• Biomolecules & Therapeutics
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• v.13 no.3
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• pp.185-189
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• 2005

We isolated a coumarin compound, isoimperatorin ($C_{16}H_{14}O_4$ mw: 270) from Angelica koreana through silica gel column chromatography, and characterized it by NMR. Here, for the first time we observed that isoimperatorin (25, 50 and 100 ${\mu}M$) treatment for 24-72h inhibited growth and induced death in human prostate carcinoma DU145 cells. Further, in mechanistic investigation, isoimperatorin-induced cell growth inhibition was associated with a strong increase in G1 arrest in cell cycle progression, which started at 24h of the treatment. These findings suggest a novel anticancer efficacy of isoimperatorin mediated via induction of G1 arrest against hormone refractory human prostate carcinoma DU145 cells.

• Biomolecules & Therapeutics
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• v.18 no.4
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• pp.375-385
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• 2010

Conventional cancer chemotherapy is seriously limited by tumor cells exhibiting multidrug resistance (MDR), which is caused by changes in the levels or activity of membrane transporters that mediate energy-dependent drug efflux and of proteins that affect drug metabolism and/or drug action. Cancer scientists and oncologists have worked together for some time to understand anticancer drug resistance and develop pharmacological strategies to overcome such resistance. Much focus has been on the reversal of the MDR phenotype by inhibition of ATP-binding cassette (ABC) drug transporters. ABC transporters are a family of transporter proteins that mediate drug resistance and low drug bioavailability by pumping various drugs out of cells at the expense of ATP hydrolysis. Many inhibitors of MDR transporters have been identified, and though some are currently undergoing clinical trials, none are in clinical use. Herein, we briefly review the status of MDR in human cancer, explore the pathways of MDR in chemotherapy, and outline recent advances in the design and development of MDR modulators.

• Journal of Applied Biological Chemistry
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• v.48 no.4
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• pp.170-177
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• 2005

Oriental medicinal herb extracts (OHE) showing anticancer activities were investigated for effectiveness as antiviral drugs. Infection of MuLV to cell line resulted in formation of giant syncytia. Number of giant syncytia in culture treated with OHE decreased by 40% compared to that of non-OHE-treated cell culture. To determine OHE effects on progeny release, RT-PCR was performed. In vivo animal studies demonstrated effectiveness of OHE as antiviral drug when administered orally. After OHE administration, viral cytopathic effects decreased. Infected mice showed splenomegaly and over-proliferation of lymphocytes with decreased CD4+ cell counts. These symptoms decreased in OHE-treated mice, indicating OHE maybe useful therapeutics against MuLV/MAIDS as Human Immunodeficiency Virus (HIV)/AIDS animal model. Results show XC plaque assay and in vivo MAIDS model using MuLV are suitable tools for screening anti-retroviral drug candidates.

• BMB Reports
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• v.45 no.1
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• pp.1-6
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• 2012

Hsp90 is one of the most conserved molecular chaperones ubiquitously expressed in normal cells and over-expressed in cancer cells. A pool of Hsp90 was found in cancer mitochondria and the expression of the mitochondrial Hsp90 homolog, TRAP1, was also elevated in many cancers. The mitochondrial pool of chaperones plays important roles in regulating mitochondrial integrity, protecting against oxidative stress, and inhibiting cell death. Pharmacological inactivation of the chaperones induced mitochondrial dysfunction and concomitant cell death selectively in cancer cells, suggesting they can be target proteins for the development of cancer therapeutics. Several drug candidates targeting TRAP1 and Hsp90 in the mitochondria have been developed and have shown strong cytotoxic activity in many cancers, but not in normal cells in vitro and in vivo. In this review, recent developments in the study of mitochondrial chaperones and the mitochondria-targeted chaperone inhibitors are discussed.

• Biomolecules & Therapeutics
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• v.3 no.2
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• pp.97-103
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• 1995

The purpose of this study was to determine pharmacokinetic parameters of BR-28702-2, a new antineoplastic agent which is the conjugate of nucleotide and phospholipid, and to compare them with those of ara-C. Male rats were cannulated in the left femoral vein and received a single i.v. bolus dose of either BR-28702-2 or ara-C. BR-28702-2 was also administered i.p. and plasma samples were analyzed by reversedphase HPLC. The t$_{1}$2($\beta$)/ of ara-C(1.22 hr.) was significantly smaller than that of BR-28702-2(4.420 hr.). The absolute bioavailability of BR-28702-2 after i.p. injection was 1.125%. This lower bioavailability, together with previous reports that marked antineoplastic activity was observed when given i.p., indicates that BR-28702-2 would act as a depot system to release active moieties. Further works, therefore, need to be done to characterize active metabolites.

