• Title, Summary, Keyword: potential therapeutic target

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High NDRG3 expression facilitates HCC metastasis by promoting nuclear translocation of β-catenin

  • Shi, JiKui;Zheng, HongZhen;Yuan, LingYan
    • BMB Reports
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    • v.52 no.7
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    • pp.451-456
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    • 2019
  • NDRG1 has been reported to exert pivotal roles in tumor progression and metastasis via Wnt/${\beta}$-catenin signaling pathway. However, little is known about the role of NDRG3 in hepatocarcinogenesis despite its classification in the same subfamily of NDRG1. The present study was aimed to characterize the expression pattern and understand the biological roles of NDRG3 in hepatocarcinogenesis, as a means to exploit its therapeutic potential. It was observed that NDRG3 was up-regulated in HCC tissues and higher NDRG3 expression was associated with significantly shorter overall survival. Furthermore, a lower level of NDRG3 exhibited marked positive correlation with metastasis-free survival. In vitro and in vivo experiments revealed that knock-down of NDRG3 inhibits HCC metastasis and angiogenesis. We further demonstrated that activation of WNT/${\beta}$-catenin signaling and enhanced CSC-like properties were responsible for NDRG3-mediated promoting effect on HCC. In conclusion, the principal findings demonstrated that high NDRG3 expression facilitates HCC metastasis via regulating the turnover of ${\beta}$-catenin, as well as provides a potential therapeutic target for future therapeutic interventions.

Therapeutic potential of targeting kinase inhibition in patients with idiopathic pulmonary fibrosis

  • Kim, Suji;Lim, Jae Hyang;Woo, Chang-Hoon
    • Yeungnam University Journal of Medicine
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    • v.37 no.4
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    • pp.269-276
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    • 2020
  • Fibrosis is characterized by excessive accumulation of extracellular matrix components. The fibrotic process ultimately leads to organ dysfunction and failure in chronic inflammatory and metabolic diseases such as pulmonary fibrosis, advanced kidney disease, and liver cirrhosis. Idiopathic pulmonary fibrosis (IPF) is a common form of progressive and chronic interstitial lung disease of unknown etiology. Pathophysiologically, the parenchyma of the lung alveoli, interstitium, and capillary endothelium becomes scarred and stiff, which makes breathing difficult because the lungs have to work harder to transfer oxygen and carbon dioxide between the alveolar space and bloodstream. The transforming growth factor beta (TGF-β) signaling pathway plays an important role in the pathogenesis of pulmonary fibrosis and scarring of the lung tissue. Recent clinical trials focused on the development of pharmacological agents that either directly or indirectly target kinases for the treatment of IPF. Therefore, to develop therapeutic targets for pulmonary fibrosis, it is essential to understand the key factors involved in the pathogenesis of pulmonary fibrosis and the underlying signaling pathway. The objective of this review is to discuss the role of kinase signaling cascades in the regulation of either TGF-β-dependent or other signaling pathways, including Rho-associated coiled-coil kinase, c-jun N-terminal kinase, extracellular signal-regulated kinase 5, and p90 ribosomal S6 kinase pathways, and potential therapeutic targets in IPF.

Mitochondrial metabolism in cancer stem cells: a therapeutic target for colon cancer

  • Song, In-Sung;Jeong, Yu Jeong;Han, Jin
    • BMB Reports
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    • v.48 no.10
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    • pp.539-540
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    • 2015
  • It has been proposed that the selective elimination of cancer stem cells (CSCs) using targeted therapy could greatly reduce tumor growth, recurrence, and metastasis. To develop effective therapeutic targets for CSC elimination, we aimed to define the properties of CSC mitochondria, and identify CSC-mitochondria-specific targets in colon cancer. We found that colon CSCs utilize mitochondrial oxidative phosphorylation (OXPHOS) to produce ATP. We also found that forkhead box protein 1 (FOXM1)-induced peroxiredoxin 3 (PRDX3) maintains the mitochondrial function, and the FOXM1/PRDX3 mitochondrial pathway maintains survival of colon CSCs. Furthermore, FOXM1 induces CD133 (PROM1/prominin 1) expression, which maintains the stemness of colon CSCs. Together, our findings indicate that FOXM1, PRDX3, and CD133 are potential therapeutic targets for the elimination of CSCs in colon cancer.

