Publications by authors named "Kyungsu Kang"

42 Publications

Natural photosensitizers from Tripterygium wilfordii and their antimicrobial photodynamic therapeutic effects in a Caenorhabditis elegans model.

J Photochem Photobiol B 2021 May 29;218:112184. Epub 2021 Mar 29.

Natural Product Informatics Research Center, Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangwon-do 25451, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Gangneung, Gangwon-do 25451, Republic of Korea. Electronic address:

Tripterygium wilfordii Hook. f. is a traditional medicinal plant and has long been used in East Asia to treat many diseases. However, the extract and active components have never been investigated as potential photosensitizers for photodynamic treatment to kill pathogenic microorganisms. Here, the antimicrobial photodynamic treatment (APDT) effects of the extract, fractions, and compounds of T. wilfordii were evaluated in vitro and in vivo. Ethanolic extract (TWE) and the photosensitizer-enriched fraction (TW-F5) were prepared from dried T. wilfordii. Six active compounds were isolated from TW-F5 by semipreparative high-performance liquid chromatography, and their chemical structures were characterized through spectroscopic and spectrometric analysis. The singlet oxygen from extracts, fractions, and compounds was measured by using the imidazole-N,N-dimethyl-4-nitrosoaniline method. These extracts, fractions, and compounds were used as photosensitizers for the inactivation of bacteria and fungi by red light at 660 nm. The in vitro APDT effects were also evaluated in the model animal Caenorhabditis elegans. APDT with TWE showed effective antimicrobial activity against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans. TW-F5, consisting of six pheophorbide compounds, also showed strong APDT activity. The photosensitizers were taken up into the bacterial cells and induced intracellular ROS production by APDT. TWE and TW-F5 also induced a strong APDT effect in vitro against skin pathogens, including Staphylococcus epidermidis and Streptococcus pyogenes. We evaluated the APDT effects of TWE and TW-F5 in C. elegans infected with various pathogens and found that PDT effectively controlled pathogenic bacteria without strong side effects. APDT reversed the growth retardation of worms induced by pathogen infection and decreased the viable pathogenic bacterial numbers associated with C. elegans. Finally, APDT with TWE increased the survivability of C. elegans infected with S. pyogenes. In summary, TWE and TW-F5 were found to be effective antimicrobial photosensitizers in PDT.
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http://dx.doi.org/10.1016/j.jphotobiol.2021.112184DOI Listing
May 2021

Synthesis and biological evaluation of chalcone derivatives as neuroprotective agents against glutamate-induced HT22 mouse hippocampal neuronal cell death.

Bioorg Med Chem Lett 2020 11 3;30(22):127597. Epub 2020 Oct 3.

Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; Convergent Research Center for Diagnosis, Treatment, and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; Division of Bio-Medical Science and Technology, University of Science and Technology (UST), Daejun 34113, Republic of Korea. Electronic address:

Seventeen chalcone analogues were synthesized from 7-methoxy-3,4-dihydronaphthalen1(2H)-one and various aromatic aldehydes under basic conditions and their therapeutic properties were studied in mouse hippocampal cell line HT-22 against neuronal cell death induced by glutamate. From this study, we selected an analogue C01 as a active compound which showed significantly high neuroprotection. This compound inhibited Ca influx and reactive oxygen species (ROS) accumulation inside cells. The glutamate-induced cell death was analyzed by flow cytometry and it showed that C01 significantly reduced apoptotic or dead cell induced by 5 mM glutamate. Western blot analysis indicates that glutamate-mediated activation of MAPKs were inhibited by compound C01 treatment. In addition, the C01enhanced Bcl-2 and decreased Bax, the anti and pro apoptotic proteins respectively. Further analysis showed that, C01 prevented the nuclear translocation of AIF (apoptosis inducing factor) and inhibited neuronal cell death. Taken together, compound C01 treatment resulted in decreased neurotoxicity induced by 5 mM of glutamate. Our finding confirmed that compound C01 has neuro-therapeutic potential against glutamate-mediated neurotoxicity.
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http://dx.doi.org/10.1016/j.bmcl.2020.127597DOI Listing
November 2020

Improvement in host metabolic homeostasis and alteration in gut microbiota in mice on the high-fat diet: A comparison of calcium supplements.

Food Res Int 2020 10 27;136:109495. Epub 2020 Jun 27.

Department of Environmental Health Sciences, School of Public Health, Seoul National University, Seoul 08826, Republic of Korea; Center for Human and Environmental Microbiome, Seoul National University, Seoul 08826, Republic of Korea; KoBioLabs, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address:

Despite the previously reported health benefits of calcium intake for the attenuation of metabolic disease, few studies have investigated the relationships among calcium intake, gut microbiota, and host metabolism. In this study, we assessed the effects of calcium supplementation on host microbial community composition and metabolic homeostasis. Mice were fed a high-fat diet with different calcium concentrations (4 and 12 g/kg) of 2 calcium supplements, calcium carbonate and calcium citrate. Supplementation with the higher concentration of calcium citrate significantly prevented body weight gain and decreased plasma biomarkers for metabolic disorder compared to calcium carbonate supplementation. Both calcium supplementation led to changes in microbial composition, increased propionate production and increased anorexigenic GLP-1 gene expression. The calcium citrate groups also experienced less metabolic endotoxemia. Our findings suggested that calcium supplementation could ameliorate host metabolic disorder caused by a high-fat diet, due to gut microbiota changes as well as decreased intestinal inflammation.
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http://dx.doi.org/10.1016/j.foodres.2020.109495DOI Listing
October 2020

Synthesis and biological evaluation of isoliquiritigenin derivatives as a neuroprotective agent against glutamate mediated neurotoxicity in HT22 cells.

Bioorg Med Chem Lett 2020 04 24;30(8):127058. Epub 2020 Feb 24.