• Natural Product Sciences
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• v.26 no.2
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• pp.118-131
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• 2020

Mushrooms are known for their various attributes in the fields of nutrition and therapeutics. With exceptional taste, aroma, and nutritional value, they are considered 'functional food'-improving health and providing nutritional benefits to the body. Mushrooms have also been widely applied therapeutically as they possess diverse bioactive compounds known as secondary metabolites. These secondary metabolites demonstrated diverse biological properties such as anticancer, anti-diabetic, immunomodulatory, antimicrobial, anti-inflammatory, antiviral, anti-allergic, and antioxidative activities. This review presents bioactive compounds from the field of mushroom metabolite research and discusses important findings regarding bioactive compounds identified during the last five years (2015 - 2019).

• Biomolecules & Therapeutics
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• v.31 no.5
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• pp.559-565
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• 2023

Ataxia-telangiectasia mutated (ATM), a master kinase of the DNA damage response (DDR), phosphorylates a multitude of substrates to activate signaling pathways after DNA double-strand breaks (DSBs). ATM inhibitors have been evaluated as anticancer drugs to potentiate the cytotoxicity of DNA damage-based cancer therapy. ATM is also involved in autophagy, a conserved cellular process that maintains homeostasis by degrading unnecessary proteins and dysfunctional organelles. In this study, we report that ATM inhibitors (KU-55933 and KU-60019) provoked accumulation of autophagosomes and p62 and restrained autolysosome formation. Under autophagy-inducing conditions, the ATM inhibitors caused excessive autophagosome accumulation and cell death. This new function of ATM in autophagy was also observed in numerous cell lines. Repression of ATM expression using an siRNA inhibited autophagic flux at the autolysosome formation step and induced cell death under autophagy-inducing conditions. Taken together, our results suggest that ATM is involved in autolysosome formation and that the use of ATM inhibitors in cancer therapy may be expanded.

• Biomolecules & Therapeutics
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• v.4 no.4
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• pp.349-353
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• 1996

The present study examined pharmacokinetic profiles of KBP31705-Cl27 and KBP30603-901, new platinum coordination complexes synthesized as anticancer candidates, in comparison with two well-known platinum-containing anticancer agents, cisplatin and carboplatin in rats. Under sodium pentobarbital anesthesia of male Sprague-Dawley rats, urinary bladder, and femoral artery and vein were catheterized for urine collection, blood sampling and drug injection, respectively Following i.v. administration of cisplatin (2 mg/kg), KBP31705-C127 (2 mg/kg), carboplatin (20 mg/kg) or KBP30603-901 (20 mg/kg), blood samples were collected at 2, 4, 6, 8, 10, 15, 20, 30, 45, 60 and 120 minutes. Urine samples were collected at 1-hr interval for 4 hr. Platinum concentrations in plasma and urine were measured using an inductively coupled plasmamass spectrometer. The plasma concentration-time curves were biphasic for all drugs during the time period studied. Compared with cisplatin, KBP31705-C127 showed similar decay patters in the alpha- and betaphases with slightly lower plasma concentrations. Urinary platinum excretion for cisplatin and KBP31705-C 127 was 56 and 52% of the administered dose in 4 hr, respectively. With regard to carboplatin and KBP 30603-901, a similar decay pattern was also observed in the alpha-phase. The half life of KBP30603-901 in the beta-phase, however, was much longer than that of carboplatin, which was consistent with the urinary excretion results that 46 and 59% of the administered dose were excreted in the urine in 4hr, respectively. The results suggest that platinum coordination complexes are primarily excreted via the renal route and KBP30603-901 can elicit longer duration of action due to slower renal excretion compared to carboplatin.

• Biomolecules & Therapeutics
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• v.20 no.6
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• pp.513-519
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• 2012

Although the immense efforts have been made for cancer prevention, early diagnosis, and treatment, cancer morbidity and mortality has not been decreased during last forty years. Especially, lung cancer is top-ranked in cancer-associated human death. Therefore, effective strategy is strongly required for the management of lung cancer. In the present study, we found that novel daphnane diterpenoids, yuanhualine (YL), yuanhuahine (YH) and yuanhuagine (YG) isolated from the flower of Daphne genkwa (Thymelaeaceae), exhibited potent anti-proliferative activities against human lung A549 cells with the $IC_{50}$ values of 7.0, 15.2 and 24.7 nM, respectively. Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells. The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A, cyclin B1, cyclin E, cyclin dependent kinase 4, cdc2, phosphorylation of Rb and cMyc expression. In the analysis of signal transduction molecules, the daphnane diterpenoids suppressed the activation of Akt, STAT3 and Src in human lung cancer cells. The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549, gefitinib-, erlotinib-resistant H292 cells. Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine, gefitinib or erlotinib in A549 cells. Taken together, these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers.

• Biomolecules & Therapeutics
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• v.23 no.5
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• pp.434-441
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• 2015

Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP ($IC_{50}=0.67{\mu}M$) than in DU145 cells ($IC_{50}=1.10{\mu}M$) and PC3 cells ($IC_{50}=5.60{\mu}M$) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.