Hae-Ryong Park

Japanese Foundation for Cancer Research, Edo, Tōkyō, Japan

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Publications (42)82.49 Total impact

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    ABSTRACT: Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. Here, we show that compound C (also known as dorsomorphin), a small-molecule inhibitor of AMP-activated protein kinase (AMPK) and bone morphogenetic protein (BMP) signaling, inhibit the UPR-induced transcription program depending on the glucose deprivation conditions. We found that compound C prevented UPR marker glucose-regulated protein 78 (GRP78) accumulation and exerted enhanced cytotoxicity during glucose deprivation. Gene expression profiling, together with biochemical analysis, revealed that compound C had a unique mode of action to suppress the transcriptional activation of UPR-targeted genes, as compared with the classic UPR inhibitors versipelostatin and biguanides. Surprisingly, the UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. We further found that combination treatments of compound C and the classic UPR inhibitors resulted in synergistic cell death with UPR suppression during glucose deprivation. Our findings demonstrate that compound C could be a unique tool for developing a UPR-targeted antitumor therapy.
    PLoS ONE 01/2012; 7(9):e45845. · 3.73 Impact Factor
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    ABSTRACT: 4,8-Dihydroxy-5-methoxy-2-naphthaldehyde (Compound I) was isolated from blackened heartwood of Diospyros kaki and was methylated with diazomethane. Antioxidant and cytotoxic activities of Compound I and two methylated derivatives [4-hydroxy-5,8-dimethoxy-2-(2-oxopropyl)-naphthalene (D-1) and 2-glycidyl-4-hydroxy-5,8-dimethoxy naphthalene (D-2)] were evaluated. Compound I showed higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and reducing power than D-1 and D-2. However, D-1 and D-2 exhibited slightly stronger 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)+ (ABTS+) radical scavenging activity than Compound I. Compound I also exhibited stronger cytotoxic activity than D-1 and D-2 against the growth of HT-29 colon cancer cells. The results supported the hypothesis that methylation of naphthalene derivatives slightly increased ABTS+ radical scavenging activity, but significantly decreased DPPH radical scavenging activity, reducing power, and cytotoxic activity. Key wordsNaphthalene derivatives–Persimmon wood–Antioxidant activity–Cytotoxic activity
    Journal of Wood Science 01/2011; 57(2):161-165. · 0.77 Impact Factor
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    Sang-Bong Lee, Hae-Ryong Park
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    ABSTRACT: Natural products have recently become the focus of increased research interest due to their potential pharmacological activities. Therefore, we established a program to screen natural products for cytotoxic activity using the MTT reduction assay system to test HT-29 human colon cancer cells. During the course of screening, we found that the acetone extracts of guava (Psidium guajava L.) branch (GBA) had cytotoxic effects on HT-29 cells. The GBA showed highly cytotoxic effects via the MTT reduction assay, LDH release assay, and colony formation assay. In particular, the GBA of the 250 µ µ µ µg/ml showed 35.5% inhibition against growth of HT-29 cells. As expected, GBA induced characteristic apoptotic effects in HT-29 cells, including chromatin condensation and sharking that occurred 24 h after the cells had been treated at a concentration level of 250 µ µ µ µg/ml. To examine the functions on apoptosis, we used a flow cytometric analysis. The apoptotic cells were distributed according to the cell cycle phase shown by sub-G1 DNA content.
    Journal of Medicinal Plants Research. 04/2010; 4:891-896.
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    ABSTRACT: Cancer cells in poorly vascularized solid tumors are constantly or intermittently exposed to stressful microenvironments, including glucose deprivation, hypoxia, and other forms of nutrient starvation. These tumor-specific conditions, especially glucose deprivation, activate a signaling pathway called the unfolded protein response (UPR), which enhances cell survival by induction of the stress proteins. We have established a screening method to discover anticancer agents that could preferentially inhibit tumor cell viability under glucose-deprived conditions. Here we identify arctigenin (ARC-G) as an active compound that shows selective cytotoxicity and inhibits the UPR during glucose deprivation. Indeed, ARC-G blocked expression of UPR target genes such as phosphorylated-PERK, ATF4, CHOP, and GRP78, which was accompanied by enhanced phosphorylation of eIF2 alpha during glucose deprivation. The UPR inhibition led to apoptosis involving a mitochondrial pathway by activation of caspase-9 and -3. Furthermore, ARC-G suppressed tumor growth of colon cancer HT-29 xenografts. Our results demonstrate that ARC-G can be served as a novel type of antitumor agent targeting the UPR in glucose-deprived solid tumors.