Convergence Research Center for Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Natural Product Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; Division of Bio-medical Science & Technology, University of Science and Technology, Daejun 34113, Republic of Korea.. Electronic address:

Glutamate-induced neurotoxicity is characterized by cellular Ca uptake, which is upstream of reactive oxygen species (ROS)-induced apoptosis signaling and MAPKs activation. In the present study, we synthesized isoliquiritigenin analogs with electron-donating and electron-withdrawing functional groups. These analogs were evaluated for neuroprotective effect against glutamate-induced neurotoxicity in HT22 cells. Among these analogs, compound BS11 was selected as a potent neuroprotective agent. Cellular Ca concentration, ROS level, MAPKs activation and AIF translocation to the nucleus were increased upon treatment with 5 mM glutamate. In contrast, we identified that compound BS11 reduced the cellular Ca concentration and ROS level upon glutamate exposure. Western blot analysis showed that MAPK activation was decreased by treatment with compound BS11. We further identified that cotreatment of compound BS11 and glutamate inhibited translocation of AIF to the nucleus.
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http://dx.doi.org/10.1016/j.bmcl.2020.127058DOI Listing
April 2020

Protective effect of Lactobacillus casei HY2782 against particulate matter toxicity in human intestinal CCD-18Co cells and Caenorhabditis elegans.

Biotechnol Lett 2020 Apr 23;42(4):519-528. Epub 2020 Jan 23.

Natural Product Informatics Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, 25451, Republic of Korea.

Objectives: To investigate the preventive effect of Lactobacillus casei HY2782 on toxicity induced by particulate matter (PM, inhalable particles less than 10 μm in diameter) in human intestinal CCD-18Co cells and a model animal Caenorhabditis elegans.

Results: L. casei HY2782 treatment prevented PM-induced intestinal cell death via cellular reactive oxygen species production and membrane disruption attenuation. PM significantly decreased the total number of eggs laid and the body bending activity of C. elegans, demonstrating PM toxicity. L. casei HY2782 treatment restored the reproductive toxicity and decline in locomotion activity induced by PM in C. elegans. Overall, L. casei HY2782 attenuated PM toxicity in vitro in cultured intestinal cells and in vivo in the model nematode.

Conclusion: Our study provides a potential clue for developing L. casei HY2782 probiotics that attenuate PM-induced cellular and physiological toxicity; however, further in-depth preclinical trials using mammalian animal models and clinical trials are required.
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http://dx.doi.org/10.1007/s10529-020-02814-3DOI Listing
April 2020

Measuring the Effects of Bacteria and Chemicals on the Intestinal Permeability of Caenorhabditis elegans.

J Vis Exp 2019 12 3(154). Epub 2019 Dec 3.

Gangneung Institute of Natural Products, Korea Institute of Science and Technology; Division of Bio-Medical Science & Technology, Korea University of Science and Technology (UST);

In living organisms, intestinal hyperpermeability is a serious symptom that leads to many inflammatory bowel diseases (IBDs). Caenorhabditis elegans is a nonmammalian animal model that is widely used as an assay system due to its short lifespan, transparency, cost-effectiveness, and lack of animal ethics issues. In this study, a method was developed to investigate the effects of different bacteria and 3,3'-diindolylmethane (DIM) on the intestinal permeability of C. elegans with a high-throughput image analysis system. The worms were infected with different gut bacteria or cotreated with DIM for 48 h and fed with fluorescein isothiocyanate (FITC)-dextran overnight. Then, the intestinal permeability was examined by comparing the fluorescence images and the fluorescence intensity inside the worm bodies. This method may also have the potential to identify probiotic and pathogenic intestinal bacteria that affect intestinal permeability in the animal model and is effective for examining the effects of harmful or health-promoting chemicals on intestinal permeability and intestinal health. However, this protocol also has some considerable limitations at the genetic level, especially for determining which genes are altered to control illness, because this method is mostly used for phenotypic determination. In addition, this method is limited to determining exactly which pathogenic substrates cause inflammation or increase the permeability of the worms' intestines during infection. Therefore, further in-depth studies, including investigation of the molecular genetic mechanism using mutant bacteria and nematodes as well as chemical component analysis of bacteria, are required to fully evaluate the function of bacteria and chemicals in determining intestinal permeability.
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http://dx.doi.org/10.3791/60419DOI Listing
December 2019

Antimicrobial Biophotonic Treatment of Ampicillin-Resistant with Hypericin and Ampicillin Cotreatment Followed by Orange Light.

Pharmaceutics 2019 Dec 1;11(12). Epub 2019 Dec 1.

Natural Products Informatics Research Center, Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangwon-do 25451, Korea.

Bacterial antibiotic resistance is an alarming global issue that requires alternative antimicrobial methods to which there is no resistance. Antimicrobial photodynamic therapy (APDT) is a well-known method to combat this problem for many pathogens, especially Gram-positive bacteria and fungi. Hypericin and orange light APDT efficiently kill , methicillin-resistant (MRSA), and the yeast . Although Gram-positive bacteria and many fungi are readily killed with APDT, Gram-negative bacteria are difficult to kill due to their different cell wall structures. is one of the most important opportunistic, life-threatening Gram-negative pathogens. However, it cannot be killed successfully by hypericin and orange light APDT. is ampicillin resistant, but we hypothesized that ampicillin could still damage the cell wall, which can promote photosensitizer uptake into Gram-negative cells. Using hypericin and ampicillin cotreatment followed by orange light, a significant reduction (3.4 log) in PAO1 was achieved. PAO1 inactivation and gut permeability improvement by APDT were successfully shown in a model.
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http://dx.doi.org/10.3390/pharmaceutics11120641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956302PMC
December 2019

3,3'-Diindolylmethane Improves Intestinal Permeability Dysfunction in Cultured Human Intestinal Cells and the Model Animal .

J Agric Food Chem 2019 Aug 6;67(33):9277-9285. Epub 2019 Aug 6.

Natural Product Informatics Research Center , Korea Institute of Science and Technology , Gangneung , Gangwon-do 25451 , Republic of Korea.

