-jin Shin ),( Sang-hoon Kwon ),( Soon-do Cha ),( Chi-heum Cho ) 대한산부인과학회 2016 Obstetrics & Gynecology Science Vol.59 No.4
Objective The identification of cancer stem-like cells is a recent development in ovarian cancer. Compared to other cancer cells, cancer stem-like cells present more chemo-resistance and more aggressive characteristics. They play an important role in the recurrence and drug resistance of cancer. Therefore, the target therapy of cancer stem-like cell may become a promising and effective approach for ovarian cancer treatment. It may also help to provide novel diagnostic and therapeutic strategies. Methods The OVCAR3 cell line was cultured under serum-free conditions to produce floating spheres. The CD44+CD117+ cell line was isolated from the human ovarian cancer cell line OVCAR3 by using immune magnetic-activated cell sorting system. The expression of stemness genes such as OCT3/4, NANOG and SOX2 mRNA were determined by reverse transcription polymerase chain reaction. OVCAR3 parental and OVCAR3 CD44+CD117+ cells were grown in different doses of paclitaxel and salinomycin to evaluate the effect of salinomycin. And growth inhibition of OVCAR3 CD44+CD117+ cells by paclitaxel combined with salinomycin was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl-2H-tetrazolium bromide (MTT) assay. Results Tumor spheroids generated from the OVCAR3 cell line are shown to have highly enriched CD44 and CD117 expression. Treatment with a combination of paclitaxel and salinomycin demonstrated growth inhibition of OVCAR3 CD44+CD117+ cells. Conclusion The present study is a detailed investigation on the expression of CD44 and CD117 in cancer stem cells and evaluates their specific tumorigenic characteristics in ovarian cancer. This study also demonstrates significant growth inhibition of cancer stem-like cells by paclitaxel combined with salinomycin. Identification of these cancer stem-like cell markers and growth inhibition effect of salinomycin may be the next step to the development of novel target therapy in ovarian cancer.
Chung, Hyewon,Yu, Kyung-Sang,Hong, Kyung Taek,Choi, Jung Yoon,Hong, Che Ry,Kang, Hyoung Jin,Park, Kyung Duk,Shin, Hee Young,Lee, SeungHwan Raven Press 2017 Therapeutic drug monitoring Vol.39 No.3
<P>Busulfan is a cytotoxic agent used in preconditioning for hematopoietic stem cell transplantation. Therapeutic drug monitoring of busulfan is necessary owing to its narrow therapeutic range. Patients undergoing preconditioning are susceptible to infection and might require coadministration of antibiotics. We present a case study of a 3-year-old girl with precursor T-cell acute lymphoblastic leukemia who received intravenous busulfan before hematopoietic stem cell transplantation. Metronidazole was coadministered before the third dose of busulfan because of Clostridium difficile infection. The daily pharmacokinetic analysis revealed that the clearance reduced to 57% of that before the coadministration. Although the underlying mechanism is unclear, a significant pharmacokinetic interaction was observed between busulfan and metronidazole, underscoring the importance of therapeutic drug monitoring.</P>
Chung, Hyewon,Kim, Ae-kyeong,Jung, Sun-Ah,Kim, Si Wouk,Yu, Kweon,Lee, Joon H. Elsevier 2010 FEBS letters Vol.584 No.16
<P><B>Abstract</B></P><P>Methionine sulfoxide reductase A (msrA) was previously found to increase resistance to oxidative stress and longevity in animals. We identified <I>Drosophila</I> msrA (<I>dmsrA</I>), a <I>Drosophila</I> homolog of human <I>msrA</I>, as a downstream effector of forkhead box O (FOXO) signaling in <I>Drosophila</I>, which enhances resistance to oxidative stress and increases survival under stressed conditions. Additionally, overexpression of <I>dmsrA</I> in neurons extended the lifespan of flies. Moreover, overexpression of <I>dmsrA</I> in fat body cells caused FOXO to translocate to the nucleus, implying that this possible positive feedback loop between <I>dmsrA</I> and FOXO could potentiate the antioxidant activity of <I>dmsrA</I> and increase the lifespan in <I>Drosophila</I>.</P>
Chung, Seock-Jin,Yoon, Hai-Jeon,Youn, Hyewon,Kim, Mi Jeong,Lee, Yun-Sang,Jeong, Jae Min,Chung, June-Key,Kang, Keon Wook,Xie, Lin,Zhang, Ming-Rong,Cheon, Gi Jeong Society of Nuclear Medicine 2018 The Journal of nuclear medicine Vol.59 No.5
