• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.200-209
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• 2023

Patients with non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) amplification or sensitive mutations initially respond to the tyrosine kinase inhibitor gefitinib, however, the treatment becomes less effective over time by resistance mechanism including mesenchymal-epithelial transition (MET) overexpression. A therapeutic strategy targeting MET and EGFR may be a means to overcoming resistance to gefitinib. In the present study, we found that picropodophyllotoxin (PPT), derived from the roots of Podophyllum hexandrum, inhibited both EGFR and MET in NSCLC cells. The antitumor efficacy of PPT in gefitinib-resistant NSCLC cells (HCC827GR), was confirmed by suppression of cell proliferation and anchorage-independent colony growth. In the targeting of EGFR and MET, PPT bound with EGFR and MET, ex vivo, and blocked both kinases activity. The binding sites between PPT and EGFR or MET in the computational docking model were predicted at Gly772/Met769 and Arg1086/Tyr1230 of each ATP-binding pocket, respectively. PPT treatment of HCC827GR cells increased the number of annexin V-positive and subG1 cells. PPT also caused G2/M cell-cycle arrest together with related protein regulation. The inhibition of EGFR and MET by PPT treatment led to decreases in the phosphorylation of the downstream-proteins, AKT and ERK. In addition, PPT induced reactive oxygen species (ROS) production and GRP78, CHOP, DR5, and DR4 expression, mitochondrial dysfunction, and regulated involving signal-proteins. Taken together, PPT alleviated gefitinib-resistant NSCLC cell growth and induced apoptosis by reducing EGFR and MET activity. Therefore, our results suggest that PPT can be a promising therapeutic agent for gefitinib-resistant NSCLC.

• Journal of Korean Neurosurgical Society
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• v.46 no.6
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• pp.552-557
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• 2009

Objective : Interferon-$\beta$, (IFN-$\beta$) has been used in the treatment of cancers. Inhibition of the enzyme cyclooxygenase (COX) with celecoxib had a significantly suppressive effect on tumor growth, angiogenesis, and metastasis in a variety of tumors. The aim of this study was to elucidate the antiglioma effect of combined treatment with IFN-$\beta$ and celecoxib in U87 glioma model. Methods : The in vitro effects of IFN-$\beta$ (50-1,000 IU/mL) and celecoxib ($50-250\;{\mu}M$) alone or combination of both on the proliferation and apoptosis of U87 cells were tested using MTT assay, FACS analysis and DNA condensation. To determine the in vivo effect, nude mice bearing intracerebral U87 xenograft inoculation were treated with IFN-$\beta$ intraperitoneally ($2{\times}10^5\;IU/day$ for 15 days), celecoxib orally (5, 10 mg/kg) or their combination. Results : IFN-$\beta$ or celecoxib showed an inhibitory effect on the proliferation of U87 cells. When U87 cells were treated with IFN-$\beta$ and celecoxib combination, it seemed that IFN-$\beta$ interrupted the antiproliferative and apoptotic activity of celecoxib. No additive effect was observed on the survival of the tumor bearing mice by the combination of IFN-$\beta$ and celecoxib. Conclusion : These results suggest that IFN-$\beta$ seems to inhibit the antiglioma effect of celecoxib, therefore combination of IFN-$\beta$ and celecoxib may be undesirable in the treatment of glioma.

• Journal of Veterinary Clinics
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• v.38 no.1
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• pp.27-31
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• 2021

Shea butter (Vitellaria paradoxa) is a fat extracted from shea tree nuts and contains relatively high levels of non-glycerides. Triterpenes, the main non-glyceride component, exhibit a variety of biological activities such as antitumor, antibacterial, and anti-inflammatory. Shea butter extract (SBE) has been used to treat various skin problems such as burns, eczema, and rash in human medicine, but little is known about the activity of SBE on canine skin. This study evaluated the cytotoxicity and anti-inflammatory effect of SBE in canine keratinocytes. Cytotoxicity of lipopolysaccharide (LPS, 5-50 ng/mL) and SBE (50-200 ㎍/mL) was evaluated using the CCK-8 assay. Non-cytotoxic concentrations of LPS and SBE were administered to canine cell cultures to evaluate anti-inflammatory effects. To evaluate the anti-inflammatory activity of SBE, the levels of IL-1β, IL-8, IL-12, and TNF-α were measured using ELISA kits. The concentration of each cytokine was quantified in control, LPS-treated, LPS + SBE-treated groups. Increased levels of IL-1β, IL-8, and IL-12 were found in LPS-treated groups relative to control groups. LPS + SBE-treated groups showed a lower level of IL-1β, IL-8, and IL-12 than LPS-treated groups. These results suggest that SBE may have application as a topical agent for canine inflammatory skin diseases. However, further in vivo study is needed to evaluate the safety and efficacy of SBE in dogs.