3,3'-Diindolylmethane (DIM), a digestive metabolite originating from cruciferous vegetables, has dietary potential for the treatment of various human intestinal diseases. Although intestinal permeability dysfunction is closely related to the initiation and progression of human intestinal inflammatory diseases (IBDs), the effect of DIM on intestinal permeability is unclear. We evaluated the effect of DIM on the intestinal permeability of human intestinal cell monolayers and the animal model which were treated with IL-1β and , respectively, to mimic IBD conditions. DIM substantially restored the intestinal permeability of differentiated Caco-2 cells by enhancing the expression of tight junction proteins (including occludin and ZO-1). Compared to the IL-1β single treatment (551.0 ± 49.0 Ω·cm), DIM (10 μM) significantly increased the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers (919.0 ± 66.4 Ω·cm, < 0.001). DIM also ameliorated the impaired intestinal permeability and extended the lifespan of fed . The mean lifespan of DIM-treated worms (10.8 ± 1.3 days) was higher than that of control-treated worms (9.7 ± 1.1 days, < 0.01). Thus, DIM is a potential nutraceutical candidate for the treatment of leaky gut syndrome by improving intestinal permeability.
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http://dx.doi.org/10.1021/acs.jafc.9b03039DOI Listing
August 2019

Anti-Obesity Effect of Standardized Extract of Microalga Containing Fucoxanthin.

Mar Drugs 2019 May 27;17(5). Epub 2019 May 27.

Smart Farm Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, Korea.

Fucoxanthin (FX), a marine carotenoid found in macroalgae and microalgae, exhibits several beneficial effects to health. The anti-obesity activity of FX is well documented, but FX has not been mass-produced or applied extensively or commercially because of limited availability of raw materials and complex extraction techniques. In this study, we investigated the anti-obesity effect of standardized FX powder ( extract (PE)) developed from microalga as a commercial functional food. The effects of PE on adipogenesis inhibition in 3T3-L1 adipocytes and anti-obesity in high-fat diet (HFD)-fed C57BL/6J mice were evaluated. PE and FX dose-dependently decreased intracellular lipid contents in adipocytes without cytotoxicity. In HFD-fed obese mice, PE supplementation for six weeks decreased body weight, organ weight, and adipocyte size. In the serum parameter analysis, the PE-treated groups showed attenuation of lipid metabolism dysfunction and liver damage induced by HFD. In the liver, uncoupling protein-1 (UCP1) upregulation and peroxisome proliferator activated receptor γ (PPARγ) downregulation were detected in the PE-treated groups. Additionally, micro computed tomography revealed lower fat accumulation in PE-treated groups compared to that in the HFD group. These results indicate that PE exerts anti-obesity effects by inhibiting adipocytic lipogenesis, inducing fat mass reduction and decreasing intracellular lipid content, adipocyte size, and adipose weight.
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http://dx.doi.org/10.3390/md17050311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562887PMC
May 2019

Effects of fermented milk treatment on microbial population and metabolomic outcomes in a three-stage semi-continuous culture system.

Food Chem 2018 Oct 23;263:216-224. Epub 2018 Apr 23.

Systems Biotechnology Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea. Electronic address:

We investigated the impact of a fermented milk product on gut microbiota and their metabolism in 3 different conditions of the colon with a systemic viewpoint. An in vitro semi-continuous anaerobic cultivation was used to assess the colon compartment-specific influence of fermented milk, followed by a multiomics approach combining 16S rDNA amplicon sequencing and nuclear magnetic resonance (NMR) spectroscopy. The microbiome profiling and metabolomic features were significantly different across three colon compartments and after fermented milk treatment. Integrative correlation analysis indicated that the alteration of butyrate-producing microbiota (Veillonella, Roseburia, Lachnospira, and Coprococcus) and some primary metabolites (butyrate, ethanol, lactate, and isobutyrate) in the treatment group had a strong association with the fermented milk microorganisms. Our findings suggested that fermented milk treatment significantly affected microbial population in an in vitro cultivation system as well as the colonic metabolome in different ways in each of colon compartment.
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http://dx.doi.org/10.1016/j.foodchem.2018.04.095DOI Listing
October 2018

High-throughput and direct measurement of androgen levels using turbulent flow chromatography liquid chromatography-triple quadrupole mass spectrometry (TFC-LC-TQMS) to discover chemicals that modulate dihydrotestosterone production in human prostate cancer cells.

Biotechnol Lett 2018 Feb 21;40(2):263-270. Epub 2017 Nov 21.

Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung, 25451, Republic of Korea.

Objectives: To develop a high-throughput screening system to measure the conversion of testosterone to dihydrotestosterone (DHT) in cultured human prostate cancer cells using turbulent flow chromatography liquid chromatography-triple quadrupole mass spectrometry (TFC-LC-TQMS).

Results: After optimizing the cell reaction system, this method demonstrated a screening capability of 103 samples, including 78 single compounds and 25 extracts, in less than 12 h without manual sample preparation. Consequently, fucoxanthin, phenethyl caffeate, and Curcuma longa L. extract were validated as bioactive chemicals that inhibited DHT production in cultured DU145 cells. In addition, naringenin boosted DHT production in DU145 cells.

Conclusion: The method can facilitate the discovery of bioactive chemicals that modulate the DHT production, and four phytochemicals are potential candidates of nutraceuticals to adjust DHT levels in male hormonal dysfunction.
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http://dx.doi.org/10.1007/s10529-017-2480-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813082PMC
February 2018

Measuring the Effect of Chemicals on the Growth and Reproduction of Caenorhabditis elegans.

J Vis Exp 2017 10 5(128). Epub 2017 Oct 5.

