Publications by authors named "Won S Kim"

16 Publications

  • Page 1 of 1

Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors.

Behav Brain Res 2021 Sep 13;413:113466. Epub 2021 Jul 13.

Behavioral and Systems Neuroscience Area, Department of Psychology, Rutgers University-New Brunswick, Piscataway, NJ, 08854, USA. Electronic address:

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impairments in social interaction, cognition, and communication, as well as the presence of repetitive or stereotyped behaviors and interests. ASD is most often studied as a neurodevelopmental disease, but it is a lifelong disorder. Adults with ASD experience more stressful life events and greater perceived stress, and frequently have comorbid mood disorders such as anxiety and depression. It remains unclear whether adult exposure to chronic stress can exacerbate the behavioral and neurodevelopmental phenotypes associated with ASD. To address this issue, we first investigated whether adult male and female Engrailed-2 deficient (En2-KO, En2-/-) mice, which display behavioral disturbances in avoidance tasks and dysregulated monoaminergic neurotransmitter levels, also display impairments in instrumental behaviors associated with motivation, such as the progressive ratio task. We then exposed adult En2-KO mice to chronic environmental stress (CSDS, chronic social defeat stress), to determine if stress exacerbated the behavioral and neuroanatomical effects of En2 deletion. En2-/- mice showed impaired instrumental acquisition and significantly lower breakpoints in a progressive ratio test, demonstrating En2 deficiency decreases motivation to exert effort for reward. Furthermore, adult CSDS exposure increased avoidance behaviors in En2-KO mice. Interestingly, adult CSDS exposure also exacerbated the deleterious effects of En2 deficiency on forebrain-projecting monoaminergic fibers. Our findings thus suggest that adult exposure to stress may exacerbate behavioral and neuroanatomical phenotypes associated with developmental effects of genetic En2 deficiency.
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http://dx.doi.org/10.1016/j.bbr.2021.113466DOI Listing
September 2021

Survival outcomes for extranodal natural-killer T-cell lymphoma - Authors' reply.

Lancet Haematol 2020 06;7(6):e442

Division of Hematology-Oncology, Samsung Medical Center, Seoul 06351, Korea. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(20)30152-6DOI Listing
June 2020

Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network.

Br J Haematol 2018 06 19;181(6):760-769. Epub 2018 Apr 19.

Stanford University Medical Center, Stanford, CA, USA.

Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1-2), and high risk (HiR, 74 patients, 24%, score 3-4), having a 3-year OS of 76% [95% confidence interval 61-88], 43% [35-51], and 11% [4-21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.
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http://dx.doi.org/10.1111/bjh.15258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033106PMC
June 2018

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.

N Engl J Med 2018 01 10;378(4):331-344. Epub 2017 Dec 10.

From the University of British Columbia and the Department of Medical Oncology, British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, Canada (J.M.C., K.J.S.); the Department of Hematology, Jagiellonian University, Krakow (W.J.), the Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw (E.L.-M.), the Department of Hematology and Transfusion Medicine, Center of Postgraduate Medical Education, Warsaw (E.L.-M.), the Department of Experimental Hematology, Medical University of Lodz, Lodz (P.S.), and the Department of Lymphoid Malignancy, the Maria Sklodowska-Curie Memorial Institute and Oncology Center, Warsaw (J.W.) - all in Poland; Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York (D.J.S., A.Y.); the Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN (S.M.A.); the Division of Hematology and Oncology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea (W.S.K.); Research Innovation and Statistics, Antoine-Lacassagne Cancer Center, Nice, France (A.G.); Petrov Research Institute of Oncology, St. Petersburg, Russia (S.A.); the Department of Hematology, Faculty of Medicine, University of Debrecen, Debrecen (Á.I.), and the Department of Hematology, National Institute of Oncology, Budapest (A.R.) - both in Hungary; the Department of Advanced Biomedical Science, Federico II University Hospital, Naples (M.P.), and the Institute of Hematology Seràgnoli, University of Bologna, Bologna (P.L.Z.) - both in Italy; the Department of Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston (Y.O.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ (T.F.); the Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis (N.L.B.); the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA (R.C.); the Department of Hematology-Oncology, Barbara Ann Karmanos Cancer Center, Detroit (R.R.); Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton (D.C.), and the Department of Medical Oncology, University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester (J.R.) - both in the United Kingdom; the Department of Clinical Development, Seattle Genetics, Bothell, WA (N.C.J., E.S.); and Oncology Clinical Research (J.S., H.A.J., D.H.) and Global Biostatistics (R.L.), Millennium Pharmaceuticals, Cambridge, MA.

Background: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma.

Methods: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival.

Results: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.

Conclusions: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).
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http://dx.doi.org/10.1056/NEJMoa1708984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819601PMC
January 2018

Research on Biosimilars: pivotal trials and principles.

