• Development and Reproduction
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• v.16 no.2
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• pp.129-135
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• 2012

Previously, we identified that the overexpression of IEX-1 induces apoptosis in ovarian cancer cells. Herein we report a new binding partner of IEX-1, CATHEPSIN B, as a lysosomal enzyme which contributes to the various apoptotic signaling in tumor cells. To investigate how IEX-1 regulates cellular survival and death event, we performed yeast two-hybrid screening of rat ovarian cDNA library using IEX-1 as the bait and found CATHEPSIN B. In the present study, CATHEPSIN B and IEX-1 proteins were overexpressed in 293T cells and their specific association was determined by immunoprecipitation and immunoblot analysis. In addition, the endogenous interaction between CATHEPSIN B and IEX-1 was confirmed in HeLa cells. The current finding of lysosomal CATHEPSIN B as the IEX-1-binding partner implies that IEX-1 may involve in lysosome-mediated apoptotic signaling pathways.

• Korean Journal of Pharmacognosy
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• v.45 no.1
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• pp.1-10
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• 2014

Ginsenoside Rg3 (G-Rg3) is one of protopanaxadiol ginsenosides characteristic of red ginseng, steamed and dried ginseng (Panax ginseng), which has recently attracted much attention for its antitumor properties in vitro and in vivo animal models. Experimental studies have demonstrated that it could promote cancer cell apoptosis, inhibit cancer cell growth, the apoptosis of cancer cells, adhesion, invasion and metastasis, and also prevent an angiogenetic formation in prostate, breast, ovarian, colorectal, gastric, liver and lung cancer etc. It has shown the antitumor activities by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (vascular endothelial growth factor), tumor suppressors (p53 and p21), cell death mediators (caspases, Bcl-2, Bax), inflammatory response molecules ($NF-{\kappa}B$ and COX-2), protein kinases (JNK, Akt, and AMP-activated protein kinase) and Wnt/${\beta}$-catenin signaling. In addition, the combination of Rg3 and chemotherapeutic agents have synergistically enhanced therapeutic efficacy and reduced antagonistically side effects. Furthermore, it can reverse the multidrug resistance of cancer cells, prolong the survival duration and improve life quality of cancer patients. Taken together, accumulating evidences could provide the potential of G-Rg3 in the treatment of cancers and the feasibility of further randomized placebo controlled clinical trials.

• Archives of Pharmacal Research
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• v.29 no.12
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• pp.1067-1073
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• 2006

Cisplatin, a platinum coordinated complex, is a widely used antineoplastic agent for the treatment of metastatic tumors of the testis, metastatic ovarian tumors, lung cancer, advanced bladder cancer and many other solid tumors. The cytotoxic action of the drug is often thought to be associated with its ability to bind DNA to form cisplatin-DNA adducts. The development of resistance to cisplatin during treatment is common and constitutes a major obstacle to the cure of sensitive tumors. Although to understand the clinically relevant mechanisms of resistance, many studies have been aimed at clarifying the biochemical/molecular alterations of cisplatin-resistance cells, these studies did not conclusively identify the basis of cellular resistance to cisplatin. In this review, cisplatin resistance was discussed in terms of the relevant transporters, such as copper transporters (CTRs), organic cation transporters (OCTs) and multi-drug resistance related transporters (MDRs). These transporters seem to be contributed to cisplatin resistance through the reduction of drug accumulation in the cell. Better understanding the mechanism of cisplatin resistance associated with transporters will provide the useful informations for overcoming the cisplatin resistance.

• YAKHAK HOEJI
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• v.52 no.1
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• pp.67-72
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• 2008

The use of doxorubicin, which is one of the most effective anticancer agents, is often limited by occurrence of acquired resistance in tumor cells. GSH has been shown to be involved in the development of this drug resistance. Transcription factor Nrf2 governs the expression of GSH synthesizing glutamylcysteine ligase (GCL), as well as multiple phase 2 detoxifying enzymes. Here we show that Nrf2 is one of factors determining doxorubicin sensitivity. Nrf2-deficient fibroblasts (murine embryonic fibroblasts, MEF) were more susceptible to doxorubicin mediated cell death than wild-type cells. Doxorubicin treatment elevated levels of Nrf2-regulated genes including NAD(P)H: quinone oxidoreductase (Nqo1) and GCL in wild-type fibroblasts, while no induction was observed in Nrf2-deficient cells. Doxorubicin resistance in human ovarian SK-OV cells was reversed by treatment with L-buthionine-sulfoxamine (BSO), which is depleting intracellular GSH. Finally, transfection of SK-OV cells with Nrf2 siRNA resulted in exacerbated cytotoxicity following doxorubicin treatment compared to scrambled RNA control. These results indicate that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to anticancer agents.

