• Journal of Physiology & Pathology in Korean Medicine
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• v.17 no.5
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• pp.1243-1250
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• 2003

This study was designed to elucidate the synergistic cytotoxic mechanisms of the co-treatment of adriamycin and Paljinhangahm-dan in human hepatoma malignant cancer cell line, HepG2. The combination of adriamycin and the ethanol extract of Paljinhangahm-dan synergistically augmented the cytotoxicity of Adriamycin and Paljinhangahm-dan in HepG2 cells. The cytotoxicity of two drugs was revealed as apoptosis characterized by DNA fragmentaton in agarose gel electrophoresis. The apoptotic cytotoxicity of adriamycin and Paljinhangahm-dan was accompanied by the cleavage of procaspase -3 protease and PARP. Of note, anti apoptotic Bcl2 protein was obviously decreased, but Fas was dramatically increased in HepG2 cells co-treated with Adriamycin and Paljinhangahm -dan. In addition, through 2-D gel electorphoresis, we observed that the expression levels of a lot of proteins were obviously changed by the status of drug treatments. This results suggest that the synergistic cytotoxicity of the co-treatment of adriamycin and Paljinhangahm-dan might be caused by the changes of the expression levels of a lot of proteins which play pivotal roles in cell survival or death.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.195-200
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• 2011

Neuronal cell death is a common characteristic feature of a variety of neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. However, there have been no effective drugs to successfully prevent neuronal death in those diseases. In the present study, docosyl cafferate (DC), a derivative of caffeic acid, was isolated from Rhus verniciflua and its protective effects on tBHP-induced neuronal cell death were examined in SH-SY5Y human neuroblastoma cells. Pretreatment of DC significantly attenuated tBHP-induced neuronal cell death in a concentration-dependent manner. DC also significantly suppressed tBHP-induced caspase-3 activation. In addition, DC restored tBHP-induced depletion of intracellular Bcl-2, an anti-apoptotic member of the Bcl-2 family. Furthermore, DC significantly suppressed tBHP-induced degradation of IKB, which retains $NF-{\kappa}B$ in the cytoplasm, resulting in the suppression of nuclear translocation of $NF-{\kappa}B$ and its subsequent activation. Taken together, the results clearly demonstrate that DC exerts its neuroprotective activity against tBHP-induced oxidative stress through the suppression of nuclear translocation of $NF-{\kappa}B$.

• Biomolecules & Therapeutics
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• v.18 no.1
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• pp.48-55
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• 2010

Neural progenitor cells (NPCs) differentiate into astrocytes, neurons and oligodendrocytes, which is controlled by various factors in brain. Recent evidences suggest that small molecules modulating the proliferation and differentiation of NPCs may have therapeutic value as well as the potential use as chemical probes. Phylligenin is a lignan with anti-inflammatory activity that is isolated from the fruits of Forsythia koreana. We investigated effects of phylligenin on proliferation and differentiation of NPCs. Treatment of phylligenin decreased the number of proliferating NPCs in culture without effects on the differentiation and survival of neural cells such as neurons and astrocytes. To examine the mechanism of the decreased NPCs number, we performed cell cycle analysis. Proliferation of NPCs was decreased via G1-S transition block by phylligenin treatment, and it was mediated by the increase of p21 level. However, phylligenin did not induce apoptosis of NPCs as determined by TUNEL assay and PARP cleavage. We also found that viability of glioma cell lines such as C6 and U87MG glioma cells, but not that of primary neuron and astrocyte, was inhibited by phylligenin. These results suggest that phylligenin selectively inhibits proliferation of rapidly growing cells such as neural stem cells and glioma cells. Given that the possible role of brain tumor stem cells in the pathology of brain cancers, the inhibitory effects of phylligenin might be useful in the development of new therapeutic agents against brain cancers.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.117-123
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• 2016