Lancet Haematol 2017 09;4(9):e409-e410

Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1016/S2352-3026(17)30152-7DOI Listing
September 2017

Onboard centralized frame tree database for intelligent space operations of the Mars Science Laboratory Rover.

IEEE Trans Cybern 2014 Nov;44(11):2109-21

Planetary surface science operations performed by robotic space systems frequently require pointing cameras at various objects and moving a robotic arm end effector tool toward specific targets. Earlier NASA Mars Exploration Rovers did not have the ability to compute actual coordinates for given object coordinate frame names and had to be provided with explicit coordinates. Since it sometimes takes hours to more than a day to get final approval of certain calculated coordinates for command uplink via the Earth-based mission operations procedures, a highly desired enhancement for future rovers was to have the onboard automated capability to compute the coordinates for a given frame name. The Mars Science Laboratory (MSL) rover mission is the first to have a centralized coordinate transform database to maintain the knowledge of spatial relations. This onboard intelligence significantly simplifies communication and control between Earth-based human mission operators and the robotic rover on Mars by supporting higher level abstraction of commands using object and target names instead of coordinates. More specifically, the spatial relations of many object frames are represented hierarchically in a tree data structure, called the frame tree. Individual frame transforms are populated by their respective modules that have specific knowledge of the frames. Through this onboard centralized frame tree database, client modules can query transforms between any two frames and support spacecraft commands that use any frames maintained in the frame tree. Various operational examples in the MSL mission that have greatly benefitted from this onboard centralized frame tree database are presented.
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http://dx.doi.org/10.1109/TCYB.2014.2301442DOI Listing
November 2014

Comparative genomics of Japanese Erwinia pyrifoliae strain Ejp617 with closely related erwinias.

Genome 2013 Feb 14;56(2):83-90. Epub 2012 Dec 14.

Department of Biological Environment, College of Agriculture and Life Sciences, Kangwon National University, Chuncheon 200-701, Korea.

Japanese Erwinia pyrifoliae strains cause bacterial shoot blight of pear (BSBP) in Japan. The genetics of Japanese Erwinia remains largely unknown relative to the abundant genomic information available for other Erwinia strains. We compared the genome of Japanese and Korean E. pyrifoliae strains along with those of E. amylovora and E. tasmaniensis. Comparisons with the Korean E. pyrifoliae strain revealed numerous gene insertions/deletions, rearrangements, and inversions in the central regions of the chromosomes. Approximately 80% (2843) of coding DNA sequences (CDSs) are shared by these two genomes which represent about three-quarters of the genome, and there are about 20% unique CDSs. Comparative analysis with closely related erwinias showed that 1942 (more than 50%) core open reading frames (ORF) are shared by all these strains. In addition to two type III secretion systems (hrp/dsp and inv/spa), the genome of Ejp617 encodes numerous virulence factors, including a type VI secretion system, an exopolysaccharide synthesis cluster, and another protein secretion system present in plant pathogenic Erwinia strains. The availability of whole genome sequence should provide a resource to further improve the understanding of pathogenesis in Japanese E. pyrifoliae Ejp617 and to facilitate evolutionary studies among the species of the genus Erwinia.
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http://dx.doi.org/10.1139/gen-2012-0094DOI Listing
February 2013

Efficacy and safety of a novel botulinum toxin type A product for the treatment of moderate to severe glabellar lines: a randomized, double-blind, active-controlled multicenter study.

Dermatol Surg 2013 Jan;39(1 Pt 2):171-8

Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea.

Background: A new botulinum toxin type A (NBoNT) produced from the same strain of Clostridium botulinum as onabotulinumtoxinA (OBoNT) is widely used in Asia.

Objectives: To compare the efficacy and safety of NBoNT and OBoNT for moderate to severe glabellar wrinkles.

Methods: A double-blind, randomized, active-controlled, phase III study was performed. Three hundred fourteen patients were randomized at a 1:1 ratio to receive 20 U of toxin. The primary end point was the responder rate according to investigator live assessment at maximum frown at week 4. Secondary end points were responder rates according to investigator live assessment with frowning and at rest at weeks 8, 12, and 16, with additional photographic assessment by a panel of blinded raters 4 weeks after injection. Subjective satisfaction scores were also evaluated.

Results: Four weeks after treatment, responder rates for maximum frown were 93.7% (133/142) in the NBoNT group and 94.5% (138/146) in the OBoNT group. For secondary end points, there was no significant difference between the two groups for any variable at any time point. Noninferiority of NBoNT was confirmed. There were no serious adverse effects with either toxin.

Conclusion: NBoNT is equally as effective as OBoNT for the treatment of glabellar frown lines. Both toxins were well tolerated.
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http://dx.doi.org/10.1111/dsu.12072DOI Listing
January 2013

Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL).