• Archives of Pharmacal Research
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• v.19 no.4
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• pp.286-291
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• 1996

Phenolic compounds are prevalent as toxins or environmental pollutants, but they are also widely used as drugs for various purpose including anticancer agent. A novel biphenolic compound, bis(2-hydroxy-3-tert-butyl-5-methylphenyl)methane (GERI-BPO02-A) was isolated from the fermentation broth of Aspergillus fumigatus F93 previously, and it has revealed cytotoxicity against human solid tumor cells. Its effective doses that cause 50% inhibition of cell growth in vitro against non-small cell lung cancer cell A549, ovarian cancer cell SK-OV-3, skin cancer cell SK-MEL-2 and central nerve system cancer cell XF498 were 8.24, 10.60, 8.83, $9.85\mug/ml$ respectively. GERI-BPO02-A has also revealed cytotoxicity against P-glycoproteinexpressed human colon cancer cell HCT15 and its multidrug-resistant subline HCT15/CL02, and its cytotoxicity was not affected by P-glycoprotein. We have also tested cytotoxicities of structurally related compounds of GERI-BPO02-A such as diphenylmethane, 1,1-bis(3,4dimethylphenyl)ethane, 2,2-diphenylpropane, 2-benzylpyridine, 3-benzylpyridine, $4,4^I-di-tert-butylphenyl$, bibenzyl, $2,2^I-dimethylbibenzyl$, cis-stilbene, trans-stilbene, 3-tert-butyl-4-hydroxy-5-methylphenyisulfide, sulfadiazine and sulfisomidine for studying of structure and activity relationship, and from these data we could suppose that hydroxyl group of GERI-BPO02A conducted important role in its cytotoxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3191-3196
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• 2013

Leaf extracts of Cassia alata L (akapulko), traditionally used for treatment of a variety of diseases, were evaluated for their potential antitumor properties in vitro. MTT assays were used to examine the cytotoxic effects of crude extracts on five human cancer cell lines, namely MCF-7, derived from a breast carcinoma, SK-BR-3, another breast carcinoma, T24 a bladder carcinoma, Col 2, a colorectal carcinoma, and A549, a nonsmall cell lung adenocarcinoma. Hexane extracts showed remarkable cytotoxicity against MCF-7, T24, and Col 2 in a dose-dependent manner. This observation was confirmed by morphological investigation using light microscopy. Further bioassay-directed fractionation of the cytotoxic extract led to the isolation of a TLC-pure isolate labeled as f6l. Isolate f6l was further evaluated using MTT assay and morphological and biochemical investigations, which likewise showed selectivity to MCF-7, T24, and Col 2 cells with $IC_{50}$ values of 16, 17, and 17 ${\mu}g/ml$, respectively. Isolate f6l, however, showed no cytotoxicity towards the non-cancer Chinese hamster ovarian cell line (CHO-AA8). Cytochemical investigation using DAPI staining and biochemical investigation using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-a method used to detect DNA fragmentation-together with caspase assay, demonstrated apoptotic cell death. Spectral characterization of isolate f6l revealed that it contained polyunsaturated fatty acid esters. Considering the cytotoxicity profile and its mode of action, f6l might represent a new promising compound with potential for development as an anticancer drug with low or no toxicity to non-cancer cells used in this study.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.194-201
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• 2017

Lysophosphatidylethanolamine (LPE), a lyso-type metabolite of phosphatidylethanolamine, has been reported to be an intercellular signaling molecule. LPE mobilizes intracellular $Ca^{2+}$ through G-protein-coupled receptor (GPCR) in some cells types. However, GPCRs for lysophosphatidic acid (LPA) were not implicated in the LPE-mediated activities in LPA GPCR overexpression systems or in SK-OV3 ovarian cancer cells. In the present study, in human SH-SY5Y neuroblastoma cells, experiments with $LPA_1$ antagonists showed LPE induced intracellular $Ca^{2+}$ increases in an $LPA_1$ GPCR-dependent manner. Furthermore, LPE increased intracellular $Ca^{2+}$ through pertussis-sensitive G proteins, edelfosine-sensitive-phospholipase C, 2-APB-sensitive $IP_3$ receptors, $Ca^{2+}$ release from intracellular $Ca^{2+}$ stores, and subsequent $Ca^{2+}$ influx across plasma membranes, and LPA acted on $LPA_1$ and $LPA_2$ receptors to induce $Ca^{2+}$ response in a 2-APB-sensitive and insensitive manner. These findings suggest novel involvements for LPE and LPA in calcium signaling in human SH-SY5Y neuroblastoma cells.

