Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na(+) Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE(2) and EP Receptor-Mediated cAMP/PKA Pathway.

Exposure to Extremely Low-Frequency Electromagnetic Fields Modulates Na(+) Currents in Rat Cerebellar Granule Cells through Increase of AA/PGE(2) and EP Receptor-Mediated cAMP/PKA Pathway.

PLoS One. 2013;8(1):e54376

Authors: He YL, Liu DD, Fang YJ, Zhan XQ, Yao JJ, Mei YA

Abstract
Although the modulation of Ca(2+) channel activity by extremely low-frequency electromagnetic fields (ELF-EMF) has been studied previously, few reports have addressed the effects of such fields on the activity of voltage-activated Na(+) channels (Na(v)). Here, we investigated the effects of ELF-EMF on Na(v) activity in rat cerebellar granule cells (GCs). Our results reveal that exposing cerebellar GCs to ELF-EMF for 10-60 min significantly increased Na(v) currents (I(Na)) by 30-125% in a time- and intensity-dependent manner. The Na(v) channel steady-state activation curve, but not the steady-state inactivation curve, was significantly shifted (by 5.2 mV) towards hyperpolarization by ELF-EMF stimulation. This phenomenon is similar to the effect of intracellular application of arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) on I(Na) in cerebellar GCs. Increases in intracellular AA, PGE(2) and phosphorylated PKA levels in cerebellar GCs were observed following ELF-EMF exposure. Western blottings indicated that the Na(V) 1.2 protein on the cerebellar GCs membrane was increased, the total expression levels of Na(V) 1.2 protein were not affected after exposure to ELF-EMF. Cyclooxygenase inhibitors and PGE(2) receptor (EP) antagonists were able to eliminate this ELF-EMF-induced increase in phosphorylated PKA and I(Na). In addition, ELF-EMF exposure significantly enhanced the activity of PLA(2) in cerebellar GCs but did not affect COX-1 or COX-2 activity. Together, these data demonstrate for the first time that neuronal I(Na) is significantly increased by ELF-EMF exposure via a cPLA2 AA PGE(2) EP receptors PKA signaling pathway.

PMID: 23349866 [PubMed - in process]

coxinhibitors c-met inhibitors zm-447439

The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer.

The Blocking of c-Met Signaling Induces Apoptosis through the Increase of p53 Protein in Lung Cancer.

Cancer Res Treat. 2012 Dec;44(4):251-61

Authors: Jung HY, Joo HJ, Park JK, Kim YH

Abstract
PURPOSE: c-Met is an attractive potential target for novel therapeutic inhibition of human cancer, and c-Met tyrosine kinase inhibitors (TKIs) are effective growth inhibitors of various malignancies. However, their mechanisms in anticancer effects are not clear. In the present study, we investigated the possibility that blocking c-Met signaling induces p53-mediated growth inhibition in lung cancer.
MATERIALS AND METHODS: The growth inhibitory effects of c-Met TKI (SU11274) on lung cancer cells and a xenograft model were assessed using the MTT assay, flow cytometry, and terminal deoxyribonucleotide transferase-mediated nick-end labeling staining. The role of p53 protein in the sensitivity of c-Met TKI (SU11274) was examined by Western blot analysis and immunohistochemistry.
RESULTS: SU11274 significantly induced apoptosis in A549 cells with wild-type p53, compared with that in Calu-1 cells with null-type p53. SU11274 increased p53 protein by enhancing the stability of p53 protein. Increased p53 protein by SU11274 induced up-regulation of Bax and PUMA expression and down-regulation of Bcl-2 expression, subsequently activating caspase 3. In p53 knock-out and knock-in systems, we confirmed that SU11274 caused apoptosis through the p53-mediated apoptotic pathway. Likewise, in the A549 xenograft model, SU11274 effectively shrank tumor volume and induced apoptosis via increased p53 protein expression. Blocking c-Met signaling increased the level of p53 protein.
CONCLUSION: Our finding suggested that p53 plays an important role in SU11274-induced apoptosis, and p53 status seems to be related to the sensitivity to SU11274 in lung cancer.

PMID: 23341789 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: A case report.

Role of mammalian target of rapamycin inhibitor in the treatment of metastatic epithelioid angiomyolipoma: A case report.

