• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.667-671
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• 2016

Oridonin, an ent-kaurane diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens, has shown various pharmacological and physiological effects such as anti-tumor, anti-bacterial, and anti-inflammatory properties. However, the effect of oridonin on human ovarian cancer cell lines has not been determined. In this study, we demonstrated that oridonin inhibited ovarian cancer cell proliferation, migration and invasion in a dose-dependent manner. Furthermore, we showed oridonin inhibited tumor growth of ovarian cancer cells (SKOV3) in vivo. We then assessed mechanisms and found that oridonin specifically abrogated the phosphorylation/activation of mTOR signaling. In summary, our results indicate that oridonin is a potential inhibitor of ovarian cancer by blocking the mTOR signaling pathway.

• Journal of Microbiology and Biotechnology
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• v.32 no.5
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• pp.657-662
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• 2022

Glycosyltransferase (GT)-specific degenerate PCR screening followed by in silico sequence analyses of the target clone was used to isolate a member of family1 GT-encoding genes from the established fosmid libraries of soil actinomycetes Micromonospora echinospora ATCC 27932. A recombinant MeUGT1 was heterologously expressed as a His-tagged protein in E. coli, and its enzymatic reaction with semi-synthetic phenoxodiol isoflavene (as a glycosyl acceptor) and uridine diphosphate-glucose (as a glycosyl donor) created two different glycol-attached products, thus revealing that MeUGT1 functions as an isoflavonoid glycosyltransferase with regional flexibility. Chromatographic separation of product glycosides followed by the instrumental analyses, clearly confirmed these previously unprecedented glycosides as phenoxodiol-4'-α-O-glucoside and phenoxodiol-7-α-O-glucoside, respectively. The antioxidant activities of the above glycosides are almost the same as that of parental phenoxodiol, whereas their anti-proliferative activities are all superior to that of cisplatin (the most common platinum chemotherapy drug) against two human carcinoma cells, ovarian SKOV-3 and prostate DU-145. In addition, they are more water-soluble than their parental aglycone, as well as remaining intractable to the simulated in vitro digestion test, hence demonstrating the pharmacological potential for the enhanced bio-accessibility of phenoxodiol glycosides. This is the first report on the microbial enzymatic biosynthesis of phenoxodiol glucosides.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3325-3331
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• 2015

Pim kinase-3(Pim-3), a member of serine/threonine protein kinases, has been implicated in multiple human cancers and involved in Myc-induced tumorigenesis. However, little is known regarding its expression and biological function in human ovarian cancer. In this study we showed that the clinical significance and biological functions of Pim-3 in ovarian cancer and found that higher Pim-3 mRNA level are detected in ovarian cancer tissues than those in normal ovarian tissues. There are significant correlations between higher Pim-3 expression levels with the FIGO stage, histopathological subtypes, and distant metastasis in ovarian cancer patients. Lentivirus-mediated gene overexpression of Pim-3 significantly promotes the proliferation and migration of SKOV3 cell lines. Furthermore, MACC1 and Pim-3 expression were significantly correlated in human ovarian cancer cells, and overexpression of Pim-3 in ovary cancer cells increased MACC1 mRNA and protein expression. The data indicate that Pim-3 acts as a putative oncogene in ovary cancer and could be a viable diagnostic and therapeutic target for ovarian cancer.

• Journal of Ginseng Research
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• v.48 no.1
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• pp.40-51
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• 2024

Background: Ginsenoside 20(S)-Rg3 shows promising tumor-suppressive effects in ovarian cancer via inhibiting NF-kB signaling. This study aimed to explore the downstream tumor suppressive mechanisms of ginsenoside Rg3 via this signaling pathway. Materials and methods: A systematical screening was applied to examine the expression profile of 41 kinesin family member genes in ovarian cancer. The regulatory effect of ginsenoside Rg3 on KIF20A expression was studied. In addition, we explored interacting proteins of KIF20A and their molecular regulations in ovarian cancer. RNA-seq data from The Cancer Genome Atlas (TCGA) was used for bioinformatic analysis. Epithelial ovarian cancer cell lines SKOV3 and A2780 were used as in vitro and in vivo cell models. Commercial human ovarian cancer tissue arrays were used for immunohistochemistry staining. Results: KIF20A is a biomarker of poor prognosis among the kinesin genes. It promotes ovarian cancer cell growth in vitro and in vivo. Ginsenoside Rg3 can suppress the transcription of KIF20A. GST pull-down and co-immunoprecipitation (IP) assays confirmed that KIF20A physically interacts with BTRC (β-TrCP1), a substrate recognition subunit for SCF^β-TrCP E3 ubiquitin ligase. In vitro ubiquitination and cycloheximide (CHX) chase assays showed that via interacting with BTRC, KIF20A reduces BTRC-mediated CDC25A poly-ubiquitination and enhances its stability. Ginsenoside Rg3 treatment partly abrogates KIF20A overexpression-induced CDC25A upregulation. Conclusion: This study revealed a novel anti-tumor mechanism of ginsenoside Rg3. It can inhibit KIF20A transcription and promote CDC25A proteasomal degradation in epithelial ovarian cancer.