Taxol (paclitaxel) is a powerful anti-cancer drug widely used against several types of malignant tumors. Because Taxol may exert several side effects, a variety of formulations have been developed. One of these features liposomes, regarded as one of the most promising drug carriers, biocompatible and best able to reduce drug toxicity without changing efficacy against tumor cells. Eruca sativa seed extract (SE) is considered a promising natural product from cruciferous vegetables against breast cancer, increasing chemotherapeutic and eliminating harmful side effects. The effects of Taxol-encapsulated liposomes (T) alone and in combination between Eruca sativa seed extract on nuclear factor kappa B (NF-${\kappa}B$), cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) gene expression levels were investigated in rat mammary gland carcinogenesis induced by 7,12 dimethylbenz(${\alpha}$) anthracene (DMBA) using qRT-PCR. The results showed that DMBA increased NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and lipid peroxidation (LP), while decreasing glutathione-S-transferase (GST) and superoxide dismutase (SOD) activities and total antioxidant concentration (TAC) compared to the control group. T and T-SE treatment reduced NF-${\kappa}B$, COX-2 and Bcl-2 gene expression levels and LP. Hence, T and T-SE treatment appeared to reduce inflammation and cell proliferation, while increasing apoptosis, GST and SOD activities and TAC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.10
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• pp.6089-6094
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• 2013

Berberine, a common isoquinoline alkaloid, has been shown to possess anti-cancer activities. However, the underlying molecular mechanisms are still not completely understood. In the current study, we investigated the effects of berberine on cell growth, colony formation, cell cycle distribution, and whether it improved the anticancer efficiency of cisplatin and doxorubicin in human breast cancer estrogen receptor positive (ER+) MCF-7 cells and estrogen receptor negative (ER-) MDA-MB-231 cells. Notably, berberine treatment significantly inhibited cell growth and colony formation in the two cell lines, berberine in combination with cisplatin exerting synergistic growth inhibitory effects. Accompanied by decreased growth, berberine induced G1 phase arrest in MCF-7 but not MDA-MB-231 cells. To provide a more detailed understanding of the mechanisms of action of berberine, we performed genome-wide expression profiling of berberine-treated cells using cDNA microarrays. This revealed that there were 3,397 and 2,706 genes regulated by berberine in MCF-7 and MDA-MB-231 cells, respectively. Fene oncology (GO) analysis identified that many of the target genes were involved in regulation of the cell cycle, cell migration, apoptosis, and drug responses. To confirm the microarray data, qPCR analysis was conducted for 10 selected genes based on previously reported associations with breast cancer and GO analysis. In conclusion, berberine exhibits inhibitory effects on breast cancer cells proliferation, which is likely mediated by alteration of gene expression profiles.

• Korean Journal of Medicinal Crop Science
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• v.21 no.2
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• pp.136-141
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• 2013

Chelidonium majus (CM) contains several isoquinoline alkaloids that have been reported to have various biological activities such as anti-inflammatory, antimicrobial, antioxidant, immune-modulatory, and antitumoral. It has been reported that the extract of CM had an antioxidant potential, however the mechanism has not been verified. In this study, we found that CM extract activated FOXO3a. FOXO3a is a transcription factor that involved in various biological processes such as cell cycle arrest, apoptosis, DNA repair, and ROS detoxification. Transcriptional activities of FOXO3a were regulated by post-translational modifications including phosphorylation, acetylation, and ubiquitination. Protein level of FOXO3a was increased by CM extract. Promoter activities of FOXO-transcriptional target genes such as MnSOD, p27 and GADD45 were activated by CM extract in a dose dependent manner. In addition, protein level of MnSOD, major antioxidant enzyme, was increased by CM extract. Thereby ROS level was decreased by CM in old HEF cells. These results suggest that CM extract has an antioxidant activity through FOXO activation.

• Herbal Formula Science
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• v.16 no.2
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• pp.229-241
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• 2008

Objectives : The purpose of this study is to investigate the effect of Ulmi Cortex(UC) on the cisplatin-induced cell death. Materials and Methods : I examined several kinds of cell populations such as $CD4^+$ T cells, $CD8^+$ T cells, macrophages and dendritic cells in spleen. Result : When cisplatin was injected to mice, UC recovered total number of cells in spleen and also the number of T cells, macrophages and dendritic cells. UC also effected the activation of $CD4^+$ and $CD8^+$ T cells such as $CD25^+$, $CD69^+$ cells. To further investigate the effect of UC on the cisplatin-induced cell death, I examined the death of splenocyte and total T cells. UC inhibited cisplatin-induced cell death. Conclusion : Taken together, my results suggest that UC may be a beneficial oriental medicine for side effects during anti-tumor therapy.