Systems Biotechnology Research Center, Korea Institute of Science and Technology;

Toxicological evaluation is crucial for understanding the effects of chemicals on living organisms in basic and applied biological science fields. A non-mammalian soil round worm, Caenorhabditis elegans, is a valuable model organism for toxicology studies due to its convenience and lack of animal ethics issues compared with mammalian animal systems. In this protocol, a detailed procedure of toxicological evaluation of chemicals in C. elegans is described. A clinical anticancer drug, etoposide, which targets human topoisomerase II and inhibits DNA replication of human cancer cells, was selected as a model testing chemical. Age-synchronized C. elegans eggs were exposed to either dimethyl sulfoxide (DMSO) or etoposide, and then the growth of C. elegans was monitored every day for 4 days by the stereo microscope observation. The total number of eggs laid from C. elegans treated with DMSO or etoposide was also counted by using the stereo microscope. Etoposide treatment significantly affected the growth and reproduction of C. elegans. By comparison of the total number of eggs laid from worms with different treatment periods of chemicals, it can be decided that the reproductive toxicity of chemicals on C. elegans reproduction is reversible or irreversible. These protocols may be helpful for both the development of various drugs and risk assessment of environmental toxicants.
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http://dx.doi.org/10.3791/56437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752366PMC
October 2017

Data on the anti-tumor effects of extract and amentoflavone combined with doxorubicin in mice.

Data Brief 2017 Aug 17;13:162-165. Epub 2017 May 17.

Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of Korea.

Here, we report animal experimental data associated with the article entitled "AKR1B10-inhibitory extract and amentoflavone decrease the growth of A549 human lung cancer cells in vitro and in vivo" (Jung et al., 2017) [1]. We tested the synergistic anti-tumor effects of extract and amentoflavone combined with doxorubicin hydrochloride in a nude mouse xenograft model of A549 human lung cancer cells. In our experiment, extract and amentoflavone were administered orally; and doxorubicin hydrochloride was injected intraperitoneally. We expect our preliminary data will be helpful to the development of the anticancer agent using extract or amentoflavone.
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http://dx.doi.org/10.1016/j.dib.2017.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451183PMC
August 2017

AKR1B10-inhibitory Selaginella tamariscina extract and amentoflavone decrease the growth of A549 human lung cancer cells in vitro and in vivo.

J Ethnopharmacol 2017 Apr 9;202:78-84. Epub 2017 Mar 9.

Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea; Department of Biological Chemistry, University of Science and Technology (UST), Daejeon 34113, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Selaginella tamariscina (P.Beauv.) Spring is a traditional medicinal plant used to treat various human diseases, including cancer, in Asia. The detailed molecular mechanism underlying the anti-cancer effects of this plant and the anti-cancer action of the combinatorial treatment of S. tamariscina and doxorubicin have not yet been investigated.

Aim Of The Study: We evaluated the inhibitory activity of S. tamariscina extract (STE) and its major compound, amentoflavone, on human aldo-keto reductase family 1B10 (AKR1B10), which is a detoxification enzyme involved in drug resistance, to evaluate their anti-cancer effects and their potential as adjuvant agents for doxorubicin cancer chemotherapy.

Materials And Methods: We tested the AKR1B10 inhibitory activity of STE and amentoflavone via an in vitro biochemical assay using recombinant human AKR1B10. We tested the anti-proliferative activity in A549, NCI-H460, SKOV-3, and MCF-7 human cancer cells, which contain different expression levels of AKR1B10, and determined the combination index to evaluate whether the addition of STE and amentoflavone is synergistic or antagonistic to the anti-cancer action of doxorubicin. We finally evaluated the in vivo anti-tumor effects of STE in a nude mouse xenograft model of A549 cells.

Results: STE and amentoflavone potently inhibited human AKR1B10 and synergistically increased the doxorubicin anti-proliferative effect in A549 and NCI-H460 human lung cancer cells that express a high level of AKR1B10 mRNA and protein. STE also significantly inhibited A549 tumor growth in animal experiments.

Conclusion: Our results suggest that STE and amentoflavone could be potential anti-cancer agents that target AKR1B10 and might be candidate adjuvant agents to boost the anti-cancer effect of doxorubicin.
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http://dx.doi.org/10.1016/j.jep.2017.03.010DOI Listing
April 2017

Toxicological evaluation of the topoisomerase inhibitor, etoposide, in the model animal Caenorhabditis elegans and 3T3-L1 normal murine cells.

Environ Toxicol 2017 Jun 16;32(6):1836-1843. Epub 2017 Feb 16.

Systems Biotechnology Research Center, Korea Institute of Science and Technology, Gangneung, 25451, Korea.

Etoposide, a topoisomerase II inhibitor, has been widely used as a clinical anticancer drug to treat diverse cancer patients. Since not only rapidly dividing cancer cells but also the cells of normal human tissues and every living organism in environmental ecosystems have topoisomerases, it is crucial to study the toxicity of etoposide in other organisms in addition to cancer cells. In this study, we evaluated the toxicity of etoposide in both a soil nematode, Caenorhabditis elegans, and 3T3-L1 normal murine cells. Etoposide significantly retarded the growth, egg laying, and hatching in C. elegans. Etoposide also affected the reproductive gonad tissue, decreased the number of germ cells and induced abnormally enlarged nuclei in C. elegans. In addition, etoposide inhibited 3T3-L1 cell proliferation, with IC values of 37.8 ± 7.3 and 9.8 ± 1.8 μM after 24 and 48 hours of treatment, respectively, via the induction of cell cycle arrest at the G2/M phase and apoptotic cell death. Etoposide also induced nuclear enlargement in 3T3-L1 normal murine cells. The reproductive toxicity and abnormal nuclear morphological changes seemed to correlate with the adverse effects of etoposide. We suggest that these experimental platforms, i.e., the toxicological evaluation of both nematodes and 3T3-L1 cells, may be useful to study the mechanisms underlying the side effects of chemicals, including topoisomerase inhibitors.
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http://dx.doi.org/10.1002/tox.22406DOI Listing
June 2017

Direct analysis of prostaglandin-E2 and -D2 produced in an inflammatory cell reaction and its application for activity screening and potency evaluation using turbulent flow chromatography liquid chromatography-high resolution mass spectrometry.

J Chromatogr A 2016 Sep 10;1463:128-35. Epub 2016 Aug 10.

Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea; Department of Biological Chemistry, University of Science and Technology, Youseng-gu, Daejeon 305-350, Republic of Korea. Electronic address:

Direct analysis of prostaglandin-E2 (PGE2) and -D2 (PGD2) produced from a RAW264.7 cell-based reaction was performed by liquid chromatography high-resolution mass spectrometry (LC-HRMS), which was online coupled with turbulent flow chromatography (TFC). The capability of this method to accurately measure PG levels in cell reaction medium containing cytokines or proteins as a reaction byproduct was cross-validated by two conventional methods. Two methods, including an LC-HRMS method after liquid-liquid extraction (LLE) of the sample and a commercial PGE2 enzyme-linked immunosorbent assay (ELISA), showed PGE2 and/or PGD2 levels almost similar to those obtained by TFC LC-HRMS over the reaction time after LPS stimulation. After the cross-validation, significant analytical throughputs, allowing simultaneous screening and potency evaluation of 80 natural products including 60 phytochemicals and 20 natural product extracts for the inhibition of the PGD2 produced in the cell-based inflammatory reaction, were achieved using the TFC LC-HRMS method developed. Among the 60 phytochemicals screened, licochalcone A and formononetin inhibited PGD2 production the most with IC50 values of 126 and 151nM, respectively. For a reference activity, indomethacin and diclofenac were used, measuring IC50 values of 0.64 and 0.21nM, respectively. This method also found a butanol extract of Akebia quinata Decne (AQ) stem as a promising natural product for PGD2 inhibition. Direct and accurate analysis of PGs in the inflammatory cell reaction using the TFC LC-HRMS method developed enables the high-throughput screening and potency evaluation of as many as 320 samples in less than 48h without changing a TFC column.
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http://dx.doi.org/10.1016/j.chroma.2016.08.020DOI Listing
September 2016

Identification of dialkyl diacetylene diols with potent cancer chemopreventive activity.

Bioorg Med Chem Lett 2015 Sep 6;25(18):4020-3. Epub 2015 Jun 6.

College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 406-799, Republic of Korea. Electronic address:

An increasing importance of chemoprevention for controlling cancer risks prompted the discovery of new active cancer chemopreventive agents. In this study, we designed and synthesized substituted hexa-2,4-diyne-1,6-diols, more structurally simplified, tunable, and easily preparable than natural gymnasterkoreaynes, and evaluated their cancer chemopreventive activities by measuring concentration of doubling quinone reductase activity (CD), cell viability, and chemopreventive index (CI). Most of the diols exhibited good CD activity and low cytotoxicity. In particular, tetradeca-5,7-diyne-4,9-diol and 2-methyltetradeca-5,7-diyne-4,9-diol showed the best cancer chemopreventive activity, approximately equipotent to that of sulforaphane. And, by synthesizing optically active stereoisomers of selected active compounds, the effect of stereochemistry was also studied. Eventually, we produced a chemopreventive compound for in vivo study.
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http://dx.doi.org/10.1016/j.bmcl.2015.05.098DOI Listing
September 2015

Isolation of major phenolics from Launaea spinosa and their protective effect on HepG2 cells damaged with t-BHP.

Pharm Biol 2016 8;54(3):536-41. Epub 2015 Jun 8.

b Department of Pharmacognosy, Faculty of Pharmacy , Cairo University , Cairo , Egypt .

Context: Some Launaea species (Asteraceae) are used traditionally to treat liver oxidative stress.

Objective: The present study investigates the protective effects of isolated compounds from Launaea spinosa Sch. Bip. (Asteraceae) against oxidative stress on t-BHP-induced HepG2 cells.

Materials And Methods: Major phenolic content from flowering aerial parts of L. spinosa was isolated and identified. The protective effects of isolated compounds (10 and 20 μM) against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells were investigated through the measurement of aspartate aminotransferase (AST), alanine transaminase (ALT), and superoxide dismutase (SOD) levels.

Results: A new phenolic compound identified as 2,3-diferulyl R,R-(+) methyl tartrate (6), in addition to five known metabolites, esculetin (1), esculetin-7-O-d-glucoside (cichoriin) (2), fertaric acid (3), acacetin-7-O-d-glucoside (4), and acacetin-7-O-d-glucuronic acid (5), were isolated. Oxidant-induced damage by 200 μM t-BHP in HepG2 cells was inhibited by compounds 1, 4, and 5 (10 and 20 μM), or quercetin (10 μM; positive control). The protective effects of compounds 1, 4, and 5 were associated with decreasing in AST, ALT, and SOD levels. Compound 4 (20 μM) decreased the AST level from 128.5 ± 13.9 to 7.9 ±1.8 U/mL. Meanwhile, compound 1 (20 μM) decreased ALT activity from 20.3 ± 7.0 to 7.6 ± 2.4 U/mL, while compound 5 decreased SOD levels from 41.6 ± 9.0 to 28.3 ± 3.4 mU/mg.

Conclusion: The major phenolic compounds isolated from L. spinosa displayed a significant cytoprotective effect against oxidative stress, leading to maintenance of the normal redox status of the cell.
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http://dx.doi.org/10.3109/13880209.2015.1052885DOI Listing
October 2016

Daurinol Enhances the Efficacy of Radiotherapy in Lung Cancer via Suppression of Aurora Kinase A/B Expression.

Mol Cancer Ther 2015 Jul 16;14(7):1693-704. Epub 2015 Apr 16.

College of Pharmacy, Gachon University, Incheon, Republic of Korea.