Asia Pac J Clin Oncol 2011 Jun;7(2):136-45

Division of Hematology/Oncology, Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Republic of Korea.

Aim: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti-CD20 monoclonal antibody rituximab ((131)I-rituximab) for treating Korean patients with relapsed or refractory B-cell non-Hodgkin's lymphomas (NHL).

Methods: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of (131)I-rituximab. The tumor response was evaluated 1 month later by contrast enhanced (18) F-fludeoxyglucose positron emission tomography-computed tomography.

Results: Between May 2004 and October 2006, 24 patients received single treatment with (131)I-rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B-cell NHL (LGL) and 9% (one PR) for patients with diffuse large B-cell lymphoma (DLBCL). After a median follow-up of 55 months, the median progression-free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3-4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively.

Conclusion: RIT with (131)I-rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of (131)I-rituximab for treating the patients with DLBCL.
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http://dx.doi.org/10.1111/j.1743-7563.2011.01393.xDOI Listing
June 2011

Application of carborundum abrasion for investigating the leaf epidermis: molecular cloning of Catharanthus roseus 16-hydroxytabersonine-16-O-methyltransferase.

Plant J 2008 Jan 5;53(2):225-36. Epub 2007 Dec 5.

Department of Biological Sciences, Brock University, St Catharines, Ontario, L2S 3A1, Canada.

The Madagascar periwinkle (Catharanthus roseus) produces the well-known and remarkably complex anti-cancer dimeric alkaloids vinblastine and vincristine that are derived from the coupling of vindoline and catharanthine monomers. This study describes the novel application of a carborundum abrasion (CA) technique for large-scale isolation of leaf epidermis-enriched proteins in order to purify to apparent homogeneity 16-hydroxytabersonine-16-O-methyltransferase (16OMT), which catalyses the second of six steps in the conversion of tabersonine into vindoline, and to clone the gene. Functional expression and biochemical characterization of recombinant 16OMT demonstrated its very narrow substrate specificity and high affinity for 16-hydroxytabersonine. In addition to allowing the cloning of this gene, the CA technique clearly showed that 16OMT is predominantly expressed in Catharanthus leaf epidermis. The results provide compelling evidence that most of the pathway for vindoline biosynthesis, including the O-methylation of 16-hydroxytabersonine, occurs exclusively in the leaf epidermis, with subsequent steps occurring in other leaf cell types.
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http://dx.doi.org/10.1111/j.1365-313X.2007.03337.xDOI Listing
January 2008

Clinical features and treatment outcomes of angioimmunoblastic T-cell lymphoma.

Leuk Lymphoma 2007 Apr;48(4):716-22

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The objective of this retrospective study was to investigate clinical features and treatment outcomes in patients with angioimmunoblastic T-cell lymphoma (AITL), data of which were collected over a 15-year period. Sixty-five patients diagnosed with AITL were included in the study. About half of the patients (46.2%) presented with poor performance status (ECOG > or = 2); 72.3% of patients belonged to high intermediate or high-risk of IPI and same proportion belonged to Class 2 of PIT (Prognostic index for PTCL-U), and most patients (95.4%) were diagnosed at an advanced stage. At diagnosis, 27 patients (41.5%) presented with malignant pleural effusion, and 22 patients (33.8%) had skin involvement. Most of the initial chemotherapy regimens were anthracycline-based (88.2%). Overall response rate to initial chemotherapy was 86.2% (64.7% of complete response, 21.5% of partial response). The median progression-free survival and overall survival of all patients was 7.1 months (95% CI, 2.8 - 11.4) and 15.1 months (95% CI, 6.7 - 23.5), respectively. Age, performance status, and PIT scores were predictive prognostic factors for survival. In conclusion, although AITLs showed a good response to the initial chemotherapy, their response durations were short; therefore, chemotherapy for AITL should be modified or intensified as in high-dose chemotherapy.
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http://dx.doi.org/10.1080/10428190601123989DOI Listing
April 2007

Prognostic factor analysis and proposed prognostic model for conventional treatment of high-grade primary gastric lymphoma.

Eur J Haematol 2006 Oct 27;77(4):304-8. Epub 2006 Jul 27.

Department of Hematology-Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.

Objectives: We conducted a clinical risk factors analysis to define a prognostic model for high-grade primary gastric lymphoma (HG-PGL).

Methods And Results: The median event-free survival and overall survival of 214 HG-PGL patients were 54 and 104.5 months, respectively, after a median follow-up duration of 60 months. According to the prognostic factor analysis, survival, advanced age, male gender, higher LDH levels and the presence of ascites were identified as independent prognostic factors for HG-PGL. We identified four groups at different risk: group 1, no adverse effect; group 2, one factor; group 3, two factors; group 4, three or four factors. The new prognostic model showed excellent prognostic capacity to differentiate subgroups according to their risk stratification.