• Journal of Food Hygiene and Safety
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• v.16 no.2
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• pp.117-124
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• 2001

The main constituent of green tea, catechins have been reported to have numberous biological anti-vites including antimutagenic, antibacterial, hypocholesterolemic, antioxidant and antitumor properties. In the present study, we examined the protective effect of catechin on UVB-induced skin damage. Catechin (3 mg/mouse) was topically treated to dorsal area of SHK-1 hairless mouse daily for 2 weeks. UVB (100 mJ/$\textrm{cm}^2$) was also treated soon after application of catechin alone or with catechin for 2 weeks. Catechin reduced UVB-induced infiltration of inflammatory cells, fibrosis of cells and collagen-fiber formation. In addition, catechin also prevented UVB-induced DNA fragmentation and apoptosis cell number, but not changed p53 level. Furthermore catechin inhibited UVB-induced cell proliferation. There results showed that catechin have preventive effect aganinst UVB-induced skin damages. and these effects could contribute to the antitumor promoters activity.

• Korean Journal of Pharmacognosy
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• v.18 no.2
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• pp.127-135
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• 1987

In vitro sensitivity testing was performed for 21 kinds putative anticancer drugs selected from references and information. Cellular damage of P815 mastocytoma cells following exposure to water extracts of drugs was evaluated by colony formation assay. Highly effective drugs with more than 50% inhibition of colony formation were seven (Houttuyniae Herba, Sanguisorbae Radix, Nepetae Herba, Manitis Squama, Lonicerae Flos, Amomi Semen, Polyporus), though not more effective than BCNU. According to the results of $^3H-thymidine$ incorporation assay for determination of selective cytotoxicity, 3 of these drugs (Houttuyniae Herba, Polyporus, Manitis Squama) were found to be low cytotoxic to normal mouse lymphoid cells. These findings suggest that the above 3 drugs may be used for effective anticancer drugs in vivo.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.3035-3042
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• 2015

Background: Isorhamnetin (Iso), a novel and essential monomer derived from total flavones of Hippophae rhamnoides that has long been used as a traditional Chinese medicine for angina pectoris and acute myocardial infarction, has also shown a spectrum of antitumor activity. However, little is known about the mechanisms of action Iso on cancer cells. Objectives: To investigate the effects of Iso on A549 lung cancer cells and underlying mechanisms. Materials and Methods: A549 cells were treated with $10{\sim}320{\mu}g/ml$ Iso. Their morphological and cellular characteristics were assessed by light and electronic microscopy. Growth inhibition was analyzed by MTT, clonogenic and growth curve assays. Apoptotic characteristics of cells were determined by flow cytometry (FCM), DNA fragmentation, single cell gel electrophoresis (comet) assay, immunocytochemistry and terminal deoxynucleotidyl transferase nick end labeling (TUNEL). Tumor models were setup by transplanting Lewis lung carcinoma cells into C57BL/6 mice, and the weights and sizes of tumors were measured. Results: Iso markedly inhibited the growth of A549 cells with induction of apoptotic changes. Iso at $20{\mu}g/ml$, could induce A549 cell apoptosis, up-regulate the expression of apoptosis genes Bax, Caspase-3 and P53, and down-regulate the expression of Bcl-2, cyclinD1 and PCNA protein. The tumors in tumor-bearing mice treated with Iso were significantly smaller than in the control group. The results of apoptosis-related genes, PCNA, cyclinD1 and other protein expression levels of transplanted Lewis cells were the same as those of A549 cells in vitro. Conclusions: Iso, a natural single compound isolated from total flavones, has antiproliferative activity against lung cancer in vitro and in vivo. Its mechanisms of action may involve apoptosis of cells induced by down-regulation of oncogenes and up-regulation of apoptotic genes.

• Applied Biological Chemistry
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• v.40 no.4
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• pp.307-312
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• 1997

As a preliminary experiment to investigate the antitumor activity of colored rice in vivo, inhibitory effect of solvent extracts from colored rice brans on DNA strand scission and tumor promotion was examined in vitro. Two colored rice cultivars, Sanghaehyanghyulla and Suwon 415 were compared with Chuchung as a control. The antimutagenic activity of each rice cultivars increased in order of Chuchung

• Journal of Ginseng Research
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• v.17 no.1
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• pp.52-60
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• 1993

