• Archives of Pharmacal Research
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• v.27 no.2
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• pp.127-135
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• 2004

Multiple drug administration is common in elderly, HIV, and cancer patients. Such treatments may result in drug-drug interactions due to interference at the metabolic enzyme level, and due to modulation of transporter protein functions. Both kinds of interference may result in altered drug distribution and toxicity in the human body. In this review, we have dealt with drug-drug interactions related to the most studied human transporter, P-glycoprotein. This transporter is constitutively expressed in several sites in the human body. Its function can be studied in vitro with different cell lines expressing P-glycoprotein in experiments using methods and equipment such as flow cytometry, cell proliferation, cell-free ATP as activity determination and Transwell culture equipment. In vivo experiments can be carried out by mdr1a(-/-) animals and by noninvasive methods such as NMR spectrometry. Some examples are also given for determination of possible drug-drug interactions using the above-mentioned cell lines and methods. Such preclinical studies may influence decisions concerning the fate of new drug candidates and their possible dosages. Some examples of toxicities obtained in clinics and summarized in this review indicate careful consideration in cases of polypharmacy and the requirement of preclinical studies in drug development activities.

• Toxicological Research
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• v.32 no.3
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• pp.225-230
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• 2016

Zingiber officinale Roscoe has been widely used as a folk medicine to treat various diseases, including cancer. This study aims to re-examine the therapeutic potential of co-administration of natural products and cancer chemotherapeutics. Candidate material for this project, ${\alpha}$-zingiberene, was extracted from Zingiber officinale Roscoe, and ${\alpha}$-zingiberene makes up $35.02{\pm}0.30%$ of its total essential oil. ${\alpha}$-Zingiberene showed low $IC_{50}$ values, $60.6{\pm}3.6$, $46.2{\pm}0.6$, $172.0{\pm}6.6$, $80.3{\pm}6.6$ (${\mu}g/mL$) in HeLa, SiHa, MCF-7 and HL-60 cells each. These values are a little bit higher than $IC_{50}$ values of general essential oil in those cells. The treatment of ${\alpha}$-zingiberene produced nucleosomal DNA fragmentation in SiHa cells, and the percentage of sub-diploid cells increased in a concentration-dependent manner in SiHa cells, hallmark features of apoptosis. Mitochondrial cytochrome c activation and an in vitro caspase-3 activity assay demonstrated that the activation of caspases accompanies the apoptotic effect of ${\alpha}$-zingiberene, which mediates cell death. These results suggest that the apoptotic effect of ${\alpha}$-zingiberene on SiHa cells may converge caspase-3 activation through the release of mitochondrial cytochrome c into cytoplasm. It is considered that anti-proliferative effect of ${\alpha}$-zingiberene is a result of apoptotic effects, and ${\alpha}$-zingiberene is worth furthermore study to develop it as cancer chemotherapeutics.

• Journal of Nutrition and Health
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• v.49 no.2
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• pp.72-79
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• 2016

Purpose: The initiation of mandatory folic acid fortification using pteroylmonoglutamic acid (PteGlu) has reduced the rate of congenital malformations. However, it also appears to be responsible for several adverse effects, including increased cancer incidence. This may be related to physicho-chemical characteristics of PteGlu. This study examines the potential effect of high concentrations of PteGlu on a population subjected to mandatory folic acid fortification using an in vitro model. Methods: Caco-2 (colorectal cancer) and MCF7 (breast cancer) cell lines were cultured at 6 different PteGlu concentrations (0, 0.1, 1, 50, 250, and $500{\mu}g/ml$) for 6 days. Cell growth was determined using thiazolyl blue tetrazolium bromide assay. The genotype of dihydrofolate reductase 19bp deletion/insertion (DHFR 19-del) was also scored in cell lines using a restriction fragment length polymorphism technique to examine whether genetic variations may factor in cell proliferation. Results: PteGlu exhibited differential growth promoting properties between cell lines. Caco-2 cells did not show a significant growth difference at low concentrations compared to control, however, at higher concentrations, the growth showed a contrasting trend in the early experimental period, while MCF7 showed enhanced cell growth at all concentrations. The DHFR 19-del genotype differed in the two cell lines. Conclusions: Altered response to PteGlu by Caco-2 and MCF7 may reflect a tissue specific disease aetiology or genotype specific differential enzyme activity, for example by DHFR, to critical levels of PteGlu. As folic acid fortification is a blanket intervention, and DHFR and other enzyme activities vary between individuals, PteGlu intake may have an as yet undefined effect on health. These findings may be relevant when considering mandatory folic acid fortification for disease prevention.

