• The Korean Journal of Physiology and Pharmacology
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• v.19 no.4
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• pp.365-372
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• 2015

Aripiprazole (ARI) is a commonly prescribed medication used to treat schizophrenia and bipolar disorder. To date, there have been no studies regarding the molecular pathological and immunotoxicological profiling of aripiprazole. Thus, in the present study, we prepared two different formulas of aripiprazole [Free base crystal of aripiprazole (ARPGCB) and cocrystal of aripiprazole (GCB3004)], and explored their effects on the patterns of survival and apoptosis-regulatory proteins under acute toxicity and cytotoxicity test conditions. Furthermore, we also evaluated the modulatory activity of the different formulations on the immunological responses in macrophages primed by various stimulators such as lipopolysaccharide (LPS), pam3CSK, and poly(I:C) via toll-like receptor 4 (TLR4), TLR2, and TLR3 pathways, respectively. In liver, both ARPGCB and GCB3004 produced similar toxicity profiles. In particular, these two formulas exhibited similar phospho-protein profiling of p65/nuclear factor $(NF)-{\kappa}B$, c-Jun/activator protein (AP)-1, ERK, JNK, p38, caspase 3, and bcl-2 in brain. In contrast, the patterns of these phospho-proteins were variable in other tissues. Moreover, these two formulas did not exhibit any cytotoxicity in C6 glioma cells. Finally, the two formulations at available in vivo concentrations did not block nitric oxide (NO) production from activated macrophage-like RAW264.7 cells stimulated with LPS, pam3CSK, or poly(I:C), nor did they alter the morphological changes of the activated macrophages. Taken together, our present work, as a comparative study of two different formulas of aripiprazole, suggests that these two formulas can be used to achieve similar functional activation of brain proteins related to cell survival and apoptosis and immunotoxicological activities of macrophages.

• Journal of Life Science
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• v.29 no.7
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• pp.809-816
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• 2019

The ubiquitous plant metabolite p-coumaric acid (p-CA) has antioxidant and anti-inflammatory properties, but its anti-cancer activity has not been established in gastric cancer cell lines. In this study, we investigated the effects of p-CA on the proliferation and transcriptome profile of SNU16 gastric cancer cells. Treatment with p-CA induced apoptosis of the SNU-16 cells by regulating the expression of pro-apoptotic and anti-apoptotic proteins, such as Bcl-2, poly (ADP-ribose) polymerase (PARP), Bax, procaspase-3, and cleaved-caspase-3. The genes differentially expressed in response to p-CA treatment of the SNU-16 cells were identified by RNA sequencing analysis. Genes regulated by p-CA were involved mainly in the inflammatory response, apoptotic processes, cell cycle, and immune response. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the phosphatidylinositol-3-kinase-Akt and cancer signaling pathways were altered by p-CA. Protein-protein interaction (PPI) network analysis also revealed that p-CA treatment was correlated with differential expression of genes associated with the inflammatory response and cancer. Collectively, these results suggest that p-CA has potential utility in gastric cancer prevention.

• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.553-561
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• 2022

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.11
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• pp.1589-1594
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• 2016

Piperine [(E,E)-5-(3,4-methtylenedioxyphenyl)-2,4-pentadienolypiperidide] is a principal of Piperaceae, including Piper nigrum L. and Piper longum Linn., which has been used as a spice and traditional medicine. In this study, we investigated whether or not piperine has anti-cancer effects on AGS human gastric cancer cells. The results demonstrated that piperine not only inhibited proliferation using MTT assay but also induced apoptotic bodies using DAPI assay in a dose-dependent manner in response to piperine. Expression levels of p53, Bax (pro-apoptotic), cleaved caspase-9, and cleaved-PARP increased, whereas expression levels of Bcl-2, XIAP (anti-apoptotic), and Akt decreased in a dose-dependent manner compared with the control by western blotting analysis. To identify the connection between phospo-Akt and Bcl-2 family in response to piperine, LY249002 (Akt inhibitor) was treated with piperine ($150{\mu}M$). The results were shown that expression of phospo-Akt was reduced whereas expression of Bax and cleaved-PARP increased in a dose-dependent manner. These results indicate that piperine induced apoptosis in AGS cells and may serve as a chemopreventive or therapeutic agent for human gastric cancer.