The aurora kinases constitute one family of serine/threonine kinases whose activity is essential for mitotic progression. The aurora kinases are frequently upregulated in human cancers and are associated with sensitivity to chemotherapy in certain ones. In the present study, we investigated whether aurora kinases could be a target to overcome radioresistance or enhance the radiosensitivity of lung cancer. For that purpose, we determined the therapeutic potential of daurinol, an investigational topoisomerase inhibitor, alone and in combination with radiation, by observing its effect on aurora kinases. Daurinol decreased cell viability and proliferation in human colon and lung cancer cells. Gene expression in daurinol-treated human colon cancer cells was evaluated using RNA microarray. The mRNA expression of 18 genes involved in the mitotic spindle check point, including aurora kinase A (AURKA) and aurora kinase B (AURKB), was decreased in daurinol-treated human colon cancer cells as compared with vehicle-treated cells. As expected, radiation increased expression levels of AURKA and AURKB. This increase was effectively attenuated by siRNAs against AURKA and AURKB, which suppressed cell growth and increased apoptosis under radiation. Furthermore, the expression of AURKA and AURKB was suppressed by daurinol in the presence or absence of radiation in colon and lung cancer cells. Daurinol alone or in combination with radiation decreased lung cancer growth in xenograft mouse models. Our data clearly confirm the antitumor and radiosensitizing activity of daurinol in human lung cancer cells through the inhibition of AURKA and AURKB.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0960DOI Listing
July 2015

Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase.

Int J Oncol 2014 Aug 16;45(2):558-66. Epub 2014 May 16.

Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea.

Daurinol, a lignan from the ethnopharmacological plant Haplophyllum dauricum, was recently reported to be a novel topoisomerase II inhibitor and an alternative to the clinical anticancer agent etoposide based on a colorectal cancer model. In the present study, we elucidated the detailed biochemical mechanism underlying the inhibition of human topoisomerase IIα by daurinol based on a molecular docking study and in vitro biochemical experiments. The computational simulation predicted that daurinol binds to the ATP-binding pocket of topoisomerase IIα. In a biochemical assay, daurinol (10-100 µM) inhibited the catalytic activity of topo-isomerase IIα in an ATP concentration-dependent manner and suppressed the ATP hydrolysis activity of the enzyme. However, daurinol did not inhibit topoisomerase I activity, most likely because topoisomerase I does not contain an ATP-binding domain. We also evaluated the anti-proliferative activity of daurinol in ovarian, small cell lung and testicular cancer cells, common target cancers treated with etoposide. Daurinol potently inhibited SNU-840 human ovarian cancer cell proliferation through cell cycle arrest in S phase, while etoposide induced G2/M phase arrest. Daurinol induced the increased expression of cyclin E, cyclin A and E2F-1, which are important proteins regulating S phase initiation and progression. Daurinol did not induce abnormal cell and nuclear enlargement in SNU-840 cells, in contrast to etoposide. Based on these data, we suggest that daurinol is a potential anticancer drug candidate for the treatment of human ovarian cancer with few side effects.
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http://dx.doi.org/10.3892/ijo.2014.2442DOI Listing
August 2014

Crepidiastrum denticulatum extract protects the liver against chronic alcohol-induced damage and fat accumulation in rats.

J Med Food 2014 Apr 20;17(4):432-8. Epub 2014 Mar 20.

Functional Food Center, Korea Institute of Science and Technology , Gangneung, Korea.

Alcohol is a severe hepatotoxicant that causes liver abnormalities such as steatosis, cirrhosis, and hepatocarcinoma. Crepidiastrum denticulatum (CD) is a well-known, traditionally consumed vegetable in Korea, which was recently reported to have bioactive compounds with detoxification and antioxidant properties. In this study, we report the hepatoprotective effect of CD extract against chronic alcohol-induced liver damage in vivo. The rats that were given CD extract exhibited decreased alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activities, which are liver damage markers that are typically elevated by alcohol consumption. The results were confirmed by histopathology with hematoxylin and eosin staining. Chronic alcohol consumption induced the formation of alcoholic fatty liver. However, treatment with CD extract dramatically decreased the hepatic lipid droplets. Treatment with CD extract also restored the antioxidative capacity and lipid peroxidation of the liver that had been changed by alcohol consumption. Furthermore, treatment with CD extract normalized the activities of the antioxidative enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase, which had been decreased by alcohol consumption. The results indicate that CD extract has protective effects against chronic alcohol hepatotoxicity in rats by increasing the liver's antioxidant capacity, and has potential as a dietary supplement intervention for patients with alcohol-induced liver damage.
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http://dx.doi.org/10.1089/jmf.2013.2799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993054PMC
April 2014

Apigenin isolated from Daphne genkwa Siebold et Zucc. inhibits 3T3-L1 preadipocyte differentiation through a modulation of mitotic clonal expansion.

Life Sci 2014 Apr 26;101(1-2):64-72. Epub 2014 Feb 26.

Functional Food Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do 210-340, Republic of Korea. Electronic address:

Aims: Obesity develops when energy intake chronically exceeds total energy expenditure. We sought to assess whether the flavonoid-rich fraction of crude extracts from Daphne genkwa Siebold et Zuccarini (GFF) might inhibit adipogenesis of 3T3-L1 cells.

Main Methods: Cell viability of 3T3-L1 preadipocytes was assessed by MTT assays, and lipid accumulation was measured by Oil Red O. Adipogenesis related factors were checked by Western blot analysis. Flow cytometry was used to analyze the mitotic cell cycle during the mitotic clonal expansion phase.

Key Findings: Among five flavonoids isolated from GFF, only apigenin potently inhibited the differentiation of 3T3-L1 cells. Apigenin reduced CCAAT/enhancer binding protein (C/EBP) α and peroxisome proliferator-activated receptor γ levels. Apigenin-treated 3T3-L1 cells failed to undergo clonal expansion during the early phase of adipocyte differentiation. Apigenin arrested cell cycle progression at the G0/G1 phase. This effect was associated with a marked decrease in cyclin D1 and cyclin-dependent kinase 4 expression, with the concomitant and sustained expression of p27(Kip1). In addition, apigenin inhibited the DNA-binding activity of C/EBPβ in differentiating 3T3-L1 cells by down-regulating the 35kDa isoform of C/EBPβ (liver-enriched activating protein) and up-regulating the expression of two different sets of C/EBP inhibitors: C/EBP homologous protein and the phospho-liver-enriched inhibitory protein isoform of C/EBPβ.