• Journal of Life Science
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• v.15 no.5 s.72
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• pp.802-808
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• 2005

Human Disabled-2 (Dab2) is a candidate tumor suppressor gone that regulates cell growth by c-Fos suppression in normal cells. In many cancer cells, Dab2 expression is lost or greatly diminished in $\∼85\%$ of the breast and ovarian cancers. In this study, we have examined the methylation status of CpG island on Dab2 gene promoter using bisulfite-assisted genomic sequencing and methylation specific PCR (MSP) method in human breast cancer cell line, MDA MB-231 cells. In normal human uterus endometrial cells, Dab2 was completely unmethylated. In contrast, Dab2 was methylated on CpG dinucleotides near the TATA_ box in MDA MB-231 cells. following MDA MB-231 cells by treatment with 5-azacytidine, Dab2 gene were demethylated and reexpressed. Result of this study suggested that silencing of Dab2 gene is correlated to CpG island methylation in human breast cancer cell line, MBA MD-231 cells.

• The Journal of Dong Guk Oriental Medicine
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• v.9
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• pp.139-154
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• 2000

This studies were examined in orther to investigate the object and the method of animal experimental papers on medicinal herbs of cancer therapeutic activities from the reported 23 literatures containing anti-cancer effects of medicinal herbs. The results were obtained as follows: 1. The oriental medicinal therapies on cancer were Pujeung(扶正法), Kuesa(祛邪法), Pujeungkuesa(扶正法邪法). 2. The experimental medicinal herbs of cancers therapy were 103 species, which was used for experimental cancer single or combine. Among then, Houttuyniae herba, Polyporus, Manitis squama, Evodiae fructus, Aucklandiae radix and Pharbitidis semen were effective for cancer treatment, while Houttuyniae herba inhibited tumor cells, but not normal cells. Also, Evodiae fructus, Aucklandiae radix and Pharbitidis semen showed strong cytoxicities on 20 different tumor cell lines, whereas Saururi herba seu rhizoma showed cytoxicity against HT-29 cell, melanoma, SK-MEL-5 cell, and Anemarrhenae rhizoma against ovarian tumor cell only, and Schizonepetae herba against HT-29 cell line only with a potent inhivitory activities. 3. P815 cell, Yac-1 cell, Sarcoma 180 cell, K 562 cell, and SNU-1 cells were frequently used as experimental cancer therapy.

• Journal of Veterinary Clinics
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• v.32 no.6
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• pp.530-535
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• 2015

An 11-year-old intact female miniature poodle presented with a four-month history of hemorrhagic effusion. The patient was alert on physical examination, although muffled heart sounds were noted upon auscultation of the right hemithorax. The radiographic finding was pleural effusion. Ultrasonography revealed cystic changes in both ovaries and several nodules in the liver. A refractory opacity in the right lung field, as visualized with computer tomography (CT), was diagnosed as right middle lung lobe torsion with a collapsed bronchus. Five days after diagnosis, a right fifth intercostal thoracotomy was performed to remove the right middle lung lobe; the right middle lung lobe was grossly shrunken as a result of chronic lung lobe torsion. Ovariohysterectomy was also performed. Histopathologic examination revealed papillary adenocarcinoma in both ovaries and suspected metastasized ovarian adenocarcinoma cells in the lung lobe. The patient recovered favorably and had been doing well up to two months post-surgery. However, after four months, the dog presented with respiratory difficulty. The radiographic findings were pleural effusion and collapse of the right cranial and left caudal lung lobes. Malignant cells of epithelial origin were observed in the pleural effusion. The tumor cells were suspected to be metastasized cells from the previously resected lung lobe. Although cancer treatment was recommended, the suggestion was suspended and the dog was discharged from hospital. This was a case of lung lobe torsion that had occurred because of hemorrhagic effusion due to tumor. Although ovariohysterectomy and lobectomy were performed, there was a relapse of hemorrhagic effusion because of metastasized tumor from the previously resected lung lobe.