Hyun Bark

Chosun University, Goyang, Gyeonggi, South Korea

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Publications (7)20.88 Total impact

  • H Bark, Cheol-Hee Choi
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    ABSTRACT: Multidrug resistance (MDR) is one of the major causes of clinical cancer chemotherapy failure. PSC833 is well known as a non-immunosuppressant cyclosporine analogue that functionally inhibits P-glycoprotein (Pgp), a product of the MDR1 gene. We investigated whether PSC833 could also alter MDR1 expression and, if so, which mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) pathways were involved in this event. MTT assay and flow cytometry were used for the analysis of cytotoxicity and intracellular drug accumulation, respectively. RT-PCR and Western blot assays for analysis of gene expression and electrophoretic mobility shift assays for determination of DNA-binding activity of transcription factors were used. The doxorubicin-resistant lung cancer cell subline (SK-MES-1/DX1000), selected from SK-MES-1/WT cells, upregulated MDR1 expression, thereby showing MDR phenotypes. PSC833 sensitized SK-MES-1/DX1000 cells to doxorubicin. PSC833 (5 microM) also decreased the intracellular accumulation of fluorescent Pgp substrates such as rhodamine 123 and daunorubicin in SK-MES-1/DX1000 cells. PSC833 downregulated MDR1 mRNA and Pgp expression in a time- and concentration-dependent manner. PSC833 activated c-Jun NH2-terminal kinase (JNK)/c-Jun and enhanced AP-1 DNA-binding activity, but suppressed nuclear translocation of NF-kappaB, all of which were prevented by pretreatment with a JNK inhibitor SP600125. These results indicate that PSC833 not only sensitizes SK-MES-1/DX1000 cells to doxorubicin by enhancing drug accumulation, but also downregulates MDR1 expression by activating JNK/c-Jun/AP-1 and suppressing NF-kappaB.
    Cancer Chemotherapy and Pharmacology 09/2009; 65(6):1131-6. · 2.80 Impact Factor
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    ABSTRACT: This study investigated whether P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are linked in terms of expression. RT-PCR and Western blot analyses showed that the lung cancer cell line SK-MES-1/WT expressed BCRP. In a drug-free state, BCRP expression was significantly down-regulated in doxorubicin-resistant SK-MES-1/DX1000 cells overexpressing Pgp. Pharmacological inhibitors (PSC833 or verapamil) or siRNA for Pgp inhibited the down-regulation of BCRP, which was confirmed by confocal microscopy. PSC833 induced the phosphorylation of c-Jun NH2-terminal kinase (JNK) and c-Jun, while the JNK inhibitor SP600125 inhibited this effect. Dominant negative c-Jun decreased the expression of BCRP, but increased that of Pgp. These results indicate that Pgp down-regulates BCRP expression in a drug-free state in which JNK/c-Jun is involved.
    FEBS Letters 08/2008; 582(17):2595-600. · 3.58 Impact Factor
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    ABSTRACT: This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.
    Leukemia Research 10/2007; 31(9):1267-76. · 2.76 Impact Factor
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    ABSTRACT: Nitric oxide (NO) is an important regulator of immune responses. Effects of cytokines, such as tumor necrosis factor (TNF)-alpha or IFN-gamma, and bacterial products, such as lipopolysaccharide, on macrophage NO production have been well documented; however, the role of the extracellular matrix proteins, including collagen, in this process remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, was expressed in human macrophages, and its activation facilitated their differentiation as well as cytokine/chemokine production. Here, we examined the role for DDR1 in collagen-induced NO production using the murine macrophage cell line J774 cells that endogenously express DDR1. Activation of J774 cells with collagen induced the expression of inducible NO synthase (iNOS) and NO production. Inhibition of DDR1, but not beta1-integrins, abolished collagen-induced iNOS and NO production. Activation of J774 cells with collagen-activated nuclear factor-kappaB, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) and a pharmacological inhibitor of each signaling molecule significantly reduced collagen-induced NO production. Thus, we have demonstrated, for the first time, that the interaction of DDR1 with collagen induces iNOS expression and subsequent NO synthesis in J774 cells through activation of NF-kappaB, p38 MAPK, and JNK and suggest that intervention of DDR1 signaling in macrophages may be useful in controlling inflammatory diseases in which NO plays a critical role.
    Free Radical Biology and Medicine 03/2007; 42(3):343-52. · 5.27 Impact Factor
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    ABSTRACT: . Objective and design: Mast cell-mediated allergic inflammation is involved in many diseases such as asthma, sinusitis, and rheumatoid arthritis. Mast cells induce production of pro-inflammatory cytokines with immune regulatory properties. We investigated the effect of quercetin on the expression of pro-inflammatory cytokines in human mast cell line, HMC-1. Methods: HMC-1 cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 (PMACI). Results: Quercetin decreased the gene expression and production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in PMACI-stimulated HMC-1 cells. Quercetin attenuated PMACI-induced activation of NF-κB and p38 mitogen-activated protein kinase. Conclusion: Our study provides evidence that quercetin may suitable for the treatment of mast cell-derived allergic inflammatory diseases.
    Inflammation Research 01/2007; 56(5):210-215. · 1.96 Impact Factor
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    ABSTRACT: The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.
    Immunopharmacology and Immunotoxicology 02/2006; 28(3):545-55. · 1.36 Impact Factor
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    ABSTRACT: The multidrug resistance-associated protein (MRP1) belongs to a drug efflux membrane pump that confers multidrug resistance to the cells. The MRP1 mediates the cellular efflux of various xenobiotics including heavy metals and mediates cellular resistance to heavy metals. Mercury is a well-known health hazard and an environmental contaminant. Recently, information about the uptake of the heavy metals such as mercury has been suggested. However, little is known regarding molecular mechanisms of exporting mercury. This study was designed to determine if mercury could be extruded by MRP1 in acute myeloid leukemia cells (AML-2). The MRP-1-overexpressing AML-2/DX100 cells showed a higher resistance to mercury than AML-2/WT. Probenecid, which is a specific MRP1 inhibitor, decreased the resistance to mercury. Exposing the AML-2 cells to mercury-induced MRP1 gene expression and production without altering the MRP1 activity. Mercury activated p38 mitogen-activated protein kinase (MAPK) and SB 203580, a specific p38 MAPK inhibitor, blocked the mercury-induced MRP1 production. These results suggest that MRP1 can control mercury and p38 MAPK mediates the mercury-induced MRP1 gene expression.
    Toxicology Letters 02/2005; 155(1):143-50. · 3.15 Impact Factor