Conclusions: The proposed new prognostic model for HG-PGL demonstrated a balanced distribution of patients into four groups with good prognostic capacity.
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http://dx.doi.org/10.1111/j.1600-0609.2006.00709.xDOI Listing
October 2006

Arsenic trioxide represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.

J Cell Biochem 2005 Mar;94(4):695-707

Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.

It has been proposed that eukaryotic nuclear factor nuclear factor kappa-B (NF-kappaB) and cyclooxygenase-2 (COX-2) are implicated in the pathogenesis of many human diseases including cancer. Arsenic has been widely used in medicine in Oriental countries. Recent studies have shown that arsenic trioxide (As(2)O(3)) could induce in vitro growth inhibition and apoptosis of malignant lymphocytes, and myeloma cells. However, the molecular mechanisms by which As(2)O(3) initiates cellular signaling toward cell death are still unclear. In the present study, the effects of As(2)O(3) on NF-kappaB and COX-2 expression in HL-60 cells were investigated. As(2)O(3) suppressed DNA-binding activity of NF-kappaB composed of p65/p50 heterodimer through preventing the degradation of IkappaB-alpha and the nuclear translocation of p65 subsequently as well as interrupting the binding of NF-kappaB with their consensus sequences. Inhibitory effect of As(2)O(3) on NF-kappaB DNA activity was dependent upon intracellular glutathione (GSH) and H(2)O(2) level, but not superoxide anion. Futhermore, we found that As(2)O(3) also downregulated the expression of COX-2, which has NF-kappaB binding site on its promoter through repressing the NF-kappaB DNA-binding activity.
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http://dx.doi.org/10.1002/jcb.20337DOI Listing
March 2005

Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells.

Cell Signal 2005 Jan;17(1):111-9

Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.

L-ascorbic acid (LAA) shows cytotoxicity and induces apoptosis of malignant cells in vitro, but the mechanisms by which such effects occur have not been elucidated. In the present study, we provide evidence that the ERK MAP kinase pathway is activated in response to LAA (< 1 mM) in acute myeloid leukemia cell lines. LAA treatment of cells induces a dose-dependent phosphorylation of extracellular signal-regulated kinases (ERK) and results in activation of its catalytic domain. Our data also demonstrate that the small G protein Raf1 and MAPK-activated protein kinase 2 are activated by LAA as an upstream and a downstream regulator of ERK, respectively. Although the ERK pathway has been known to activate cell proliferation, pharmacologic inhibition of ERK reduces LAA-dependent apoptosis and growth inhibitory response of acute myeloid leukemia cell lines, suggesting that this signaling cascade positively regulates induction of apoptotic response by LAA.
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http://dx.doi.org/10.1016/j.cellsig.2004.06.006DOI Listing
January 2005

L-ascorbic acid represses constitutive activation of NF-kappaB and COX-2 expression in human acute myeloid leukemia, HL-60.

J Cell Biochem 2004 Oct;93(2):257-70

Samsung Medical Center, and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.

There is increasing evidence that L-ascorbic acid (LAA) is selectively toxic to some types of cancer cells at pharmacological concentrations, functioning as a pro-oxidant rather than as an anti-oxidant. However, the molecular mechanisms by which LAA initiates cellular signaling leading to cell death are still unclear. In an effort to gain insight into these mechanisms, the effects of LAA on eukaryotic transcription nuclear factor NF-kappaB and cyclooxygenase-2 (COX-2) expression were investigated. In the present study, LAA suppressed DNA binding activity of NF-kappaB, composed of a p65/p50 heterodimer, through inhibition of degradation of inhibitory kappaB-alpha (IkappaB-alpha) and prevention of nuclear translocation of p65. The inhibitory effect of LAA on NF-kappaB activity was dependent upon glutathione levels in HL-60 cells, as well as generation of H2O2 but not superoxide anion. LAA also downregulated the expression of COX-2, which has a NF-kappaB binding site on its promoter, through repressing NF-kappaB DNA binding activity. Moreover, cotreatment of 1 microM arsenic trioxide (As2O3) with various concentrations of LAA enhanced an LAA-induced repression of NF-kappaB activity and COX-2 expression. In conclusion, our data suggest that LAA exerts its anti-tumor activity through downregulation of NF-kappaB activity and COX-2 expression, and these inhibitory effects can be enhanced by co-treatment with As2O3.
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http://dx.doi.org/10.1002/jcb.20116DOI Listing
October 2004

L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms.

Int J Biochem Cell Biol 2004 Nov;36(11):2180-95

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea.

L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H(2)O(2) accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H(2)O(2) in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose]polymerase. In conclusion, LAA can induce apoptosis in AML cells, and this is clearly due to H(2)O(2) which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.
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http://dx.doi.org/10.1016/j.biocel.2004.04.005DOI Listing
November 2004
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