ABSTRACT
Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVPTAE684, a wellknown inhibitor of ALK, was revealed to exert antitumor effects in several different malignancies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVPTAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVPTAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC1, Panc1, MIA PaCa2, Capan1, CFPAC1, Colo357 and BxPC3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVPTAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased proliferation and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVPTAE684 or siRNA synergistically enhanced gemcitabineinduced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVPTAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.
Subject(s)
Adenocarcinoma/drug therapy , Anaplastic Lymphoma Kinase/antagonists & inhibitors , Pancreatic Neoplasms/drug therapy , Pyrimidines/pharmacology , Adenocarcinoma/pathology , Anaplastic Lymphoma Kinase/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Pancreatic Neoplasms/pathology , Pyrimidines/therapeutic use , Signal Transduction/drug effectsABSTRACT
New 15-keto-prostaglandins (1-4) were isolated from the MeOH extract of the red alga, Gracilaria verrucosa. Their structures were determined to be prostaglandin B congeners (1-3) and a prostaglandin E congener (4) based on the NMR and MS data. Prostaglandins with a C-15 keto function are rare from natural sources. The presence of these metabolites in the alga is notable because 15-keto-prostaglandins (15-keto-PGs) are considered to be the metabolic products of regular prostaglandins in mammals. The occurrence of different prostaglandins in this alga might be due to the existence of different oxidative enzymes, as previously mentioned for oxygenated fatty acids of the red alga Gracilariopsis lemaneiformis. The antiinflammatory activity of these prostaglandins was examined by evaluating their inhibitory effects on nitric oxide production in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophage cells. These prostaglandins showed weak activity on nitric oxide production.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/analysis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Drug Discovery , Gracilaria/chemistry , Prostaglandins/analysis , Prostaglandins/chemistry , Alprostadil/analogs & derivatives , Alprostadil/analysis , Alprostadil/chemistry , Alprostadil/isolation & purification , Alprostadil/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cell Line, Transformed , Cell Survival/drug effects , Lipopolysaccharides/toxicity , Macrophage Activation/drug effects , Macrophages/drug effects , Macrophages/metabolism , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Nitric Oxide/metabolism , Plant Extracts/chemistry , Prostaglandins/isolation & purification , Prostaglandins/pharmacology , Prostaglandins B/analysis , Prostaglandins B/chemistry , Prostaglandins B/isolation & purification , Prostaglandins B/pharmacology , Spectrometry, Mass, Fast Atom BombardmentABSTRACT
Researching 485 cases of death in two years (2002-2003) at Bavi district, the findings showed that: The crude death rate in the whole of district is 5.20%o in the year 2002 and 4.68%o in the year 2003. The death rate is higher in men than women (5.66%o) compared to 4.77%o and compared to 3.62%o). YPLL in the years of 2002-2003: The burden of mortality is higher in men than women (2002: men/women = 1.24/1; 2003: men/women: 2.6/1).The burden of mortality focused on groups of under 5, over 60 and 20-60 years old. The burden of mortality in group of school ages is lowest. By group of disease, YPLL is highest at external causes (death from drowning, injury, accident).
Subject(s)
Death , EpidemiologyABSTRACT
Sophoricoside isolated from Sophora japonica is a glycoside of isoflavonone as an inhibitor of interleukin (IL)-5. To identify structural requirements of this isoflavonone for its inhibitory activity against IL-5, isoflavonones, isoflavanones, and their glycosides were prepared and their inhibitory activity was tested against IL-5. Among them, 5-benzyloxy-3-(4-hydroxyphenyl)chromen-4-one (4b, 87.9% inhibition at 50 microM, IC(50)=15.3 microM) shows the most potent activity, comparable with that of sophoricoside. The important structural requirements of these isoflavonone analogs exhibiting the inhibitory activity against IL-5 were recognized as (1) planarity of chromen-4-one ring, (2) existence of phenolic hydroxyl at 4-position of B ring, and (3) introduction of benzyloxy at 5-position, which may act as a bulky group for occupying hydrophobic pocket in putative binding site. However the glucopyranosyl moiety of sophoricoside is not an essential motif for the activity.