Effect of Rutin on Adhesion Molecules Expression and NO Production Induced by $\gamma$-irradiation in Human Endothelial cells

  • Son, Eun-Wha;Lee, Kang-Ro;Rhee, Dong-Kwon;Pyo, Suh-Kneung
    • Biomolecules & Therapeutics
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    • v.9 no.3
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    • pp.156-161
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    • 2001
  • Inflammation is a frequent radiation-induced following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with ${\gamma}$-irradiation (${\gamma}$IR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell surface has been known to be associated with inflammation, interfering with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that bioflavonoid rutin inhibits ${\gamma}$IR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose- and time dependent manner. Rutin also inhibited ${\gamma}$IR induced production of NO. These data suggest that rutin has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.

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Inhibition of $\gamma$-Irradiation Induced Adhesion Molecules and NO Production by Alginate in Human Endothelial Cells

  • Son, Eun-Wha;Cho, Chul-Koo;Rhee, Dong-Kwon;Pyo, Suhk-Neung
    • Archives of Pharmacal Research
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    • v.24 no.5
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    • pp.466-471
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    • 2001
  • Inflammation is a frequent radiation-induced reaction following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with $\gamma$-irradiation ($\gamma$IR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (VCAM-1 ), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell surface has been known to be associated with inflammation, interioring with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that high mannronic acid-containing alginate (HMA) inhibits $\gamma$IR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose dependent manner. HMA also inhibited $\gamma$IR induced production of Nitric oxide (NO). These data suggest that HMA has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.

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Allicin Reduces Adhesion Molecules and NO Production Induced by γ-irradiation in Human Endothelial Cells

  • Son, Eun-Wha;Cho, Chul-Koo;Pyo, Suhkneung
    • IMMUNE NETWORK
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    • v.2 no.1
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    • pp.6-11
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    • 2002
  • Background: Inflammation is a frequent reaction following therapeutic irradiation. Since the upregulation of adhesion molecules on endothelial cell surface is known to be associated with inflammation, the expression of adhesion molecules is an important therapeutic target. Methods: Treatment of human umbilical endothelial cells (HUVECs) with ${\gamma}$-irradiation (${\gamma}IR$) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Changes in the expression of these proteins on ${\gamma}$-irradiated HUVECs which had been treated previously with allicin were measured by ELISA. Results: In the present study, we demonstrate that allicin inhibits the ${\gamma}IR$ induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose-dependent manner. Allicin was also found to inhibit the ${\gamma}IR$ induced production of nitric oxide (NO). Conclusion: These data suggest that allicin has a therapeutic potential for the treatment of various inflammatory disorders associated with increase numbers of endothelial leukocyte adhesion molecules.

γ-Irradiation Induced Adhesion Molecules are Reduced by Vitamin C in Human Endothelial Cells

  • Son, Eun-Wha;Kim, Byung-Oh;Pyo, Suh-Kneung
    • Biomolecules & Therapeutics
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    • v.12 no.3
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    • pp.145-150
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    • 2004
  • Inflammation is a frequent radiation-induced reaction following therapeutic irradiation. Treatment of human umbilical endothelial cells (HUVEC) with ${\gamma}$-irradiation (${\gamma}$IR) induces the expression of adhesion proteins such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Since the upregulation of these proteins on endothelial cell Surface has been known to be associated with inflammation, interfering with the expression of adhesion molecules is an important therapeutic target. In the present study, we demonstrate that vitamin C inhibits ${\gamma}$IR induced expression of ICAM-1, VCAM-1, and E-selectin on HUVEC in a dose- and time dependent manner. Vitamin C a1so inhibited the production of Nitric oxide (NO) induced by ${\gamma}$IR. These data suggest that vitamin C has therapeutic potential for the treatment of various inflammatory disorder associated with an increase of endothelial leukocyte adhesion molecules.

