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Kim Y.,University of Ulsan | Jeong I.G.,University of Ulsan | You D.,University of Ulsan | Song S.H.,University of Ulsan | And 4 more authors.
Anti-Cancer Drugs | Year: 2014

Sodium meta-arsenite (NaAsO2), a novel compound synthesized by Komipham International Co. Ltd, is an orally bioavailable, water-soluble trivalent arsenical that has shown potent cytotoxic activity in human solid cancer cells in vitro and in vivo, and is currently undergoing phase I/II clinical trials for the treatment of prostate cancer. In this study, mechanisms of cell death induced by sodium meta-arsenite were investigated. Sodium meta-arsenite reduced cell viability and increased the sub-G1 population in cell cycle analysis in both androgen-sensitive LNCaP and androgen-insensitive CWR22RV1 cells. The apoptosis induced by sodium meta-arsenite was associated with cleavage of caspases 3, 8, and 9, and poly (ADP-ribose) polymerase (PARP) and increased annexin V-positive cells, and was inhibited by the pan-caspase inhibitor Z-VAD-fmk. Sodium meta-arsenite also increased the level of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and the number of autophagic vacuoles as shown by electron microscopy. Both the autophagy inhibitor 3-methyladenine and the necrosis inhibitor necrostatin-1 blocked cell death induced by sodium meta-arsenite. Moreover, sodium meta-arsenite led to the accumulation of intracellular reactive oxygen species (ROS) and N-acetyl-L-cysteine (NAC), a ROS scavenger, decreased sodium meta-arsenite-induced levels of cleaved PARP and LC3-II. Propidium iodide (PI) staining also showed that NAC restored membrane integrity, damaged by sodium meta-arsenite. Therefore, these results suggest that sodium meta-arsenite induces apoptotic, necrotic, and autophagic cell death through intracellular ROS accumulation in both androgen-sensitive and androgen-insensitive prostate cancer cells and may be used as a new anticancer drug for the treatment of prostate cancer. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Lee Y.S.,Gachon University | Kim D.,Gachon University | Lee E.K.,Gachon University | Kim S.,Komipharm International Co. | And 4 more authors.
Toxicology and Applied Pharmacology | Year: 2015

Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5. mg/kg/day) from 8. weeks of age for 8. weeks. The cumulative incidence of diabetes was monitored until 30. weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA on the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. © 2015 Elsevier Inc.

Paudel S.,Chungnam National University | Park J.E.,Chungnam National University | Jang H.,Komipharm International Co. | Hyun B.H.,Animal and Plant Quarantine Agency | And 2 more authors.
Veterinary Quarterly | Year: 2014

Background: Porcine epidemic diarrhea virus (PEDV) is an infectious, highly contagious virus, and is an etiological agent of acute entero-pathogenic diarrhea in swine.Objectives: Evaluation of the antibody response of two types of PEDV vaccines is to be carried out.Animals and methods: Sows were vaccinated with either live or killed commercial PEDV SM98 (GenBank: GU937797.1) vaccines. Four different groups of sows with five sows in each group were used in this study: the unvaccinated negative control group, the killed virus vaccination group with killed virus boosting (K/K), the live virus vaccinated group with live virus boosting (L/L), and the combination group vaccinated with live virus and subsequently boosted with killed vaccine (L/K). Sows were vaccinated intramuscularly twice at four and two weeks prior to farrowing with 2ml/head vaccine dose. Antibody titers in sow and piglet serum one week after farrowing and that in colostrum were compared by enzyme-linked immunosorbent assay (ELISA) and serum neutralization test.Results: Vaccination with K/K vaccine induced the highest level of IgG and IgA in sow serum, colostrum, and especially in piglet serum, with the lowest levels found in the L/L group. The major neutralizing activity was also found in the K/K group, particularly in colostrum, with piglets bearing higher neutralizing activity compared to sow sera. Among recombinant spike S1, S2, S3, and nucleocapsid N protein of PEDV, S3 protein presented the highest antibody level in the K/K group.Conclusion: Killed PEDV SM98 vaccine induced higher antibody levels.Clinical importance: This study clearly confirms that killed vaccine has induced higher antibody levels and may contribute to the design of future research and vaccine programs. © 2014 Taylor & Francis.