Significance: These findings suggest that apigenin can prevent 3T3-L1 preadipocyte differentiation by the inhibition of the mitotic clonal expansion and the adipogenesis related factors and upregulation of the expression of multiple C/EBPβ inhibitors.
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http://dx.doi.org/10.1016/j.lfs.2014.02.012DOI Listing
April 2014

Secretome profiling reveals the signaling molecules of apoptotic HCT116 cells induced by the dietary polyacetylene gymnasterkoreayne B.

J Agric Food Chem 2014 Mar 7;62(11):2353-63. Epub 2014 Mar 7.

Functional Food Center, Korea Institute of Science and Technology , Gangneung, Gangwon-do 210-340, Republic of Korea.

Dietary polyacetylenes from various foods have been receiving attention as promising cancer chemopreventive agents. However, until now, the detailed molecular mechanism and the regulatory proteins underlying these effects have not been elucidated. We investigated the effects of gymnasterkoreayne B (GKB), a model dietary polyacetylene from wild vegetables, on the programmed cell death of HCT116 human colorectal cancer cells. GKB inhibited HCT116 cell proliferation by inducing apoptotic cell death. GKB treatment resulted in ROS accumulation, leading to the activation of both intrinsic and extrinsic apoptotic pathway. We also found that FN1, TGFB1, APP, SERPINE1, HSPD1, SOD1, TXN, and ACTN4 may act as secretory signaling molecules during GKB-induced apoptotic cell death using LC-MS/MS identification followed by spectrum counting, statistical calculation, and gene ontology analysis. The secretory proteins suggested in this study may be promising candidates involved in apoptotic cell death of cancer cells induced by GKB that warrant further functional study.
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http://dx.doi.org/10.1021/jf404047zDOI Listing
March 2014

Gymnaster koraiensis and its major components, 3,5-di-O-caffeoylquinic acid and gymnasterkoreayne B, reduce oxidative damage induced by tert-butyl hydroperoxide or acetaminophen in HepG2 cells.

BMB Rep 2013 Oct;46(10):513-8

Functional Food Center, Korea Institute of Science and Technology, Gangneung 210-340, Korea

We investigated the protective effects of Gymnaster koraiensis against oxidative stress-induced hepatic cell damage. We used two different cytotoxicity models, i.e., the administration of tert-butyl hydroperoxide (t-BHP) and acetaminophen, in HepG2 cells to evaluate the protective effects of G. koraiensis. The ethyl acetate (EA) fraction of G. koraiensis and its major compound, 3,5-di-O-caffeoylquinic acid (DCQA), exerted protective effects in the t-BHP-induced liver cytotoxicity model. The EA fraction and DCQA ameliorated t-BHP-induced reductions in GSH levels and exhibited free radical scavenging activity. The EA fraction and DCQA also significantly reduced t-BHP-induced DNA damage in HepG2 cells. Furthermore, the hexane fraction of G. koraiensis and its major compound, gymnasterkoreayne B (GKB), exerted strong hepatoprotection in the acetaminophen-induced cytotoxicity model. CYP 3A4 enzyme activity was strongly inhibited by the extract, hexane fraction, and GKB. The hexane fraction and GKB ameliorated acetaminophen-induced reductions in GSH levels and protected against cell death.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133837PMC
http://dx.doi.org/10.5483/bmbrep.2013.46.10.037DOI Listing
October 2013

Antioxidant activity of phenolics in leaves of three red pepper (Capsicum annuum) cultivars.

J Agric Food Chem 2014 Jan 16;62(4):850-9. Epub 2014 Jan 16.

Functional Food Center, Korea Institute of Science and Technology (KIST) Gangneung Institute , Gangneung 210-340, Korea.

The antioxidant properties and phenolic profiles were first investigated in this paper on the leaves of three red pepper cultivars, Blackcuban (BCPL), Hongjinju (HPL), and Yeokgang-hongjanggun (YHPL). Of the ethanol extract of the three cultivars, BCPL showed potent antioxidant activities against the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical. Nine antioxidative compounds from the red pepper leaves were isolated and identified as one polyamine phenolic conjugate, N-caffeoylputrescine (1); three chlorogenic acid derivatives, 5-O-caffeoylquinic acid (2), 5-O-caffeoylquinic acid methyl ester (4), and 5-O-caffeoylquinic acid butyl ester (9); one anthocyanin, delphinidin-3-[4-trans-coumaroyl-l-rhamnosyl(1→6)glucopyranoside]-5-O-glucopyranoside (3); and four flavone glycosides, luteolin-7-O-apiofuranosyl(1→2)glucopyranoside (5), luteolin-7-O-glucopyranoside (6), apigenin 7-O-apiofuranosyl(1→2)glucopyranoside (7), apigenin-7-O-glucopyranoside (8). 1 and 3 had the greatest potential for radical-scavenging activity and HepG2 cells protecting effect against oxidative stress. BCPL exhibited the highest content of 1 and 3. Of the three cultivars BCPL may be considered a good source of antioxidants.
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http://dx.doi.org/10.1021/jf403006cDOI Listing
January 2014

Bifunctional chemopreventive effects of Adenocaulon himalaicum through induction of detoxification enzymes and apoptosis.

J Med Food 2013 Aug;16(8):701-10

Functional Food Center, Korea Institute of Science and Technology, Gangneung, Korea.

Phase II detoxification enzymes are known to play essential roles in the detoxification and elimination of activated carcinogens during tumor initiation, while apoptosis is one of the most important chemopreventive targets for inhibiting tumor promotion in cancer. In this study, we investigated the cancer chemopreventive activity of two plant extracts, the ethanolic extract of Adenocaulon himalaicum (AHE) and the butanolic fraction of AHE (AHB). Both, the AHE and AHB induced NQO1 activity and had relatively high chemoprevention indices (CI=12.4). The AHE and AHB were associated with increased NQO1 and HO-1 mRNA levels via Nrf2-ARE pathway activation. In addition, the AHB increased CYP1A1 activity through AhR-XRE pathway activation. We also found that the AHE and AHB induced apoptosis, as evidenced by phosphatidylserine externalization, an increase in the sub-G0/G1 content, chromatin condensation, poly(ADP-ribose) polymerase cleavage, and p53 induction. These data suggest that AHE and AHB act as bifunctional inducers and that their chemopreventive effects result from the biphasic induction of phase II detoxification enzymes and apoptosis. Therefore, these results suggest that A. himalaicum plant extracts have potential for use as chemopreventive agents for the prevention and/or treatment of human cancers.
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http://dx.doi.org/10.1089/jmf.2012.2625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751273PMC
August 2013

Protective effect of Paeonia anomala extracts and constituents against tert-butylhydroperoxide-induced oxidative stress in HepG2 cells.

