• Molecules and Cells
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• v.38 no.4
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• pp.373-379
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• 2015

Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of $4.92{\mu}M$, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer.

• Journal of Ginseng Research
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• v.44 no.2
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• pp.247-257
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• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• Journal of Ginseng Research
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• v.43 no.3
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• pp.460-474
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• 2019

Background: Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in NR1I2, adenosine triphosphate-binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals. Methods: Forty-two targeted variants in seven genes were genotyped in 54 participants using Sequenom MassARRAY system to investigate their association with major pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD). Subsequently, molecular docking was simulated using the AutoDock Vina program. Results: ABCC4 rs1751034 TT and rs1189437 TT were associated with increased exposure of CK and decreased exposure of 20(S)-PPD, whereas CFTR rs4148688 heterozygous carriers had the lowest maximum concentration ($C_{max}$) of CK. The area under the curve from zero to the time of the last quantifiable concentration ($AUC_{last}$) of CK was decreased in NR1I2 rs1464602 and rs2472682 homozygous carriers, while $C_{max}$ was significantly reduced only in rs2472682. ABCC4 rs1151471 and CFTR rs2283054 influenced the pharmacokinetics of 20(S)-PPD. In addition, several variations in ABCC2, ABCC4, CFTR, and NR1I2 had minor effects on the pharmacokinetics of CK. Quality of the best homology model of multidrug resistance protein 4 (MRP4) was assessed, and the ligand interaction plot showed the mode of interaction of CK with different MRP4 residues. Conlusion: ABCC4 rs1751034 and rs1189437 affected the pharmacokinetics of both CK and 20(S)-PPD. NR1I2 rs1464602 and rs2472682 were only associated with the pharmacokinetics of CK. Thus, these hereditary variances could partly explain the interindividual differences in the pharmacokinetics of CK.

• Journal of Ginseng Research
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• v.46 no.6
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• pp.738-749
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• 2022

Background: Ginseng possesses antitumor effects, and ginsenosides are considered to be one of its main active chemical components. Ginsenosides can further be hydrolyzed to generate secondary saponins, and 20(R)-panaxotriol is an important sapogenin of ginsenosides. We aimed to synthesize a new ginsengenin derivative from 20(R)-panaxotriol and investigate its antitumor activity in vivo and in vitro. Methods: Here, 20(R)-panaxotriol was selected as a precursor and was modified into its derivatives. The new products were characterized by ¹H-NMR, ¹³C-NMR and HR-MS and evaluated by molecular docking, MTT, luciferase reporter assay, western blotting, immunofluorescent staining, colony formation assay, EdU labeling and immunofluorescence, apoptosis assay, cells migration assay, transwell assay and in vivo antitumor activity assay. Results: The derivative with the best antitumor activity was identified as 6,12-dihydroxy-4,4,8,10,14-pentamethyl-17-(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl(tert-butoxycarbonyl)glycinate (A11). The focus of this research was on the antitumor activity of the derivatives. The efficacy of the derivative A11 (IC₅₀ < 0.3 µM) was more than 100 times higher than that of 20(R)- panaxotriol (IC₅₀ > 30 µM). In addition, A11 inhibited the protein expression and nuclear accumulation of the hypoxia-inducible factor HIF-1α in HeLa cells under hypoxic conditions in a dose-dependent manner. Moreover, A11 dose-dependently inhibited the proliferation, migration, and invasion of HeLa cells, while promoting their apoptosis. Notably, the inhibition by A11 was more significant than that by 20(R)-panaxotriol (p < 0.01) in vivo. Conclusion: To our knowledge, this is the first study to report the production of derivative A11 from 20(R)-panaxotriol and its superior antitumor activity compared to its precursor. Moreover, derivative A11 can be used to further study and develop novel antitumor drugs.

• Microbiology and Biotechnology Letters
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• v.37 no.3
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• pp.248-257
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• 2009

The inhibitors against Vibrio harveyi quorum sensing (QS) signaling were developed by modifying the molecular structure of the major signal, N-3-hydroxybutanoyl-L-homoserine lactone (3-OH-$C_4$-HSL). A series of structural derivatives, N-(3-hydroxysulfonyl)-L-homoserine lactones (HSHLs) were synthesized by the solid-phase organic synthesis method. The in vivo QS inhibition by these compounds was measured by a bioassay system using the V. harveyi bioluminescence, and all showed significant inhibitory effects. To analyze the interaction between these compounds and LuxN, a 3-OH-$C_4$-HSL receptor protein of V. harveyi, we tentatively determined the putative signal binding domain of LuxN based on the sequence homology with other acyl-HSL binding proteins, and predicted the partial 3-D structure of the putative signal binding domain of LuxN by using ORCHESTRA program, and further estimated the binding poses and energies (docking scores) of 3-OH-$C_4$-HSL and HSHLs within the domain. In comparison of the result from this modeling study with that of in vivo bioassay, we suggest that the in silica interpretation of the interaction between ligands and their receptor proteins can be a valuable way to develop better competitive inhibitors, especially in the case that the structural information of the protein is limited.

• KIPS Transactions on Software and Data Engineering
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• v.2 no.2
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• pp.81-90
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• 2013

During the past decade, many changes and attempts have been tried and are continued developing new technologies in the computing area. The brick wall in computing area, especially power wall, changes computing paradigm from computing hardwares including processor and system architecture to programming environment and application usage. The high performance computing (HPC) area, especially, has been experienced catastrophic changes, and it is now considered as a key to the national competitiveness. In the late 2000's, many leading countries rushed to develop Exascale supercomputing systems, and as a results tens of PetaFLOPS system are prevalent now. In Korea, ICT is well developed and Korea is considered as a one of leading countries in the world, but not for supercomputing area. In this paper, we describe architecture design of MAHA supercomputing system which is aimed to develop 300 TeraFLOPS system for bio-informatics applications like human genome analysis and protein-protein docking. MAHA supercomputing system is consists of four major parts - computing hardware, file system, system software and bio-applications. MAHA supercomputing system is designed to utilize heterogeneous computing accelerators (co-processors like GPGPUs and MICs) to get more performance/$, performance/area, and performance/power. To provide high speed data movement and large capacity, MAHA file system is designed to have asymmetric cluster architecture, and consists of metadata server, data server, and client file system on top of SSD and MAID storage servers. MAHA system softwares are designed to provide user-friendliness and easy-to-use based on integrated system management component - like Bio Workflow management, Integrated Cluster management and Heterogeneous Resource management. MAHA supercomputing system was first installed in Dec., 2011. The theoretical performance of MAHA system was 50 TeraFLOPS and measured performance of 30.3 TeraFLOPS with 32 computing nodes. MAHA system will be upgraded to have 100 TeraFLOPS performance at Jan., 2013.