Int J Urol. 2013 Jan 24;

Authors: Kohno J, Matsui Y, Yamasaki T, Shibasaki N, Kamba T, Yoshimura K, Sumiyoshi S, Mikami Y, Ogawa O

Abstract
Epithelioid angiomyolipoma has malignant potential; however, no effective therapy has been established for advanced cases. A 50-year-old woman with a history of right nephrectomy for epithelioid angiomyolipoma was referred to our institution. Computed tomography and magnetic resonance imaging showed multiple tumors in her lung, liver and pelvic cavity. The liver and pelvic tumor specimens obtained by needle biopsy confirmed the diagnosis of epithelioid angiomyolipoma recurrence. The patient was treated with everolimus (10?mg/day). Three months later, pulmonary lesions disappeared; liver and pelvic tumors significantly shrank in size, but the pelvic tumor gradually enlarged again. We carried out surgical resection of the residual liver and pelvic cavity tumors. Although the mammalian target of rapamycin inhibitor seems to be effective for treating epithelioid angiomyolipoma, its long-term effects remain unknown. Thus, aggressive administration of a multidisciplinary treatment including molecular target therapy and surgical resection is required to improve the prognosis of epithelioid angiomyolipoma.

PMID: 23347205 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

Enhanced NF?B Activity Impairs Vascular Function through PARP-1, SP-1 and COX2-Dependent Mechanisms in Type 2 Diabetes.

Enhanced NF?B Activity Impairs Vascular Function through PARP-1, SP-1 and COX2-Dependent Mechanisms in Type 2 Diabetes.

Diabetes. 2013 Jan 24;

Authors: Kassan M, Choi SK, Galan M, Bishop A, Umezawa K, Trebak M, Belmadani S, Matrougui K

Abstract
Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NF?B) signaling contributes to vascular dysfunction in T2D. We have treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NF?B inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500 ?g/kg/day) for four weeks. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium dependent relaxation (EDR) was impaired in small coronary arterioles (CA) and mesenteric resistance artery (MRA) from diabetic mice compared to control. Interestingly, diabetic mice treated with NF?B inhibitors significantly reduced MT potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NF?B-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared to db(-)/db(-) mice. Additionally, the acute in vitro down regulation of NF?B-p65 using p65NF?B shRNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NF?B inhibition did not affect blood glucose level and body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NF?B phosphorylation, cleaved PARP-1 and COX-2 expression were increased in arteries from diabetic mice, which were restored after NF?B inhibition and in db(-)/db(-p50NF?B-/-) and db(-)/db(-PARP-1-/-) mice.In the present study, we provided evidence that enhanced NF?B activity impairs vascular function by PARP-1, Sp-1 and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NF?B could be a potential target to overcome diabetes-induced vascular dysfunction.

PMID: 23349490 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Related Articles

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2012 Nov;70(5):653-63

Authors: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH

Abstract
PURPOSE: This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.
METHODS: Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ?10�days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400�mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.
RESULTS: The majority of radioactivity was recovered in feces (mean 61�%; range 52-69�%), as compared with urine (mean 16�%; range 13-21�%). Only 6-19�% of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.
CONCLUSIONS: Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.

PMID: 23010851 [PubMed - indexed for MEDLINE]

zm-447439 rad001 ecdysone

Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells.

Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells.

Front Oncol. 2012;2:212

Authors: Tosato V, Gr�ning NM, Breitenbach M, Arnak R, Ralser M, Bruschi CV

Abstract
Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression (i) the activity of pyruvate kinase (PK), which recapitulates metabolic features of cancer cells, including the Warburg effect, and (ii) chromosome bridge-induced translocation (BIT) mimiking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect), and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, PK, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and post-translational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants ("translocants"), between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the BIT system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast.

PMID: 23346549 [PubMed - in process]

dna-pk coxinhibitors c-met inhibitors

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Related Articles

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

Transfusion. 2012 Nov;52(11):2406-13

Authors: Avanzi MP, Chen A, He W, Mitchell WB

Abstract
BACKGROUND: Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes.
STUDY DESIGN AND METHODS: Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy.
RESULTS: Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization.
CONCLUSION: Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways.

PMID: 22612069 [PubMed - indexed for MEDLINE]

dna-pk coxinhibitors c-met inhibitors