Planta Med 2013 Jan 24;79(2):116-22. Epub 2013 Jan 24.

Functional Food Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea.

The fruit and root parts of Paeonia anomala L. are used for the treatment of many kinds of disorders in Mongolian traditional medicine. The protective effect of a fruit extract from P. anomala against tert-butylhydroperoxide-induced cell damage was evaluated in human hepatoma HepG2 cells and compared to that of a root extract from P. anomala on the basis of cell viability, generation of intracellular reactive oxygen species, cellular total glutathione concentration, and anti-genotoxicity. The fruit extract of P. anomala showed excellent protection against the oxidative stress when compared to the root extract, through free radical scavenging, enhancing cellular glutathione concentration, and inhibiting DNA damage. Chemical constituents in the fruit extract of P. anomala were investigated and two novel compounds, 2-hydroxy-6-methoxy-4-O-(6'-O-α-L-arabinofuranosyl-β-D-glucopyranosyl)acetophenone (1) and 3,3'-di-O-methyl-4-O-(3''-O-galloyl-β-D-glucopyranosyl)ellagic acid (2), along with 18 other known compounds were identified. Compound 2 showed better cytoprotection against tert-butylhydroperoxide than compound 1. Among other compounds isolated from the fruit extract, ellagic acid, methyl gallate, ethyl gallate, fischeroside B, and quercetin derivatives showed potent protective effects against tert-butylhydroperoxide-induced oxidative stress via inhibiting reactive oxygen species generation and increasing total glutathione levels in HepG2 cells.
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http://dx.doi.org/10.1055/s-0032-1328062DOI Listing
January 2013

Nuclear factor-E2 (Nrf2) is regulated through the differential activation of ERK1/2 and PKC α/βII by Gymnasterkoreayne B.

Cancer Lett 2013 Apr 5;330(2):225-32. Epub 2012 Dec 5.

Functional Food Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea.

Phytochemicals are well known to have cancer chemopreventive effects by induction of phase II detoxification enzymes including quinone reductase (NQO-1) and glutathione-S-transferases. These detoxification enzymes are commonly regulated by nuclear factor-E2 (Nrf2), which is a representative antioxidant and cytoprotective factor involved in cancer chemoprevention. As one of the known quinone reductase (QR) inducers and Nrf2 activators, Gymnasterkoreayne B (GKB) isolated from Gymnaster (Aster) koraiensis was used to elucidate the upstream signalling pathway for Nrf2 regulation. In this study, we confirmed that GKB significantly increases expression levels of Nrf2 in HCT116 human colon cancer cells. We found the probable mechanism of upstream signalling pathways to activate Nrf2 by GKB. To reveal the pathway that affects Nrf2 translocation by GKB, we examined changes in various kinases in HCT116 cells treated with GKB. We observed that ERK and PKC pathways are particularly involved in the activation of Nrf2 by GKB, followed by translocation of Nrf2 and induction of NQO-1. These results suggest that GKB induces Nrf2 translocation and expression by differential regulation of ERK and PKC pathways in HCT116 cells.
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http://dx.doi.org/10.1016/j.canlet.2012.11.053DOI Listing
April 2013

Dibenzocyclooctadiene lignans, gomisins J and N inhibit the Wnt/β-catenin signaling pathway in HCT116 cells.

Biochem Biophys Res Commun 2012 Nov 16;428(2):285-91. Epub 2012 Oct 16.

Functional Food Center, Korea Institute of Science and Technology, Gangneung 210-340, Republic of Korea.

Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/β-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/β-catenin signaling by disrupting the interaction between β-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the β-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/β-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/β-catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers.
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http://dx.doi.org/10.1016/j.bbrc.2012.10.046DOI Listing
November 2012

A novel topoisomerase inhibitor, daurinol, suppresses growth of HCT116 cells with low hematological toxicity compared to etoposide.

Neoplasia 2011 Nov;13(11):1043-57

Functional Food Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, Republic of Korea.

We report that daurinol, a novel arylnaphthalene lignan, is a promising potential anticancer agent with adverse effects that are less severe than those of etoposide, a clinical anticancer agent. Despite its potent antitumor activity, clinical use of etoposide is limited because of its adverse effects, including myelosuppression and the development of secondary leukemia. Here, we comprehensively compared the mechanistic differences between daurinol and etoposide because they have similar chemical structures. Etoposide, a topoisomerase II poison, is known to attenuate cancer cell proliferation through the inhibition of DNA synthesis. Etoposide treatment induces G(2)/M arrest, severe DNA damage, and the formation of giant nuclei in HCT116 cells. We hypothesized that the induction of DNA damage and nuclear enlargement due to abnormal chromosomal conditions could give rise to genomic instability in both tumor cells and in actively dividing normal cells, resulting in the toxic adverse effects of etoposide. We found that daurinol is a catalytic inhibitor of human topoisomerase IIa, and it induces S-phase arrest through the enhanced expression of cyclins E and A and by activation of the ATM/Chk/Cdc25A pathway in HCT116 cells. However, daurinol treatment did not cause DNA damage or nuclear enlargement in vitro. Finally, we confirmed the in vivo antitumor effects and adverse effects of daurinol and etoposide in nude mice xenograft models. Daurinol displayed potent antitumor effects without any significant loss of body weight or changes in hematological parameters, whereas etoposide treatment led to decreased body weight and white blood cell, red blood cell, and hemoglobin concentration.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223608PMC
http://dx.doi.org/10.1593/neo.11972DOI Listing
November 2011