Paudel S.,Chungnam National University | Park J.E.,Chungnam National University | Jang H.,Komipharm International Co. | Shin H.J.,Chungnam National University | Shin H.J.,Research Institute of Veterinary Medicine
Veterinary Quarterly | Year: 2014

Background: Porcine epidemic diarrhea virus (PEDV) is an economically important pathogen of swine.Objective: Serum neutralization (SN) and enzyme-linked immunosorbent assay (ELISA) test results as well as the utility of spike proteins S1, S2, and S3 and entire nucleocapsid protein were compared.Animals and methods: Serum samples from 400 pigs vaccinated against PEDV strain SM98P were collected from 78 farms in Korea. SN test and ELISA were performed to confirm the presence of antibodies. For prokaryotic expression of partial fragments of spike protein the size and location of S1, S2, and S3, and full nucleocapsid protein, polymerase chain reaction was performed using specific primers.Results: Comparison of these results demonstrated that there was a correlation between the SN and ELISA results. Sera with higher neutralizing activity also had higher IgG titer. The antibody profiling data presented the correlation of neutralizing activity with the level of spike protein antibody. In particular, the S3 region may have an important role in neutralizing activity.Conclusions: We confirmed that the carboxy-terminal region that includes the endodomain of the S protein induced stronger neutralizing activity than the region that includes the ectodomain.Clinical relevance: The region of the S protein may have a stronger neutralizing KPEDV-9 epitope and could be useful for the evaluation of future PEDV vaccine efficacy. © 2014 Taylor & Francis.

Woo S.R.,Sungkyunkwan University | Ham Y.,Sungkyunkwan University | Kang W.,Sungkyunkwan University | Yang H.,Sungkyunkwan University | And 6 more authors.
BioMed Research International | Year: 2014

Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated γ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma. © 2014 Seon Rang Woo et al.

Seo H.W.,Seoul National University | Han K.,Seoul National University | Kim D.,Seoul National University | Oh Y.,Seoul National University | And 4 more authors.
Clinical and Vaccine Immunology | Year: 2011

The objective of the present study was to determine the effect of an inactivated porcine circovirus type 2 (PCV2) vaccine on PCV2b virus shedding in the semen of experimentally infected boars by measuring the immunological response and the PCV2b DNA load in blood and semen. Twelve boars were randomly divided into three groups. The boars in group 1 (n = 4) were immunized with an inactivated PCV2 vaccine and were challenged with PCV2b. The boars in group 2 (n = 4) were only challenged with PCV2b. The boars in group 3 (n = 4) served as negative controls. The number of PCV2 genome copies of PCV2 in the serum and semen were significantly lower in vaccinated challenged boars than in nonvaccinated challenged boars at 7, 10, 14, 21, 32, 35, 42, 49, and 60 days postinoculation. The number of PCV2b genomes in the semen correlated with the number of PCV2b genomes in the blood in both vaccinated challenged (R = 0.714) and nonvaccinated challenged (R = 0.861) boars. The results of the present study demonstrate that the inactivated PCV2 vaccine significantly decreases the amount of PCV2b DNA shedding in semen from vaccinated boars after experimental infection with PCV2b. Copyright © 2011, American Society for Microbiology. All Rights Reserved.

PubMed | Komipharm International Co., Hanyang University and Seoul National University
Type: Comparative Study | Journal: Investigational new drugs | Year: 2016

Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkins lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-B signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10mg/day (follicular lymphoma for 16weeks and mantle cell lymphoma for 24weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkins lymphoma patients.

PubMed | Komipharm International Co. and Hanyang University
Type: Journal Article | Journal: International journal of oncology | Year: 2015

Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti-leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-B, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001-induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time-dependent manner in HL-60 and HL-60R cells. Realtime PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, -H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting.

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