Dysregulation of the Wnt pathway has been extensively studied in multiple diseases, including some angiogenic disorders. Wnt signaling activation is a major stimulator in pathological angiogenesis and thus, Wnt antagonists are believed to have therapeutic potential for neovascular disorders. Actually, some Wnt antagonists have been identified directly from the anti-angiogenic factor family. This review summarizes the recent progress toward understanding of the roles of Wnt pathway antagonists in angiogenic regulation and their mechanism of action, and exploring their therapeutic potential.
Adaptor Proteins, Signal Transducing ; metabolism ; Animals ; Humans ; Neovascularization, Pathologic ; physiopathology ; Repressor Proteins ; metabolism ; Signal Transduction ; physiology ; Wnt Proteins ; antagonists & inhibitors

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.
Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology ; Humans ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; Molecular Targeted Therapy ; Niacinamide/analogs & derivatives/therapeutic use ; Phenylurea Compounds/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism ; Receptor, IGF Type 1/antagonists & inhibitors/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Wnt Proteins/antagonists & inhibitors/metabolism

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death in Korea. Curative treatment is only possible when the disease is diagnosed at the early stage. The prognosis of patients with HCC is even dismal in advanced stages. No systemic cytotoxic chemotherapy has proven to be beneficial in overall survival. Recently, the understanding of the molecular pathogenesis led to the development of new therapies. With the evidence of dysregulation of critical genes associated with cellular proliferation, growth factor signaling, cell cycling, apoptosis, and angiogenesis in HCC, a number of molecular target agents are under clinical trials. Sorafenib is the first systemic anticancer drug which has proven to gain survival benefit in the global as well as Asia-Pacific trials. However, the survival gain is still modest, and further efforts to improve outcomes in patients with HCC are necessary by developing novel drugs or combining other forms of therapies. This article will review signaling pathways in HCC and introduce molecular target agents under investigation currently.
Antineoplastic Agents/therapeutic use ; Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology ; Humans ; Liver Neoplasms/*drug therapy/metabolism/pathology ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; Molecular Targeted Therapy ; Niacinamide/analogs & derivatives/therapeutic use ; Phenylurea Compounds/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors/metabolism ; Receptor, IGF Type 1/antagonists & inhibitors/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Wnt Proteins/antagonists & inhibitors/metabolism

OBJECTIVETo investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism.

METHODSThe multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of β-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively.

RESULTSThe 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P < 0.05 and r = -0.473, P < 0.05), while the culture medium without 17-AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of β-catenin and C-MYC proteins (P < 0.05); At same time of culture, the more high of 17-AAG concentration, the more high of cell ratio in G1 phase (P < 0.05), at same concentration of 17-AAG, the more long time of culture, the more high of cell ratio in G1 phase (P < 0.05).

CONCLUSIONThe HSP90 inhibitory 17-AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/β-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.

Apoptosis ; Benzoquinones ; pharmacology ; Cell Cycle ; Cell Division ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; drug effects ; Down-Regulation ; HSP90 Heat-Shock Proteins ; antagonists & inhibitors ; Humans ; Lactams, Macrocyclic ; pharmacology ; Multiple Myeloma ; metabolism ; pathology ; Proto-Oncogene Proteins c-myc ; metabolism ; Wnt Signaling Pathway ; drug effects ; beta Catenin ; metabolism

The Wnt/β-catenin and bone morphogenetic proteins (BMPs) pathways play important roles in controlling osteogenesis. Using a cell-based kinase inhibitor screening assay, we identified the compound bisindoylmaleimide I (BIM) as a potent agonist of the cytosolic β-catenin accumulation in preosteoblast cells. Through suppressing glycogen synthase kinase 3β enzyme activities, BIM upregulated β-catenin responsive transcription and extended duration of BMP initiated signal. Functional analysis revealed that BIM promoted osteoblast differentiation and bone formation. The treatment of human mesenchymal stem cells with BIM promoted osteoblastogenesis. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by integration of the cellular signaling pathways.
Animals ; Bone Morphogenetic Proteins ; metabolism ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Indoles ; chemistry ; pharmacology ; Maleimides ; chemistry ; pharmacology ; Mesenchymal Stem Cells ; cytology ; metabolism ; Mice ; Osteoblasts ; cytology ; drug effects ; metabolism ; RNA Interference ; RNA, Small Interfering ; metabolism ; Signal Transduction ; drug effects ; Wnt Proteins ; metabolism ; beta Catenin ; antagonists & inhibitors ; genetics ; metabolism

This study is to explore whether the Wnt/beta-catenin signaling pathway is involved in the process of tripchlorolide (T4) protecting against oligomeric Abeta(1-42)-induced neuronal apoptosis. Primary cultured cortical neurons were used for the experiments on day 6 or 7. The oligomeric Abeta(1-42) (5 micromol x L(-1) for 24 h) was applied to induce neuronal apoptosis. Prior to treatment with Abeta(1-42) for 24 h, the cultured neurons were pre-incubated with T4 (2.5, 10, and 40 nmol x L(-1)), Wnt3a (Wnt signaling agonists) and Dkk1 (inhibitors) for indicated time. Then the cell viability, neuronal apoptosis, and protein levels of Wnt, glycogen synthase kinase 3beta (GSK3beta), beta-catenin and phospho-beta-catenin were measured by MTT assay, TUNEL staining and Western blotting, respectively. The result demonstrated that oligomeric Abeta(1-42) induced apoptotic neuronal cell death in a time- and dose-dependent manner. Pretreatment with T4 significantly increased the neuronal cell survival and attenuated neuronal apoptosis. Moreover, oligomeric Abeta(1-42)-induced phosphorylation of beta-catenin and GSK3beta was markedly inhibited by T4. Additionally, T4 stabilized cytoplasmic beta-catenin. These results indicate that tripchlorolide protects against the neurotoxicity of Abeta by regulating Wnt/beta-catenin signaling pathway. This may provide insight into the clinical application of tripchlorolide to Alzheimer's disease.
Amyloid beta-Peptides ; antagonists & inhibitors ; toxicity ; Animals ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Cells, Cultured ; Cerebral Cortex ; cytology ; Diterpenes ; isolation & purification ; pharmacology ; Female ; Fetus ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Neurons ; cytology ; drug effects ; Neuroprotective Agents ; isolation & purification ; pharmacology ; Peptide Fragments ; antagonists & inhibitors ; toxicity ; Phenanthrenes ; isolation & purification ; pharmacology ; Phosphorylation ; Plants, Medicinal ; chemistry ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Tripterygium ; chemistry ; Wnt Proteins ; metabolism ; beta Catenin ; metabolism