Panax ginseng has been extensively used in the traditional oriental medicine as a restorative, tonic and Prophylactic agent. Recently, several reports regarding to anticancer effects of Panax ginseng has accumulated. These studies emphasized the fact that the anticancer activities might be due to a glycoside group called ginsenoside or pan.u saponin which has a water soluble characteristic. However, the authors and collaborates demonstrated that a highly lipid soluble component in extract of Panax ginseng roots contains a considerable cytotoxic activities against marine leukemic cells (L1210, P388) and human censer cells (HRT-18, HT-29, HCT48). This study was devised to observe the cytotoxic activities of Petroleum-ether extract of Panax giuseng roots (crude GBD and its Partially Purified fraction from silicic acid column chromatography (7 : 3 GX) against sarcoma-180 (5-180) and Walker carcinosar- coma 256 (Walker 256) in vivo, and murine leukemic Lymphocytes (L1210) and human rectal cancer cells (HRT-18) and human colon cancer cells (HT-29 and HCT48) in vitro. Each cell-line was cultured in medium containing serial concentration of the crude GX or 7 : 3 GX in vitro. A highly lipid soluble compound in the extract of Panax ginseng root was cytocidal to murine leukemic cells and human colon and rectal cancer cells in vitro. In the meantime, ginseng saponin derivatives did not have cytotoxic effects at its corresponding concentration. The growth rates of the cancer cells in medium containing ginseng extracts were inhibited gradually to a significant degree roughly in proportion to the increase of the extract concentration. The cytotoxic activity of 7 : 3 GX was about 3 times more potent than that of crude GX, one unit of cytotoxic activity against L1210 cells being equivalent to 2.54 Ug and 058 Ug for the crude GX and 7 : 3 GX, respectively. The Ri value of the active compound on silica- gel thin layer chromatography with petroleum-ether/ethyl ether/acetic acid mixture (90 : 10 : 1, v/v/v) as a developing so lvent was 053. While, the Panaxydol and Panaxynol as active compounds were purified from Petroleum-ether extract of Panax ginseng root by Drs. Ahn and Kim, and author found out that the one unit of cytotoxic activity of the Panaxydol and Panaxynol against L1210 cells being equivalent to 056 Ug and 0.3918 respectively. The survival times of mice inoculated with S-180 cells were extended about 1.5 to 2 times by the 7 : 3 GX treatment compared with their control group. The significantly decreased hemoglobin values of rats after inoculation with Walker 256 were recovered to normal range by oral administration of the crude Gt The synthetic levels of protein, DNA and RNA in human colon and rectal cancer cells were significantly diminished by treatment with the crude GX, which can explain a part of the origin of its anticancer activity.

• Environmental Analysis Health and Toxicology
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• v.27
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• pp.10.1-10.7
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• 2012

Objectives: In recent years, a number of structurally diverse Histone deacetylase (HDAC) inhibitors have been identified and these HDAC inhibitors induce growth arrest, differentiation and/or apoptosis of cancer cells in vitro and in vivo. This study aimed at investigating the antitumor activity of newly synthesized HDAC inhibitor, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide (IN-2001) using human breast cancer cells. Methods: We have synthesized a new HDAC inhibitor, IN-2001, and cell proliferation inhibition assay with this chemical in estrogen receptor-positive human breast cancer MCF-7 cells. Cell cycle analysis on MCF-7 cells treated with IN-2001 was carried out by flow cytometry and gene expression was measured by RT-PCR. Results: In MCF-7 cells IN-2001 showed remarkable anti-proliferative effects in a dose- and time-dependent manner. In MCF-7 cells, IN-2001 showed a more potent growth inhibitory effect than that of suberoylanilide hydroxamic acid. These growth inhibitory effects were related to the cell cycle arrest and induction of apoptosis. IN-2001 showed accumulation of cells at $G_2$/M phase and of the sub-$G_1$ population in a time-dependent manner, representing apoptotic cells. IN-2001-mediated cell cycle arrest was associated with HDAC inhibitor-mediated induction of CDK inhibitor expression. In MCF-7 cells, IN-2001 significantly increased $p21^{WAF1}$ expression. Conclusions: In summary, cyclin-dependent kinase (CDK) induced growth inhibition, possibly through modulation of cell cycle and apoptosis regulatory proteins, such as CDK inhibitors, and cyclins. Taken together, these results provide an insight into the utility of HDAC inhibitors as a novel chemotherapeutic regime for hormone-sensitive and insensitive breast cancer.

• The Korea Journal of Herbology
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• v.30 no.1
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• pp.33-42
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• 2015

Objectives : The aim of this study was to evaluate the antitumor effects of Cheongpyesagan-tang(CST) and YKK012 on colon cancer. Methods : MTT assay was used to evaluate the cytotoxicity of Single herbs and combinations of CST and YKK012 on murine colon cancer cells, Colon 38. To explain effects of apoptosis in colon cancer, we performed the western blot. Effects of CST and YKK012 on antitumor activity of CPT-11 using the murine colon38 allograft tumor in BDF1 mice. Results : Single herbs and combinations of CST and YKK012 was tested in vitro, Rhei Radix (RH) and Scutellariae Radix (SC) and YKK012 showed dose-response cytotoxicity on Colon 38. This might be due to the apoptosis, as we see Bax and Caspase-3, which are apoptotic factors, was expressed in RH and SC treated cells. YKK012 also showed increased expression of Caspase-3. In mouse colorectal cancer xenograft model of colon38 cells, herbal combinations showed tendencies of tumor regression, but was not significant. Furthermore, because toxicity was observed in CST group, we reduced the dose of CST for the next experiment. The anti-tumor effects of herbal combinations were insufficient to be used as single anti-tumor agent. With simultaneous usage of CPT-11, contrary to that CST showed no synergistic effects, YKK012 which was composed by the combination of four $ER{\beta}$ selective herbs, significantly reduced the size of tumor and Bax expression was increased. Conclusions : We suggest YKK012 can be a effective cancer adjuvant therapy with CPT-11 on colon cancer.