• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.368-379
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• 2022

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

• Proceedings of the Korean Society of Plant Biotechnology Conference
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• 2005.11a
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• pp.279-279
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• 2005

• Natural Product Sciences
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• v.11 no.4
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• pp.220-224
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• 2005

Extensive chemical studies on the stem bark extracts of two Guttifereous plants namely Mesua daphnifolia and Garcinia nitida have led to the isolation of eight xanthones. Mesua daphnifolia gave cudraxanthone G (1), ananixanthone (2), 1,3,5-trihydroxy-4-methoxyxanthone (3) and euxanthone (4) while Garcinia nitida gave inophyllin B (5), 1,3,7-trihydroxy-2,4-bis (3-methylbut-2-enyl)xanthone (6), 3-isomangostin (7) and rubraxanthone (8). All these compounds were assayed against the MDA-MB-231 (human estrogen receptor negative breast cancer) cells. A structure-activity relationship study showed that structurally, all the 1, 3-oxygenated xanthones which carried unsaturated prenyl side chains (either 3-methylbut-2-enyl or 1,1-dimethyl-2-propenyl) at carbones C-2 and C-4 in the xanthone ring A are essential for the outstanding activities in the assay.

• Journal of Microbiology and Biotechnology
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• v.30 no.2
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• pp.279-286
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• 2020

A novel compound named 'kanakugiol' was recently isolated from Lindera erythrocarpa and showed free radical-scavenging and antifungal activities. However, the details of the anti-cancer effect of kanakugiol on breast cancer cells remain unclear. We investigated the effect of kanakugiol on the growth of MCF-7 human breast cancer cells. Kanakugiol affected cell cycle progression, and decreased cell viability in MCF-7 cells in a dose-dependent manner. It also enhanced PARP cleavage (50 kDa), whereas DNA laddering was not induced. FACS analysis with annexin V-FITC/PI staining showed necrosis induction in kanakugiol-treated cells. Caspase-9 cleavage was also induced. Expression of death receptors was not altered. However, Bcl-2 expression was suppressed, and mitochondrial membrane potential collapsed, indicating limited apoptosis induction by kanakugiol. Immunofluorescence analysis using α-tubulin staining revealed mitotic exit without cytokinesis (4N cells with two nuclei) due to kanakugiol treatment, suggesting that mitotic catastrophe may have been induced via microtubule destabilization. Furthermore, cell cycle analysis results also indicated mitotic catastrophe after cell cycle arrest in MCF-7 cells due to kanakugiol treatment. These findings suggest that kanakugiol inhibits cell proliferation and promotes cell death by inducing mitotic catastrophe after cell cycle arrest. Thus, kanakugiol shows potential for use as a drug in the treatment of human breast cancer.

• Journal of Applied Biological Chemistry
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• v.58 no.4
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• pp.389-389
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• 2015

• Journal of Applied Biological Chemistry
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• v.59 no.2
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• pp.171-171
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• 2016

• Journal of Applied Biological Chemistry
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• v.58 no.3
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• pp.219-226
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• 2015

The anticancer activity of a methanolic extract from lemon leaves (MLL) was assessed in MCF-7-SC human breast cancer stem cells. MLL induced apoptosis in MCF-7-SC, as evidenced by increased apoptotic body formation, sub-G1 cell population, annexin V-positive cells, Bax/Bcl-2 ratio, as well as proteolytic activation of caspase-9 and caspase-3, and degradation of poly (ADP-ribose) polymerase (PARP) protein. Concomitantly, MLL induced the formation of acidic vesicular organelles, increased LC3-II accumulation, and reduced the activation of Akt, mTOR, and p70S6K, suggesting that MLL initiates an autophagic progression in MCF-7-SC via the Akt/mTOR pathway. Epithelial-mesenchymal transition (EMT), a critical step in the acquisition of the metastatic state, is an attractive target for therapeutic interventions directed against tumor metastasis. At low concentrations, MLL induced anti-metastatic effects on MCF-7-SC by inhibiting the EMT process. Exposure to MLL also led to an increase in the epithelial marker E-cadherin, but decreased protein levels of the mesenchymal markers Snail and Slug. Collectively, this study provides evidence that lemon leaves possess cytotoxicity and anti-metastatic properties. Therefore, MLL may prove to be beneficial as a medicinal plant for alternative novel anticancer drugs and nutraceutical products.

• Journal of Life Science
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• v.29 no.4
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• pp.499-508
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• 2019

Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.

• Korean Journal of Medicinal Crop Science
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• v.20 no.3
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• pp.153-158
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• 2012

In order to develop as a natural source of anticancer materials of Cudrania tricuspidata, the cytotoxicity of methanol extracts by harvesting parts and times against 8 cell lines including 293 (normal kidney cells) and A-431 (epidermoid carcinoma cells) were investigated using MTT assay. All harvesting parts had hardly cytotoxicity against 293. And methanol extracts of stem bark and root bark showed very high cytotoxicities against 7 cancer cell lines. The cytotoxicity was the highest against HeLa (cervix adenocarcinoma cells) and followed by MCF-7 (breast adenocarcinoma cells), AGS (stomach adenocarcinoma cells), HT-29 (colon adenocarcinoma cells), HepG2 (hepatoblastoma cells), A549 (lung carcinoma cells) and A-431. By the way, leaf extract had a cytotoxicity against only AGS and ripe fruit extract had no cytotoxicity. Among harvesting times, the cytotoxicity of root bark were high from April to September but that of stem bark showed a little difference. These results showed that anticancer activities of Cudrania tricuspidata extracts were eventful changes by harvesting parts and times.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.5
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• pp.2291-2295
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• 2014

Although nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis and expression has been observed in some types of human cancer and stem cells, the molecular mechanisms involved in mediation of cell proliferation and cell cycling remains largely elusive. The aim of the present study was to evaluate NS as a potential target for gene therapy of human breast carcinoma by investigating NS gene expression and its effects on SKBR-3 cell proliferation and apoptosis. NS mRNA and protein were both found to be highly expressed in all detected cancer cell lines. The apoptotic rate of the pcDNA3.1-NS-Silencer group ($12.1-15.4{\pm}3.8%$) was significantly higher than those of pcDNA3.1-NS ($7.2-12.0{\pm}1.7%$) and non-transfection groups ($4.1-6.5{\pm}1.8%$, P<0.01). MTT assays showed the knockdown of NS expression reduced the proliferation rate of SKBR-3 cells significantly. Matrigel invasion and wound healing assays indicated that the number of invading cells was significantly decreased in the pcDNA3.1-NS-siRNA group (P<0.01), but there were no significant difference between non-transfected and over-expression groups (P>0.05). Moreover, RNAi-mediated NS down-regulation induced SKBR-3 cell G1 phase arrest, inhibited cell proliferation, and promoted p53 pathway-mediated cell apoptosis in SKBR-3 cells. NS might thus be an important regulator in the G2/M check point of cell cycle, blocking SKBR-3 cell progression through the G1/S phase. On the whole, these results suggest NS might be a tumor suppressor and important therapeutic target in human cancers.