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RISS 인기검색어
- 검색키워드
- 저자 : ( Sushil C. Regmi ) (검색결과 3 건)
- 무료
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( Sushil C Regmi ),( Su Young Park ),( Seung Joo Kim ),( Suhrid Banskota ),( Sajita Shah ),( Dong Hee Kim ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7 -O-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-eaten in destruction complex, which was achieved through inhibition of regulatory compo-nents associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC<sub>50</sub> of 50.1 IJM and 15.51JM for tankyrase 1 and 2, respectively) compared to XAV939 (IC<sub>50</sub> of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TGF/LEF1 transcriptional activity (IC<sub>50</sub> of 39.8 nM), which were similar to that of XAV939 (IC<sub>50</sub> of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells in vitro, SMA significantly inhibited tumor growth in GT26 syngenic and HT29 xenograft mouse tumor models. Furthennore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phos-phorylation and increases in axin levels. These results suggest that SMA is a possible can-didate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the β-catenin destruction complex through inhibition of tankyrase and the PI3K/Akt signaling pathway.
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( Suhrid Banskota ),( Sushil C. Regmi ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Background:Although matrix metalloproteinase(MMP)-7 expression is correlated with increased metastatic potential in human colon cancer cells, the underlying molecular mechanism of incasive phenotype remains unknown. In the current study, we investigated the regulatory effects of membrane NADPH oxidase (NOX) and AMP activated protein kinase (AMPK) on MMP-7 expression and invasive phenotype change in colon cancer cells. Methods:Production of superoxide anion was measured by lucigenin chemiluminescence assay using whole cells and protein extracts(NADPH oxidase activity), and intracellular rective oxygen species (ROS) by fluorescence microscopy using 2`,4`-dichlorofluorescein diacetate(DCF-DA). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. siRNA transfecition was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Luciferase reporter assay was performed to identify transcription factors linked to gene expression.Results:Under basal conditions, less invasive human colon cancer cells (HT29 and Caco-2) showed low MMP-7 expression but high NOX1 expression and AMPK phosphorylation. Treatment of HT29 and Caco-2 cells with 12-0-tetradecanoylphorbol-13-acetate (TPA) induced an invasive phenotype response along with corresponding increases basal conditions of highly invasive human colon cancer cells(SW620 and HCT116). In addition, inverse regulation between WMPK phosphorylation and NOX2 and MMP-7 expression was obserced in HT29 cells treated with different by treatment with Vit. E, DPI, apocynin, and NOX2 siRNA but not NOX1 siRNA, indicating NOX2-derived ROS production induced an invasive phenotype. TPA-induced of MMP-7 expression was suppressed by AP-1, NF-kB, and MAPK(ERK, p38, and JNK) inhibitors, whereas TPA-induced expression of NOX2 and its regulators, p47phox and p67phox, was blocked by p38 and NF-KB inhibitors. Conclusions:Molecular switch from NOX1 to NOX2 in colon cancer cells induces ROS production and subsequently enhances MMP-7 expression by deactivating AMPK, which otherwise inhibits stimulus-induced autoregulation of ROS and NOX2 gene expression.
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( Suhrid Banskota ),( Jaya Gautam ),( Sushil C Regmi ),( Pallavi Gurung ),( Myo Hyeon Park ),( Seung Joo Kim ),( Tae Gyu Nam ),( Byeong Seon Jeong ),( Jung Ae Kim ) 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
5-Hydroxytryptamine (5-HT) induces proliferation of cancer cells and vascular cells. In addition to 5-HT production by several cancer cells including gastrointestinal and breast cancer, a significant level of 5-HT is released from activated platelets in the thrombotic environment of tumors, suggesting that inhibition of 5-HT signaling may constitute a new target for antiangiogenic anticancer drug discovery. In the current study we clearly demon-strate that 5-HT-induced angiogenesis was mediated through the 5-HT, receptor-linked Gβγ/Src/PI3K pathway, but not through the MAPKIERKlp38 pathway. In addition, 5-HT induced production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS). In an effort to develop new molecularly targeted anticancer agents against 5-HT action in tumor growth, we demonstrate that BJ-11 08, a derivative of 6-amino-2,4,5-trimethylpyri-oln-3-ol, significantly inhibited 5-HT-induced angiogenesis. In addition, BJ-11 08 induced a significant reduction in the size and weight of excised tumors in breast cancer ceil-inocu-lated CAM assay, showing proportionate suppression of tumor growth along with inhibition of angiogenesis. In human umbilical vein endothelial cells (HUVECs), BJ-11 08 signifi-cantly suppressed 5-HT-induced ROS generation and phosphorylation of P13K1Akt but not of Src. Unlike NOX inhibitors, BJ-11 08, which showed better antioxidant activity than vita-min C, barely suppressed superoxide anion induced by mevalonate or geranylgeranyl pyrophosphate which directly activates NOX without help from other signaling molecules in HUVECs, implying that the anti-angiogenic action of BJ-11 08 was not mediated through direct action on NOX activation, or free radical scavenging activity. In conclusion, BJ-1108 inhibited 5-HT-induced angiogenesis through PI3K1NOX signaling but not through Src, ERK, or p38.
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