• Biomolecules & Therapeutics
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• v.5 no.2
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• pp.125-132
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• 1997

Cisplatin, a platinum-complex, is currently one of the most effective compounds used in the treat-ment of solid tumors. However, its use is limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and improving selective cytotoxicity. We synthesized new Pt (II) complex analogue containing 1,2-diaminocyclohexane (DACH) as carrier ligand and 1,2-bis (diphenylphosphino) ethane (DPPE) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of [Pt(cia-DACH)(DPPE)] . $2NO_3$ (PC) was synthes-ized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $_{13}$carbon nuclear magnetic resonance (NMR)] .PC demonstrated acceptable and significant antitumor activity against SKOV-3 and OVCAR-3 human ovarian carcinoma cell lines as compared with that of cisplatin. The cytotoxicity of PC in normal cells was found quite less than that of cisplatin using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), ($^3$H)thymidine uptake and glucose consumption tests in rabbit renal proximal tubular cells, human renal cortical cells and tissues. In conclusion, PC is considered to be more selective cytotoxicity toward human ovarian cancer cells than normal human/rabbit kidney cells.

• Journal of Life Science
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• v.21 no.6
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• pp.767-774
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• 2011

Cell migration plays a fundamental role in cancer cell invasion and metastasis as well as in many physiological responses. Here, we screened four different sources of garlic - water extract of normal and black garlic, as well as dried normal and black garlic - for the identification of anti-invasive and anti-metastatic activity on cancer cells. Inhibition of cancer cell migration was observed in the hexane extract of dried-garlic. Inhibitory activity was further purified to near homogeneity by thin layer chromatography and named $\b{i}$nhibitor of $\b{c}$ancer $\b{m}$etastasis from garlic #27 (ICMG-27). ICMG-27 completely blocked insulin-like growth factor-1 (IGF-1)-induced OVCAR-3 cell migration at 6 ${\mu}g/ml$. ICMG-27 completely blocked IGF-1-induced OVCAR-3 and NIH-3T3 cell migration whereas IGF-1-induced mouse embryonic fibroblast (MEF) cell migration was not affected byICMG-27. ICMG-27 inhibited all the tested IGF-1-induced cancer cell migration such as OVCAR-3, SKOV-3, and MDA-MB-231 cells. Finally, ICMG-27 could inhibit IGF-1-, lysophosphatidic acid (LPA)-, sphingosine-1-phosphate (S1P)-, leukotriene B4 (LTB4)-, and angiotensin II (AngII)-induced OVCAR-3 cell migration. These results indicate that ICMG-27 inhibits cancer cell migration by blocking essential steps in many agonists-induced cancer cell migrations. Unveiling an anti-invasive mechanism of ICMG-27 on cancer cells will provide a basis for cancer therapy.

• Journal of the Korean Society of Food Science and Nutrition
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• v.44 no.2
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• pp.200-207
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• 2015

Various natural products or their derivatives, mostly originating from plants, fungi, and bacteria, have been exploited as therapeutic drugs to treat various human diseases. In addition to previously explored organisms, research on natural compounds has now expanded into unexamined living organisms in order to identify novel bioactive substances. Here, we determined whether or not the larval form of the mealworm beetle Tenebrio molitor, a species of darkling beetle, contains cytotoxic substances that exclusively affect cancer cell viability. Ethanol extract and its solvent partitioned fractions, hexane and ethyl acetate fractions, showed anticancer effects against various human cancer cells derived from the prostate (PC3 and 22Rv1), cervix (HeLa), liver (PLC/PRF5, HepG2, Hep3B, and SK-HEP-1), colon (HCT116), lung (NCI-H460), breast (MDA-MB231), and ovary (SKOV3). Cell death induced by the fractions was a mix of apoptosis, necrosis, and autophagy. The hexane fraction was administered intraperitoneally to nude mice bearing a hepatocellular carcinoma SK-HEP-1 and showed inhibition of tumor growth in vivo. Therefore, we concluded that worm extracts contain cytotoxic substances, which can be enriched by proper fractionation protocols, and further separation and purification could lead to the identification of novel molecules to treat human cancers.