• Journal of Pharmaceutical Investigation
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• v.36 no.1
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• pp.1-9
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• 2006

Human solid tumors exhibit a multicellular resistance (MCR) resulting from limited drug penetration and decreased sensitivity of tumor cells when interacting with their microenvironments. Multicellular cultures represent solid tumor condition in vivo and provide clinically relevant data. There is little data on antitumor effect of paclitaxel (PTX) in multicellular cultures although its MCR has been demonstrated. In the present study, we evaluated antiproliferative effects of PTX in multicellular layers (MCL) of DLD-1 human colorectal carcinoma cells. BrdU labeling index (LI), thickness of MCL, cell cycle distribution and cellular uptake of calcein were measured before and after exposure to PTX at 0.1 to 50 ${\mu}M$ for 24, 48 and 72 hrs. BrdU LI and thickness of MCL showed a concentration- and time-dependent decrease and the changes in both parameters were similar, i.e., 34.2% and 40.6% decrease in BrdU LI and thickness, respectively, when exposed to $50\;{\mu}M$ for 72 hr. The DLD-1 cells grown in MCL showed increase in $%G_{0}/G_{1}$ and resistance to cell cycle arrest and apoptosis compared to monolayers. Calcein uptake in MCL did not change upon PTX exposure, indicating technical problems in multicellular system. Overall, these data indicate that antitumor activity of PTX may be limited in human solid tumors (a multicellular system) and MCL may be an appropriate model to study further pharmacodynamics of PTX.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.381-388
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• 2001

This work describes the pharmacological inhibition by KR 31378 and its acetyl metabolite, KR 31612, of the apoptotic cell death induced by $H_2O_2$ in the A7r5 cells. Exposure of A7r5 cells to $H_2O_2$ (0.5 mM) induced a concentration-dependent cytotoxicity in association with oligonucleosomal DNA fragmentation. $H_2O_2-induced$ cell death was potently suppressed by KR 31378, KR 31612, ${\alpha}-tocopherol$ or trolox. Additionally, the apoptotic death of A7r5 cells (DNA ladders on electrophoresis) was also strongly suppressed by KR 31378 and KR 31612, but to a less degree by ${\alpha}-tocopherol$ and trolox. As a mechanistic study, incubation with $H_2O_2$ markedly showed a decreased Bcl-2 level and, in contrast, increased Bax protein and cytochrome C release, which were significantly and concentration-dependently reversed by KR 31378 and KR 31612 as well as by ${\alpha}-tocopherol$ and trolox. KR 31378 and ${\alpha}-tocopherol$ significantly reduced lipid peroxidation in accordance with reduced intracellular ROS and peroxyl radical. These results suggest that KR 31378 has a therapeutic potential against the apoptotic injury via mediation of anti- oxidative stress.

• Journal of Oriental Neuropsychiatry
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• v.20 no.2
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• pp.121-131
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• 2009

Objectives : From Scrophularia buergeriana water extract(SBW), has been used in vivo test for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with APP-related dementias and Alzheimer's disease(AD). $A{\beta}$ oligomer derived from proteolytic processing of the ${\beta}$-amyloid precursor protein(APP), including the amyloid-${\beta}$ peptide($A{\beta}$), play a critical role in the pathogenesis of Alzheimer's dementia. Methods : Using drosophila APP model on APP-induced neuronal cytotoxicity, we demonstrated that SBW prevents neurotoxicity of $A{\beta}$ oligomer, which are the behavior, and possibly causative, feature of AD. We investigated the neuroprotective effects of SBW against the effects of oligomeric $A{\beta}$ and fly behaveior and life span by UAS-GRIM/APP-GAL within transgenic flies. Results and Conclusions : SBW repaired damage leading to the behaveior of APP-induced fly and delayed life span. These results suggest that neuronal damage in AD might be due to two factors: a direct $A{\beta}$ oligomer toxicity and multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of $A{\beta}$ oligomer, underlie the neuroprotective effects of SBW.