In vitro Study of Nucleostemin as a Potential Therapeutic Target in Human Breast Carcinoma SKBR-3 Cells

  • Guo, Yu;Liao, Ya-Ping;Zhang, Ding;Xu, Li-Sha;Li, Na;Guan, Wei-Jun;Liu, Chang-Qing
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.5
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    • pp.2291-2295
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    • 2014
  • Although nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis and expression has been observed in some types of human cancer and stem cells, the molecular mechanisms involved in mediation of cell proliferation and cell cycling remains largely elusive. The aim of the present study was to evaluate NS as a potential target for gene therapy of human breast carcinoma by investigating NS gene expression and its effects on SKBR-3 cell proliferation and apoptosis. NS mRNA and protein were both found to be highly expressed in all detected cancer cell lines. The apoptotic rate of the pcDNA3.1-NS-Silencer group ($12.1-15.4{\pm}3.8%$) was significantly higher than those of pcDNA3.1-NS ($7.2-12.0{\pm}1.7%$) and non-transfection groups ($4.1-6.5{\pm}1.8%$, P<0.01). MTT assays showed the knockdown of NS expression reduced the proliferation rate of SKBR-3 cells significantly. Matrigel invasion and wound healing assays indicated that the number of invading cells was significantly decreased in the pcDNA3.1-NS-siRNA group (P<0.01), but there were no significant difference between non-transfected and over-expression groups (P>0.05). Moreover, RNAi-mediated NS down-regulation induced SKBR-3 cell G1 phase arrest, inhibited cell proliferation, and promoted p53 pathway-mediated cell apoptosis in SKBR-3 cells. NS might thus be an important regulator in the G2/M check point of cell cycle, blocking SKBR-3 cell progression through the G1/S phase. On the whole, these results suggest NS might be a tumor suppressor and important therapeutic target in human cancers.

Development of Vancomycin Initial Dosage Guidelines to Achieve New Target Ranges (Vancomycin 초기 투여 용량 개선 방안)

  • Yoo, Jae-Young;Kim, Jung-Hyun;Lee, Yong-Won;Kim, Eun-Yeong;Sohn, Kie-Ho
    • Korean Journal of Clinical Pharmacy
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    • v.20 no.3
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    • pp.221-228
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    • 2010
  • In 2009, American Journal of Health-System Pharmacy (AJHP) recommended that targeting vancomycin trough concentrations of 10 mg/L or more because of therapeutic failure and potential risk of developing vancomycin resistance. Therefore, new dosage guidelines that could achieve to these higher target were needed. The aims of this study were to develop dosage guidelines targeting new vancomycin trough concentration and to evaluate the performance of these new guidelines. All data analysis were performed using NONMEM(R). Population pharmacokinetic model was first developed from vancomycin dosage and concentration data collected retrospectively during routine therapeutic drug monitoring in 441 patients, then new vancomycin dosage guidelines were developed by using the model to predict vancomycin trough and peak concentrations in a simulated dataset. The estimates, such as, vancomycin concentration trough level, time to achieve target level, mean error were performed to evaluate and compare difference between conventional dosage and new dosage guidelines. The proposed dosage guidelines were predicted to achieve 43.5% of vancomycin trough level within 10~20 mg/L, which is significantly higher than current guidelines (26.3%). Time to achieve target trough level was 19.4 hours in new guidelines comparing to 93.1 hours in the conventional dosage. Thus, new vancomycin dosage guidelines have been developed to achieve new target trough concentrations earlier and more consistently than conventional guidelines.

Cyclophilin A as a New Therapeutic Target for Hepatitis C Virus-induced Hepatocellular Carcinoma

  • Lee, Jinhwa
    • The Korean Journal of Physiology and Pharmacology
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    • v.17 no.5
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    • pp.375-383
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    • 2013
  • Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.