    Journal of Cellular Physiology 03/2010; 224(1):33-40. · 4.22 Impact Factor
  • ChemInform 01/2010; 33(49).
  • Journal of the Korean Society of Food Science and Nutrition 01/2010; 39(4):500-505.
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    ABSTRACT: Oyster mushroom is a popular edible mushroom which has various colorful fruit bodies. The objective of this study was to determine the antioxidant and the anticancer activities of oyster mushrooms (OM) with different colors such as dark-grey strain (Pleurotus ostreatus), yellow strain (Pleurotus cornucopiae), and pink strain (Pleurotus salmoneostramineus). The methanolic extracts from OMs were prepared for this study. Among these OMs, the extract from the yellow strain showed the highest radical scavenging activity, reducing power, ferrous chelating ability, and total phenolic contents. Radical scavenging activity of yellow strain was about 3 times higher than that of dark-grey strain. On the other hand, the extracts of dark-grey and pink strains showed higher suppressive effect against growth of human colon cancer cell line HT-29 with survival rates of 39.9 and 40.7%, respectively, than that of yellow strain. These results showed that the antioxidant and the anticancer activities of OMs varied by the colors of fruit bodies.
    Journal of Medicinal Plants Research. 01/2010; 3:1016-1020.
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    ABSTRACT: Pancreatic cancer cells are sometimes exposed to stressful microenvironments such as glucose deprivation, hypoxia, and starvation of other nutrients. These stresses, which are characteristic of poorly vascularized solid tumors, activate the unfolded protein response (UPR). The UPR is a stress-signaling pathway present in tumor cells that is associated with molecular chaperone GRP78. Induction of GRP78 has been found to increase cell survival and decrease apoptotic potential through genetic alterations. Thus GRP78 may represent a novel target in the development of anticancer drugs. Here we established a novel screening program to identify chaperone modulators that exhibit preferential cytotoxic activity in glucose-deprived pancreatic cancer cells. During the course of our screening, we isolated an active substance, Ponciri Fructus (PF), from an herbal medicine source and identified it as a down-regulator of GRP78. As expected, PF inhibited expression of the GRP78 protein under glucose-deprivation conditions in a dose-dependent manner. Furthermore, it induced selective cytotoxicity against glucose-deprived cancer cells; this effect was not observed under normal growth conditions. We also detected apoptotic bodies on Hoechst staining and attempted to determine whether PF-induced apoptosis involved caspase-3 activation. Our results suggest that the GRP78-inhibitory action of PF was dependent on strict hypoglycemic conditions and that it resulted in the selective death of glucose-deprived pancreatic cancer cells.
    Bioscience Biotechnology and Biochemistry 10/2009; 73(10):2167-71. · 1.27 Impact Factor
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    ABSTRACT: Glucose deprivation, a cell condition that occurs in solid tumors, activates the unfolded protein response (UPR). A key feature of the UPR is the transcription program activation, which allows the cell to survive under stress conditions. Here, we show that the UPR transcription program is disrupted by the antidiabetic biguanides metformin, buformin, and phenformin depending on cellular glucose availability. These drugs inhibit production of the UPR transcription activators XBP1 and ATF4 and induce massive cell death during glucose deprivation as did the antitumor macrocyclic compound versipelostatin. Gene expression profiling shows remarkable similarity in the modes of action of biguanides and versipelostatin determined by the broad range of glucose deprivation-inducible genes. Importantly, during glucose deprivation, most of the biguanide suppression genes overlap with the genes induced by tunicamycin, a chemical UPR inducer. Gene expression profiling also identifies drug-driven signatures as a tool for discovering pharmacologic UPR modulators. Our findings show that disrupting the UPR during glucose deprivation could be an attractive approach for selective cancer cell killing and could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors.
    Cancer Research 06/2009; 69(10):4225-34. · 8.65 Impact Factor
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    ABSTRACT: We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose-deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of eukaryotic initiation factor 4E-mediated protein translation, plays a role in the UPR-inhibitory action of VST. Indeed, 4E-BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose-regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E-BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E-BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E-BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin-treated cells.