• Molecular & Cellular Toxicology
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• v.5 no.1
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• pp.14-22
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• 2009

In vitro cytotoxicity of 23 alkyl phenols (APs) on human cervical cancer cell lines (HeLa) was determined using the lactate dehydrogenase (LDH) cytotoxicity assay. Two different sets of descriptors were used to construct the calibration model based on Genetic Algorithm-Multiple Linear Regression (GA-MLR) based on the experimental data. A statistically robust Structure-Activity Relationships (QSAR) model was achieved ($R^2$=95.05%, $Q^2_{LOO}$=91.23%, F=72.02 and SE= 0.046) using three Dragon descriptors based on Me (0D-Constitutional descriptor), BELp8 (2D-Burden eigenvalue descriptor) and HATS8p (3D-GETAWAY descriptor). However, external validation could not fully prove its validity of the selected QSAR in characterization of the cytotoxicity of APs towards HeLa cells. Nevertheless, the cytotoxicity profiles showed a finding that 4-n-octylphenol (4-NOP), 4-tert-octyl-phenol (4-TOP), 4-n-nonylphenol (4-NNP) had a more potent cytotoxic effect than other APs tested, inferring that increased length and molecular bulkiness of the substituent had important influence on the LDH cytotoxicity.

• The Journal of Korean Obstetrics and Gynecology
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• v.30 no.4
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• pp.100-113
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• 2017

Objectives: Bee Venom has been used to relieve pain and to treat various diseases, such as arthritis, cancer and skin disease. Although Bee Venom has used extensively in gynecological fields, we don't have enough evidence with it. This study is to investigate efficacy and safety of Bee Venom on women by investigating papers, then we are going to suggest the direction of research. Methods: We searched for papers which had Bee Venom from Pubmed, OASIS, Journal of Korean Obstetrics & Gynecology, Journal of Korean Medicine up to August 2017, then classified according to the type of studies. Results: Eleven papers have been finally selected. One paper was a case report about atypical squamous cells of undetermined significance. Four papers were in vivo studies about 1 endometriosis and 1 polycystic ovarian syndrome and 2 human cervical cancer. Among eight papers that were in vitro studies, four papers were reported about ovarian cancer and four papers reported about human cervical cancer. Among ten papers that were experimental studies, two papers have been studied both in vivo and in vitro. Most of studies have shown that Bee Venom is useful for gynecological disorders. Conclusions: It has been identified that Bee Venom could be a good treatment for female disorder. However, more clinical reports and well-designed studies will be needed.

• Korean Journal of Pharmacognosy
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• v.42 no.4
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• pp.379-385
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• 2011

Indoleamine 2,3-dioxygenase (IDO) is predicted to be therapeutic target for treatment of cancer and immune disease. Thus, we examined methanol extracts prepared from 156 Korean local plants for their inhibitory effects on IDO in vitro. Among them sixteen extracts showed more than 50% inhibition of IDO activity at the concentration of 30 ${\mu}g/ml$. Especially, the extracts of Platycarya strobilacea, Quercus acutissima, Acer ginnala and Alnus japonica were most potent because their $IC_{50}$ value were 6.5, 8.1, 3.9 and 4.2 ${\mu}g/ml$, respectively.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.1
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• pp.57-62
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• 2012

Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), a ubiquitin-like protein, mainly functions through covalent ligation to cullin proteins. Conjugation of NEDD8 with cullins can promote ubiquitination, which plays a critical role in the degradation of many proteins. UBA3 is the subunit of NEDD8-activating enzyme which is one of the keys for NEDD8 linkage to cullin proteins. Previous research showed NEDD8 conjugation to be up-regulated in highly proliferative cell lines. In the present study, up-regulated NEDD8 conjugation was observed in melanoma cell lines by Western blot analysis. After down-regulation with a RNAi to UBA3, proliferation of M14 was suppressed in vitro and in vivo. In conclusion, up-regulated NEDD8 conjugation may be involved in the development of melanoma. Interference in this pathway might offera promising method for melanoma therapy.