• The Journal of Korean Medicine
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• v.34 no.3
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• pp.54-68
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• 2013

Objectives: This study aimed to evaluate the effects of microparticles of Socheongryong-tang (SCRT) on chronic obstructive pulmonary disease (COPD) in a mouse model. Methods: The inhalable microparticles containing SCRT were produced by spray-drying with leucine as an excipient, and evaluated with respect to the aerodynamic properties of the powder by Andersen cascade impactor (ACI). Its equivalence to SCRT extract was evaluated using lipopolysaccharide (LPS) and a cigarette-smoking (CS)-induced murine COPD model. Results: SCRT microparticles provided desirable aerodynamic properties (fine particle fraction of $49.6{\pm}5.5%$ and mass median aerodynamic diameter of $4.8{\pm}0.3{\mu}m$). SCRT microparticles did not show mortality or clinical signs over 14 days. Also there were no significant differences in body weight, organ weights or serum chemical parameters between SCRT microparticle-treated and non-treated groups. After 14 days the platelet count significantly increased compared with the non-treated group, but the values were within the normal range. Inhalation of SCRT microparticles decreased the rate of neutrophils in blood, granulocytes in peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage fluid (BALF) and level of TNF-${\alpha}$ and IL-6 in BALF on COPD mouse model induced by LPS plus CS. This effect was verified by histological findings including immunofluorescence staining of elastin, collagen, and caspase 3 protein in lung tissue. Conclusions: These data demonstrate that SCRT microparticles are equivalent to SCRT extract in pharmaceutical properties for COPD. This study suggests that SCRT microparticles would be a potential agent of inhalation therapy for the treatment of COPD.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5339-5343
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• 2012

The induction of apoptosis in target cells is a key mechanism for most anti-tumor therapies. Bufalin is a cardiotonic steroid that has the potential to induce differentiation and apoptosis of tumor cells. Research on bufalin has so far mainly involved leukemia, prostate cancer, gastric cancer and liver cancer, and has been confined to in vitro studies. The bufadienolides bufalin and cinobufagin have been shown to induce apoptosis in a wide spectrum of cancer cell. The present article reviews the anticancer effects of bufalin. It induces apoptosis of lung cancer cells via the PI3K/Akt pathway and also suppressed the proliferation of human non-small cell lung cancer A549 cell line in a time and dose dependent manner. Bufalin, bufotalin and gamabufotalin, key bufadienolides, significantly sensitize human breast cancer cells with differing ER-alpha status to apoptosis induction by the TNF-related apoptosis-inducing ligand (TRAIL). In addition, bufadienolides induce prostate cancer cell apoptosis more significantly than that in breast epithelial cell lines. Similar effects have been observed with hepatocellular carcinoma (HCC) but the detailed molecular mechanisms of inducing apoptosis in this case are still unclear. Bufalin exerts profound effects on leukemia therapy in vitro. Results of multiple studies indicate that bufalin has marked anti-tumor activities through its ability to induce apoptosis. Large-scale randomized, double-blind, placebo or positive drug parallel controlled studies are now required to confirm the efficacy and apoptosis-inducing potential of bufalin in various cancers in the cliniucal setting.

• Journal of Korean Neurosurgical Society
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• v.59 no.2
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• pp.106-116
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• 2016

Objective : Protein disulfide isomerase (PDI) acts as a chaperone on the cell surface, and it has been reported that PDI is associated with the tumor cell migration and invasion. The aims of this study are to investigate the anti-migration effect of bacitracin, which is an inhibitor of PDI, and the associated factor in this process. Methods : U87-MG glioma cells were treated with bacitracin in 1.25, 2.5, 3.75, and 5.0 mM concentrations. Western blot with caspase-3 was applied to evaluate the cytotoxicity of bacitracin. Adhesion, morphology, migration assays, and organotypic brain-slice culture were performed to evaluate the effect of bacitracin to the tumor cell. Western blot, PCR, and gelatin zymography were performed to investigate the associated factors. Thirty glioma tissues were collected following immunohistochemistry and Western blot. Results : Bacitracin showed a cytotoxicity in 3rd (p<0.05) and 4th (p<0.001) days, in 5.0 Mm concentration. The cell adhesion significantly decreased and the cells became a round shape after treated with bacitracin. The migration ability, the expression of phosphorylated focal adhesion kinase (p-FAK) and matrix metalloproteinase-2 (MMP-2) decreased in a bacitracin dose- and time-dependent manner. The U87-MG cells exhibited low-invasiveness in the 2.5 mM, compared with the untreated in organotypic brain-slice culture. PDI was expressed in the tumor margin, and significantly increased with histological glioma grades (p<0.001). Conclusion : Bacitracin, as a functional inhibitor of PDI, decreased the phosphorylated FAK and the secreted MMP-2, which are the downstream of integrin and play a major role in cell migration and invasion, might become one of the feasible therapeutic strategies for glioblastoma.