    Cancer Science 01/2009; 100(2):327-33. · 3.48 Impact Factor
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    ABSTRACT: The Cosmos bipinnatus has been used in a traditional herbal remedy for various diseases such as jaundice, intermittent fever, and splenomegaly. The present study describes the preliminary evaluation of antioxidant activities and antigenotoxic effect of Cosmos bipinnatus flowers according to four different colors (white, pink, orange, and violet). The antioxidants properties were evaluated by determining TPC, DPPH RSA, ABTS RSA, and RP. The highest TPC of methanolic CFE (at concentration of 1 mg/ml) showed in violet colored CF (1,013 microM), and IC(50) of DPPH RSA, ABTS RSA, and RP were also the lowest in violet colored CFE with values of 0.61, 1.48, and 0.82 mg/ml, respectively. The antigenotoxic effect of the CFE on DNA damage induced by H(2)O(2) in human leukocytes was evaluated by Comet assay. Pretreatments with CFE produced significant reductions in oxidative DNA damage at the concentration of 500 microg/ml, except for violet colored CFE. The ED(50) value of white colored CFE has shown the highest inhibition (0.40 mg/ml) on H(2)O(2) induced DNA damage, followed by orange > pink > violet color. These results suggested that Cosmos bipinnatus has significant antioxidant activity and protective effect against oxidative DNA damage.
    Materiae Vegetabiles 09/2008; 63(4):205-10. · 2.36 Impact Factor
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    ABSTRACT: In this paper, we report the anticancer activities of Uncaria rhynchophylla extracts, a Rubiaceae plant native to China. Traditionally, Uncaria rhynchophylla has been used in the prevention and treatment of neurotoxicity. However, the cytotoxic activity of Uncaria rhynchophylla against human colon carcinoma cells has not, until now, been elucidated. We found that the methanolic extract of Uncaria rhynchophylla (URE) have cytotoxic effects on HT-29 cells. The URE showed highly cytotoxic effects via the MTT reduction assay, LDH release assay, and colony formation assay. As expected, URE inhibited the growth of HT-29 cells in a dose-dependent manner. In particular, the methanolic URE of the 500 microg/ml showed 15.8% inhibition against growth of HT-29 cells. It induced characteristic apoptotic effects in HT-29 cells, including chromatin condensation and sharking occurring 24 h when the cells were treated at a concentration of the 500 microg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly (ADP-ribose) polymerase were detected over the course of apoptosis induction. These results indicate that URE contains bioactive materials with strong activity, and is a potential chemotherapeutic agent candidate against HT-29 human colon carcinoma cells.
    Materiae Vegetabiles 07/2008; 63(2):77-82. · 2.36 Impact Factor
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    ABSTRACT: The prior sequencing of the upstream region of the gamma-butyrolactone autoregulator receptor gene (sngR) in Streptomyces natalensis revealed the presence of a 972-bp gene encoding a BarX homologue (SngA), which acts as a pleiotropic regulator controlling secondary metabolism and morphological differentiation. In this study, we investigated the in vivo function of SngA in S. natalensis, by comparing the natamycin production, morphology, and transcription of genes related to natamycin biosynthesis in a wild-type strain and a sngA-deleted mutant. The disruption of sngA resulted in a decrease in natamycin production, and in the induction of pigment production that had not been previously observed from S. natalensis. On the other hand, the insertion of the intact sngA with its own promoter, into the wild-type strain, resulted in a 1.7-fold increase in natamycin production. Spore formation decreased in comparison to that of the wild-type strain when the sngA-deleted mutant was grown on YEME agar, MS medium, and ISP4 medium. All phenotypes were restored to the original wild-type phenotypes upon complementation with the intact sngA, suggesting that SngA has pleiotropic functions in controlling both morphological differentiation and secondary metabolite production.
    Archives of Microbiology 07/2008; 189(6):569-77. · 1.91 Impact Factor
  • Sang-Myeon Lee, Mi-Young Yoon, Hae-Ryong Park
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    ABSTRACT: This study was conducted to examine the antioxidative and neuroprotective effects of Paeonia lactiflora pall (PLE). Total phenolic content of PLE was 89.65 mg of gallic acid equivalent per gram of PLE. IC(50) values for reducing power, hydrogen peroxide scavenging activity, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity were 297.57, 3.33, and 32.74 microg, respectively. The protective effect of PLE against H(2)O(2)-induced oxidative damage to PC12 cells was investigated by an 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) reduction assay and lactate dehydrogenase (LDH) release assay. After 2 h of cell exposure to 0.5 mM H(2)O(2), a marked reduction in cell survival was observed. However, this reduction was significantly prevented by 10-100 microg/ml of PLE. H(2)O(2) also induced severe apoptosis of the PC12 cells, which was indicated by a flow cytometric analysis. Interestingly, the H(2)O(2)-stressed PC12 cells that had been incubated with PLE had greatly suppressed apoptosis. The results suggest that PLE could be a candidate for a new antioxidant against neuronal diseases.