• BMB Reports
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• v.39 no.5
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• pp.560-570
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• 2006

Mistletoe (Viscum album) lectins, which are classified as a type II ribosome-inactivating protein (RIP) due to their unique biological function and the potential medical and therapeutic application in cancer cells, receive a rising attention. The heterodimeric glycoproteins contain the A-chain with catalytic activity and the B-chain with sugar binding properties. In recent years, studies involving the lectins from the white berry European mistletoe (Viscum album) and the yellow berry Korean mistletoe (Viscum album coloratum) have been described. However, the detailed mechanism in exerting unique cytotoxic effect on cancer cells still remains unclear. Here, we aim to understand and define the molecular basis and biological effects of the type II RIPs, through the studies of the recombinant Korean mistletoe lectin. To this end, we expressed, purified the recombinant Korean mistletoe lectin (rKML), and investigated its molecular characteristics in vitro, its cytotoxicity and ability to induce apoptotic cell death in cancer cells. To gain structural basis for its catalytic activity and sugar binding properties, we performed homology modeling studies based on the high degree of sequence identity and conserved secondary structure prediction between Korean and European, Himalayan mistletoe lectins, and Ricin.

• Journal of Korean Society of Forest Science
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• v.87 no.2
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• pp.260-269
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• 1998

This study was conducted to screen the biological activity of urushiol in the sap of lac tree(Rhus verniciflua STOKES) which has been used in traditional folk remedies. Cytotoxic activity of urushiol was screened with L1210(mouse luekemia cell), PC-9(human lung adenocarcinoma cell), A427(human lung adenocarcinoma cell) and KATO III (human stomach adenocarcinoma cell) The stepwise hexane : acetone eluent fractions of the urushiol were obtained by the silica gel adsorption column chromatography and added to the culture media containing L1210, PC-9. A427, and KATO III, respectively. A hexane : acetone(90 : 10, v/v) eluent fraction of them showed the lowest 50% inhibition concentration($IC_{50}$) of $0.018{\mu}g/m{\ell}$ for the cell line of A427. Much lower level of $IC_{50}$ of the hexane : acetone(90 : 10, v/v) eluent fraction of the urushiol showed the equal inhibition effect with tetraplatin(i.e., anti-cancer drug of platinum complexes) on the cancer cell lines as follows ; 3.4 times lower for L1210, 3.9 times lower for PC-9, and 105.5 times lower for A427. However, $IC_{50}$ of the hexane : acetone(90 : 10 v/v) eluent fraction for KATO III was exceptionally 3.9 times higher than that of tetraplatin.

• Food Science and Biotechnology
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• v.14 no.4
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• pp.479-486
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• 2005

Arabinoxylan, a complex polysaccharide in cereal cell walls, has recently received research attention as a biological response modifier. The immunomodulating effect of arabinoxylans from rice bran (AXrb) was studied using a combined process of extrusion and commercial hemicellulase treatment in order to elucidate the augmentation mechanism of cell-mediated immunity in vitro. The cytotoxicity of mouse spleen lymphocytes against YAC-1 tumor cells was significantly enhanced by treatment with AXrb at $10-100\;{\mu}g/mL$. In an attempt to investigate the mechanism by which AXrb enhance NK cytotoxicity, we examined the effect of AXrb on cytokine production by spleen lymphocytes. Culture supernatants of the cells incubated with AXrb were collected and analyzed for IL-2 and IFN-${\gamma}$ synthesis by ELISA. IL-2 and IFN-${\gamma}$ production were increased significantly. These results suggest that AXrb may induce Th1 immune responses. Macrophages play an important role in host defenses against tumors by killing them and producing secretory products, which protect against bacterial, viral infection and malignant cell growth. AXrb were examined for their ability to induce secretory and cellular responses in murine peritoneal macrophages. When macrophages were treated with various concentrations ($10-100\;{\mu}g/mL$) of AXrb, AXrb induced tumoricidal activity, as well as increasing phagocytosis and the production of NO, $H_2O_2$, TNF-${\alpha}$, IL-$1{\beta}$, and IL-6. These results indicate that reactive oxygen species, reactive nitrogen species, and inflammatory cytokines are likely to be the major mediators of tumoricidal activity in AXrb-treated macrophages. Therefore, AXrb may be useful in cancer immunotherapy and it is anticipated that AXrb obtained using extrusion and subsequent enzyme treatment can be used as an ingredient in nutraceuticals and cereal-based functional food.