• Korean Journal of Clinical Laboratory Science
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• v.48 no.3
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• pp.169-175
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• 2016

Saccharin (o-benzoic sulfimide) is the first artificial and non-caloric sweetener that was first synthesized in 1879. In this study, we examined the biological activity of saccharin against various human cancer cell lines and human bone marrow-derived mesenchymal stem cells. A viability assay based on the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was performed to test for the cytotoxicity of saccharin about the four human cancer cell lines (H460, H157, A549 and SKOV3), one murine cancer cellline (Raw264.7), and MSCs. In order to find the differentially expressed gene in saccharin-treated MSCs against untreated MSCs, we performed annealing control primer (ACP)-based differential display reverse transcriptionp-olymerase chain reaction (DDRT-PCR). All tested cells were treated with saccharin at various concentrations (0.0, 4.8, 7.2, 9.6, 12.0, 14.4 mg/mL) for 48 hr. The number of metabolically active cancer cells decreased when treated with the saccharin at various concentrations for 48 hr as compared with the untreated cells. The decrease in cell survival was more evident with increasing concentrations of saccharin. Moreover, novel candidate genes, which were differentially expressed in MSCs in response to saccharin, were identified in 16 bands on 2% agarose gel. This revealed 16-7 up-regulated and 9 down-regulated-differentially expressed genes indicated by arrows. One of these candidate genes was a FK506-binding protein gene. The functional roles of FK506 binding proteins, with respect to the activities of stem cell proliferation, were not characterized. Further studies are required to get a better understanding of FK506-binding proteins in its roles in increasing stem cell proliferative activities from using saccharin.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.5883-5890
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• 2013

Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related to tumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D in the EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advanced FIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations of SEMA4D expression and M2 macrophage counts in primary tumors and M2 macrophage percentage in ascites (r=0.281 and 0.355, each P<0.05). In the Cox proportional hazard mode, SEMA4D expression was an independent indicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higher expression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants were found than that in a human primary cultured ovarian cell and its supernatant by reversed transcript PCR (RT-PCR), Western blotting and ELISA, respectively. Interestingly, peripheral blood monocytes (MOs) tended towards the M2-polarized macrophage phenotype ($CD163^{high}$) in vitro after human recombined soluble SEMA4D protein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis and could playan important role in promoting tumor dissemination and metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOC warrants further study.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.1
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• pp.31-38
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• 2023

Carboplatin, an advanced anticancer drug with excellent efficacy against ovarian cancer, was developed to alleviate the side effects that often occur with cisplatin and other platinum-based compounds. Our study reports the in vitro characteristics, viability, and activity of cells expressing the inducible nitric oxide synthase (iNOS) gene after carboplatin was conjugated with polysuccinimide (PSI) and administered in combination with other widely used anticancer drugs. PSI, which has promising properties as a drug delivery material, could provide a platform for prolonging carboplatin release, regulating its dosage, and improving its side effects. The iNOS gene has been shown to play an important role in both cancer cell survival and inhibition. Herein, we synthesized a PSI-carboplatin conjugate to create a modified anticancer agent and confirmed its successful conjugation. To ensure its solubility in water, we further modified the structure of the PSI-carboplatin conjugate with 2-aminoethanol groups. To validate its biological characteristics, the ovarian cancer cell line SKOV-3 and normal ovarian Chinese hamster ovary cells were treated with the PSI-carboplatin conjugate alone and in combination with paclitaxel and topotecan, both of which are used in conventional chemotherapy. Notably, PSI-carboplatin conjugation can be used to predict changes in the genes involved in cancer growth and inhibition. In conclusion, combination treatment with the newly synthesized polymer-carboplatin conjugate and paclitaxel displayed anticancer activity against ovarian cancer cells but was not toxic to normal ovarian cancer cells, resulting in the development of an effective candidate anticancer drug without severe side effects.