    Bioscience Biotechnology and Biochemistry 06/2008; 72(5):1272-7. · 1.27 Impact Factor
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    ABSTRACT: Glucose deprivation, a pathophysiological cell condition, causes up-regulation of GRP78 and induction of etoposide resistance in human cancer cells. The induction of drug resistance can be partly explained by the fact that GRP78 can block activation of caspase-7 induced by treatment with etoposide. Therefore, downregulating GRP78 expression may be a novel strategy anticancer drug development. Based on that premise, we established a screening program for anticancer agents that exhibit preferential cytotoxic activity for etoposide-resistant cancer cells under glucose-deprived conditions. We recently isolated an active compound, AR-054, from the culture broth of Streptomyces sp., which prevents stress-induced etoposide resistance in vitro. AR-054 was identified as piericidin A, a prototypical compound, by ESI-MS analysis and various NMR spectroscopic methods. Here, we showed that piericidin A suppressed the accumulation of GRP78 protein and was also highly toxic to etoposide-resistant HT-29 cells, with IC50 values for colony formation of 6.4 and 7.7 nM under 2-deoxyglucose supplemented and glucose-deprived conditions, respectively. Interestingly, piericidin A had no effect under normal growth conditions. Therefore, we suggest that piericidin A prevents up-regulation of GRP78, and exhibits cytotoxicity in glucose-deprived HT-29 cells that are resistant to etoposide.
    Journal of Cellular Physiology 05/2008; 215(1):243-50. · 4.22 Impact Factor
  • Journal of the Korean Society of Food Science and Nutrition 01/2008; 37(4):405-409.
  • Journal of the Korean Society of Food Science and Nutrition 01/2008; 37(12):1674-1678.
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    ABSTRACT: Natural marine products have recently become the focus of increased research interest, due to their potential pharmacological activities. Therefore, we have screened 50 varieties of marine seaweed and determined that the methanolic extracts from Plocamium telfairiae (PTE) exhibited a cytotoxic effect against HT-29 human colon carcinoma cells. In this study, we report on the cytotoxic activity and mechanism of PTE-induced apoptosis in HT-29 cells. The treatment of HT-29 cells with various PTE concentrations resulted in the inhibition of growth and the induction of apoptosis in a dose-dependent manner, as determined by the results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay, a lactate dehydrogenase release assay, a morphological assay, and a colony formation assay. Interestingly, we also detected apoptotic bodies on Hoechst staining and attempted to determine whether the PTE-induced apoptosis involved the caspase pathway, using a caspase colorimetric assay. The activation of caspases-8, -9, -3, and -7 and the specific proteolytic cleavage of poly(ADP-ribose) polymerase were detected over the course of apoptosis induction. Our results showed that PTE may function as a chemopreventive and/or chemotherapeutic agent in colon carcinoma cells via the reduction of cell viability and the induction of apoptosis.
    Journal of Medicinal Food 01/2008; 10(4):587-93. · 1.64 Impact Factor
  • Journal of the Korean Society of Food Science and Nutrition 01/2008; 37(6):677-683.

Publication Stats

402 Citations
82.49 Total Impact Points


  • 2009–2012
    • Japanese Foundation for Cancer Research
      Edo, Tōkyō, Japan
  • 2005–2012
    • Kyungnam University
      Changnyeong, South Gyeongsang, South Korea
  • 2008
    • Ewha Womans University
      • Department of Life Sciences
      Seoul, Seoul, South Korea
  • 2003–2007
    • Korea Research Institute of Bioscience and Biotechnology KRIBB
      • Biological Resource Center
      Anzan, Gyeonggi Province, South Korea
  • 2002–2007
    • The University of Tokyo
      • Institute of Molecular and Cellular Biosciences
      Tokyo, Tokyo-to, Japan