<P>Activated macrophages have been known to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). <SUP>18</SUP>F-FEDAC (<I>N</I>-benzyl-<I>N</I>-methyl-2-[7,8-dihydro-7-(2-<SUP>18</SUP>F-fluoroethyl)-8-oxo-2-phenyl-9<I>H</I>-purin-9-yl]acetamide) is a radiolabeled ligand for the 18-kDa translocator protein (TSPO), which is abundant in activated macrophages. We evaluated the feasibility of using <SUP>18</SUP>F-FEDAC in a murine RA model. <B>Methods:</B> RAW 264.7 mouse macrophages were activated by lipopolysaccharide. TSPO expression levels in activated and inactivated macrophages were measured by quantitative polymerase chain reaction and Western blotting. The cellular uptake and specific binding of <SUP>18</SUP>F-FEDAC were measured using a γ-counter. For the in vivo study, collagen-induced arthritis (CIA) was developed in DBA/1 mice, and the clinical score for arthritis was measured regularly. <SUP>18</SUP>F-FEDAC and <SUP>18</SUP>F-FDG PET images were acquired on days 23 and 37 after the first immunization. Histologic examinations were performed to evaluate macrophages and TSPO expression. <B>Results:</B> We found increased TSPO messenger RNA and protein expression in activated macrophages. Uptake of <SUP>18</SUP>F-FEDAC in activated macrophages was higher than that in nonactivated cells and was successfully blocked by the competitor, PK11195. In CIA mice, joint swelling was apparent on day 26 after the first immunization, and the condition worsened by day 37. <SUP>18</SUP>F-FEDAC uptake by arthritic joints increased early on (day 23), whereas <SUP>18</SUP>F-FDG uptake did not. However, <SUP>18</SUP>F-FDG uptake by arthritic joints markedly increased at later stages (day 37) to a higher level than <SUP>18</SUP>F-FEDAC uptake. The <SUP>18</SUP>F-FEDAC uptake correlated weakly with summed severity score (<I>P</I> = 0.019, <I>r</I> = 0.313), whereas the <SUP>18</SUP>F-FDG uptake correlated strongly with summed severity score (<I>P</I> < 0.001, <I>r</I> = 0.897). Histologic sections of arthritic joints demonstrated an influx of macrophages compared with that in normal joints. <B>Conclusion:</B> <SUP>18</SUP>F-FEDAC enabled the visualization of active inflammation sites in arthritic joints in a CIA model by targeting TSPO expression in activated macrophages. The results suggest the potential usefulness of <SUP>18</SUP>F-FEDAC imaging in the early phase of RA.</P>
Chung, Hyewon,Lee, Howard,Han, HyeKyung,An, Hyungmi,Lim, Kyoung Soo,Lee, Yong Jin,Cho, Joo-Youn,Yoon, Seo Hyun,Jang, In-Jin,Yu, Kyung-Sang Dove Medical Press 2015 Drug design, development and therapy Vol.9 No.-
<P><B>Purpose</B></P><P>SYP-1018 is a lyophilized polymeric nanoparticle formulation of voriconazole that is under development for intravenous dosing. This study compared the pharmacokinetic and tolerability profiles of SYP-1018 with those of Vfend<SUP>®</SUP>, the marketed formulation of voriconazole. The effect of CYP2C19 polymorphism on the voriconazole pharmacokinetics was also evaluated.</P><P><B>Methods</B></P><P>An open-label, two-treatment, two-period, two-sequence crossover study was conducted in 52 healthy male volunteers, who randomly received a single intravenous infusion of either of the two voriconazole formulations at 200 mg. Blood samples were collected up to 24 hours after drug administration for pharmacokinetic analysis. The plasma concentrations of voriconazole were determined using liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were estimated using a noncompartmental method. CYP2C19 genotype was identified in 51 subjects.</P><P><B>Results</B></P><P>The geometric mean ratio (90% confidence interval) of SYP-1018 to Vfend<SUP>®</SUP> was 0.99 (0.93–1.04) for the maximum plasma concentrations (C<SUB>max</SUB>) and 0.97 (0.92–1.01) for the area under the concentration–time curve (AUC) from dosing to the last quantifiable concentration (AUC<SUB>last</SUB>). Nineteen homozygous extensive metabolizers (EMs, *1/*1), 19 intermediate metabolizers (IMs, *1/*2 or *1/*3), and ten poor metabolizers (PMs, *2/*2, *2/*3, or *3/*3) were identified, and the pharmacokinetic comparability between SYP-1018 and Vfend<SUP>®</SUP> was also noted when analyzed separately by genotype. The systemic exposure to voriconazole was greatest in the PM group, followed by the IM, and then the EM groups. Furthermore, the intrasubject variability for C<SUB>max</SUB> and AUC<SUB>last</SUB> was greater in IMs and PMs than in EMs. No serious adverse event occurred, and both treatments were well tolerated.</P><P><B>Conclusion</B></P><P>SYP-1018 had comparable pharmacokinetic and tolerability profiles to Vfend<SUP>®</SUP> after a single intravenous infusion. CYP2C19 genotype affected not only the pharmacokinetics of voriconazole, but its intrasubject variability. SYP-1018 can be further developed as a clinically effective alternative to Vfend<SUP>®</SUP>.</P>
Chung, Hyewon,Kim, Anhye,Lim, Kyoung Soo,Park, Sang-In,Yu, Kyung-Sang,Yoon, Seo Hyun,Cho, Joo-Youn,Chung, Jae-Yong Lippincott, Williams and Wilkins 2017 International clinical psychopharmacology Vol.32 No.1
<P>Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.</P>