• BMB Reports
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• v.48 no.3
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• pp.153-158
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• 2015

As FK506 binding proteins (FK506BPs) are known to play an important role in the regulation of a variety of biological processes related to cell survival, this study was designed to examined the protective effects of FK506 binding protein 12 (FK506BP) on low humidity air flow induced dry eye in a rat model using transduced PEP-1-FK506BP. After the topical application of PEP-1-FK506BP, tear volumes were markedly increased and significant prevention of cornea damage was observed compared with dry eye rats. Further, immunohistochemical analysis demonstrated that PEP-1-FK506BP markedly prevented damage to the cornea, the bulbar conjunctiva, and the palpebral conjunctiva epithelial lining compared with dry eye rats. In addition, caspase-3 and PARP expression levels were found to be decreased. These results demonstrated that topical application of PEP-1-FK506BP significantly ameliorates dry eye injury in an animal model. Thus, we suggest that PEP-1-FK506BP can be developed as a new ophthalmic drop to treat dry eye diseases.

• Journal of Life Science
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• v.24 no.11
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• pp.1244-1251
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• 2014

Platycodon grandiflorum (PG) has been known to possess many biological effects, including anti-inflammatory and anti-allergy activity and anti-obesity and hyperlipidemia effects. However, little research has been conducted regarding its anticancer effects, with the exception of its ability to stimulate apoptosis in skin cells. There has also been no study regarding PG-induced autophagy. The modulation of autophagy is recognized as one of the hallmarks of cancer cells. Depending on the type of cancer and the context, autophagy can suppress or help cancer cells to overcome metabolic stress and the cytotoxicity of chemotherapy. Therefore, the present study was designed to investigate whether or not extracts from PG-induced cell death were connected with autophagy and apoptosis in HCT-116 human colon cancer cells. PG stimulation decreased cell proliferation in a dose- and time-dependent manner and induced apoptosis, which was partially dependent on the activation of caspases. PG treatment also resulted in the formation of autophagic vacuoles simultaneously with regulation of autophagy-related genes. Interestingly, a PG-mediated apoptotic effect was further triggered by pretreatment with the autophagy inhibitors 3-methyladenin and bafilomycin A1. However, cell viability recovered quite well with bafilomycin A1 treatment. These findings show that PG treatment promotes both autophagy and apoptosis and that PG-induced autophagic response might play a role in the autophagic cell death of HCT-116 cells.

• Herbal Formula Science
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• v.25 no.3
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• pp.391-412
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• 2017

Objective : In this study, we searched the experimental research about combined treatment of anticancer drug and herbal medicine for killing or inhibiting proliferation of Cancer cells searched in OASIS and KISS. This study aimed to analyze the experimental research paper about anticancer drug combined treatment with herbal medicine. Methods : We collected the research paper including killing or inhibiting proliferation of Cancer cells in OASIS and KISS using keyword anticancer drug with herbal medicine, tumor suppressor with herbal medicine, inhibition of Cancer with herbal medicine and combined treatment with herbal medicine. Assorting by cancer cells, we analyzed experimental results cancer cell viability, anticancer drug dosage, tumor weight and survival rate. Also, we checked the effects of herbal medicine on cancer and additive effect reducing side effect of anticancer drug. Results : Total 45 studies were selected. 38 studies reported combined treatment of anticancer drug and herbal medicine was more effective than only anticancer drug. The death of cancer cells was synergistically induced by the cotreatment of anticancer drug and herb extracts. The studies suggest that the cotreatment of anticancer drug and herb extracts could reduce side effect of anticancer drug. In addition, some studies reported cotreatment mechanism like apoptotic death signal processes. In combined treatment of anticancer drug and herb extracts, The expression of Fas/Fas L, Bax, Bcl2, Caspase-3 etc.. was markedly increased in cancer cells. Conclusions : Our results suggest that anticancer drug combined treatment with herbal medicine could be efficient for killing or inhibiting proliferation of cancer cells. However, this paper had some limitation as follows: First, collected studies have been published only for korean journal. Second, results of research and effects of combined treatment are not collected objectively. To solve these problems, more objective and balanced studies should be performed.