interacts_with DB01128?
Radiolabeled ligand binding to the catalytic or allosteric sites of O76074 and PDE11 . Cyclic nucleotide phosphodiesterases ( PDEs ) have been investigated for years as targets for therapeutic intervention in a number of pathophysiological processes . Phosphodiesterase-5 ( O76074 ) , which is highly specific for guanosine 3'-5'-cyclic-monophosphate ( cGMP ) at both its catalytic site and its allosteric sites , has generated particular interest because it is potently and specifically inhibited by three drugs : sildenafil ( Viagra , Pfizer ) , tadalafil ( DB00820 , Lilly- Q9Y6W8 ) , and vardenafil ( DB00862 , Bayer GSK ) . Previously , we have used [(3)H]cGMP to directly study the interaction of cGMP with the allosteric sites of O76074 , but because cGMP binds with relatively low affinity to the catalytic site , it has been difficult to devise a binding assay for this particular binding reaction . This approach using measurement of radiolabeled ligand binding continues to allow us to more precisely define functional features of the enzyme . We now use a similar approach to study the characteristics of high-affinity [(3)H]inhibitor binding to the O76074 catalytic domain . For these studies , we have prepared [(3)H]sildenafil and [(3)H]tadalafil , two structurally different competitive inhibitors of O76074 . The results demonstrate that radiolabeled ligands can be used as probes for both catalytic site and allosteric site functions of O76074 . We describe herein the methods that we have established for studying the binding of radiolabeled ligands to both types of sites on O76074 . These techniques have also been successfully applied to the study of binding of radiolabeled O76074 inhibitors to PDE11 , suggesting that these methods are applicable to the study of other PDEs , and perhaps other enzyme families . Persistent Cdk2 inactivation drives growth arrest of P11274 - P00519 -expressing cells in response to dual inhibitor of P12931 and P00519 kinases SKI606 . Complementary inhibition of tyrosine and P12931 kinases implement dual P12931 / P00519 inhibitor effects in chronic myeloid leukemia ( CML ) . Here , we show that one such inhibitor , DB06616 , induces persistent Cdk2 inactivation leading to growth arrest of P11274 - P00519 -expressing cells either IM-sensitive or driven to IM-resistance by other events than gene overexpression and point mutations . Inhibition of Akt serine/threonine kinase , a phosphatidylinositol 3 kinase ( PI-3k ) target that integrates Q92817 TK signaling with membrane-associated P12931 kinases , is a central component of restored expression and subcellular redistribution of Cdk2 regulatory signals ( P38936 and p27 and Cdc25A phosphatase ) in response to DB06616 . The putative roles of growth factor ( namely P08700 ) autocrine loop in P11274 - P00519 -expressing progenitor progression towards a drug-resistant phenotype are discussed . Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease . A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen ( PSA ) promoter androgen response element , inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( DB01128 ) at the same concentration . Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity . P09917 -activating protein inhibitors : development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ( DB05225 ) . The potent and selective P09917 -activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ( 11j ) is described . Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs . The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities , superior pharmacokinetics , and improved physical properties . The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a P09917 -activating protein ( P20292 ) binding assay , an IC(50) of 349 nM in the human blood Q06643 (4) inhibition assay , and is efficacious in a murine ovalbumin model of allergen-induced asthma . Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers . Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen-depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide-resistant subline , LNCaP- O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and/or bicalutamide responsiveness for proliferation and prostate-specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( DB02901 ) levels in xenografted tumors were analyzed by liquid chromatography-tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR(210) expression were determined . RESULTS : LNCaP- O43633 did not grow in an androgen-depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP- O43633 grew in castrated male mice , and the DB02901 level in grafted LNCaP- O43633 tumors was 7.7-fold lower than in LNCaP tumors . DB01128 stimulated LNCaP- O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP- O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP- O43633 , but AR and pAR(210) expression and PSA secretion in LNCaP- O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 -resistant LNCaP- O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR(210) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP- O43633 . Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50-year-old peri-menopausal woman diagnosed to have early-stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo-invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen-alpha and progesterone receptors ) , cytokeratin , and P00533 was detected only in the carcinomatous area , whereas beta-catenin , BCL-2 , P35354 , p16(INK4a) , P60484 , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 , CD10 , desmin , HER-2/neu , and P04637 were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy . P10275 YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration . X-linked spinal and bulbar muscular atrophy ( SBMA ) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration . SBMA is caused by polyglutamine repeat expansions in the androgen receptor ( AR ) . To determine the basis of AR polyglutamine neurotoxicity , we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells . The AR100 transgenic mice developed a late-onset , gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration , indicating striking recapitulation of the human disease . We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein ( CBP ) -mediated transcription of vascular endothelial growth factor ( P15692 ) and observed altered CBP-AR binding and P15692 reduction in AR100 mice . We found that mutant AR-induced death of motor neuron-like cells could be rescued by P15692 . Our results suggest that SBMA motor neuronopathy involves altered expression of P15692 , consistent with a role for P15692 as a neurotrophic/survival factor in motor neuron disease . 5-Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5-Azacitine ( 5-Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5-Aza may restore and enhance the responsiveness of HRPC cells to anti-hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR-deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up-regulated the expression of P48023 , phospho- Q13158 , p16(INKA) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl-2 , and Bcl-XL expression . The re-activation of hormonal response of AR-negative PC3 cell line was partially due to the AR re-expression mediated by 5-Aza treatment . In contrast , the increase in the response to anti-androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5-Aza with AR-antagonist DB01128 had additive/synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5-Aza in combination with anti-androgen therapy in patients with in AR expressing and AR-deficient HRPC . Q9NZQ7 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis . The immune system has developed several regulatory mechanisms to maintain homeostasis of adaptive immune responses . T-cell programmed death ( PD ) -1 recognition of Q9NZQ7 ( Q9NZQ7 ) expressed on P25054 and non-lymphoid tissue regulates T-cell activation . We show that Q9NZQ7 (-/-) mice exhibit exacerbated proteoglycan ( PG ) -induced arthritis and increased Th-1 P01730 (+) T-cell responses . Unexpectedly , the PG-specific antibody response in Q9NZQ7 (-/-) mice was diminished . A reduction in the number of peanut agglutinin(+) GC coincided with a decrease in P15391 (+) GL-7(+) CD95(+) GC B cells that was a result of increased caspase-induced apoptosis . The percent of P28907 (+) CD138(+) emerging plasma cells was decreased . Q9NZQ7 (-/-) mice exhibited an increased frequency of P01730 (+) P18621 (hi) P32302 (hi) Q9Y6W8 (hi) CD62L(lo) T follicular helper cells that displayed a hyperactive phenotype with increased expression of mRNA transcripts for Bcl6 , Q9HBE4 , and the apoptosis-inducer molecule P48023 . In cell transfer of Q9NZQ7 (-/-) cells into SCID mice , non-B and non-T cells were sufficient to normalize the antibody response , T-cell hyperactivity , and the development of PG-induced arthritis . These findings indicate that Q9NZQ7 on non-B and non-T cells signals through P18621 on T effector cells to prevent excessive activation and reduce autoimmune arthritis . Furthermore , these findings demonstrate a novel role for Q9NZQ7 expression in promoting B-cell survival by regulating the activation of T follicular helper cell . Effects of zileuton and montelukast in mouse experimental spinal cord injury . BACKGROUND AND PURPOSE : P09917 ( P09917 ) is the key enzyme in leukotriene ( LT ) biosynthesis from arachidonic acid ( AA ) . Here , we examined the role of the P09917 -product , cysteinyl-LT ( DB00151 -LT ) , with a P09917 inhibitor ( zileuton ) and a DB00151 -LT , receptor antagonist ( montelukast ) , in the inflammatory response and tissue injury associated with spinal cord injury ( SCI ) . EXPERIMENTAL APPROACH : SCI was induced in mice by the application of vascular clips to the dura via a two-level Q8NHM4 to T7 laminectomy for 1 min . Cord inflammation was assessed histologically and by measuring inflammatory mediators ( ELISA ) and apoptosis by annexin V , TUNEL , P48023 staining and Bax and Bcl-2 expression ( immunohistochemistry and western blots ) . Motor function in hindlimbs was assessed by a locomotor rating scale , for 10 days after cord injury . KEY RESULTS : SCI in mice resulted in tissue damage , oedema , neutrophil infiltration , apoptosis , tumour necrosis-alpha ( P01375 ) and cyclooxygenase-2 ( P35354 ) expression , prostaglandin E(2) ( PGE(2) ) and leukotriene B(4) ( Q06643 (4) ) production , and extracellular signal-regulated kinase 1/2 ( P27361 /2 ) phosphorylation in injured tissue . Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury , neutrophil infiltration , P01375 , P35354 and pERK1/2 expression , PGE(2) and Q06643 (4) production , and apoptosis . In separate experiments , zileuton or montelukast significantly improved the recovery of limb function over 10 days . CONCLUSIONS AND IMPLICATIONS : Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI . Our data underline the important role of P09917 and DB00151 -LT in neurotrauma . An overview of phenserine tartrate , a novel acetylcholinesterase inhibitor for the treatment of Alzheimer 's disease . Existing cholinesterase ( ChE ) inhibitor therapies for Alzheimer 's disease ( AD ) , while effective in improving cognitive , behavioral and functional impairments , do not alter disease progression . Novel drug design studies have focused on the classical ChE inhibitor , (-)-physostigmine , producing alterations in chemical composition and three-dimensional structure , which may offer an improved therapeutic index . The phenylcarbamate derivative , DB04892 , is a selective , non-competitive inhibitor of acetylcholinesterase ( P22303 ) . In vivo , DB04892 produces rapid , potent , and long-lasting P22303 inhibition . As a possible result of its preferential brain selectivity , DB04892 is significantly less toxic than (-)-physostigmine . In studies using the Stone maze paradigm , DB04892 has been shown to improve cognitive performance in both young learning-impaired and elderly rats . In addition to reducing inactivation of acetylcholine in the brain , DB04892 appears to have a second mode of action . Reduced secretion of beta-amyloid ( Abeta ) has been observed in cell lines exposed to DB04892 , occurring through translational regulation of beta-amyloid precursor protein ( beta- P05067 ) mRNA via a non-cholinergic mechanism . These in vitro findings appear to translate in vivo into animal models and humans . In a small study of patients with AD , DB04892 treatment tended to reduce beta- P05067 and Abeta levels in plasma samples . Clinical studies also reveal that DB04892 ( 5-10 mg b.i.d. ) had a favorable safety and pharmacological profile , produced significant improvements in cognitive function and was well tolerated in patients with AD treated for 12 weeks . Further randomized , double-blind , placebo-controlled Phase III studies assessing the efficacy , safety/tolerability and potential disease-modifying effects of DB04892 in patients with AD are currently ongoing . P05067 is a primary androgen target gene that promotes prostate cancer growth . P10275 ( AR ) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently . Here , we identify amyloid precursor protein ( P05067 ) as a primary androgen target through chromatin immunoprecipitation ( ChIP ) combined with genome tiling array analysis ( ChIP-chip ) . ChIP-treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies . Ligand-dependent AR binding was further enriched by PCR subtraction . Using chromosome 21/22 arrays , we identified P05067 as one of the androgen-regulated genes with adjacent functional AR binding sites . P05067 expression is androgen-inducible in LNCaP cells and P05067 immunoreactivity was correlated with poor prognosis in patients with prostate cancer . Gain-of-function and loss-of-function studies revealed that P05067 promotes the tumor growth of prostate cancer . The present study reveals a novel P05067 -mediated pathway responsible for the androgen-dependent growth of prostate cancer . Our findings will indicate that P05067 could be a potential molecular target for the diagnosis and treatment of prostate cancer . Modification of the reactivity of three amino-acid residues in elongation factor 2 during its binding to ribosomes and translocation . The accessibility of three amino acids of P13639 , located within highly conserved regions near the N- and C-terminal extremities of the molecule ( the E region and the DB02059 region , respectively ) to modifying enzymes has been compared within nucleotide-complexed P13639 and ribosomal complexes that mimic the pre- and posttranslocational ones : the high-affinity complex ( P13639 ) -nonhydrolysable GTP analog GuoPP[CH2]P ribosome and the low-affinity ( P13639 ) -GDP-ribosome complex , P13639 and ribosomes being from rat liver . We studied the reactivity of two highly conserved residues diphthamide-715 and DB00125 -66 , to diphtheria-toxin-dependent ADP-ribosylation and trypsin attack , and of a threonine that probably lies between residues 51 and 60 , to phosphorylation by a Ca2+/calmodulin-dependent protein kinase . DB03223 715 and this threonine residue were unreactive within the high-affinity complex but seemed fully reactive in the low-affinity complex . DB00125 -66 was resistant to trypsin in both complexes . The possible involvement of the E and DB02059 regions of P13639 in the interaction with ribosome in the two complexes is discussed . P10275 -mediated antagonism of estrogen-dependent low density lipoprotein receptor transcription in cultured hepatocytes . Postmenopausal women receiving hormone replacement therapy have a lower risk of coronary heart disease than women who do not receive hormone treatment . Multiple mechanisms are likely to underlie estrogen 's cardioprotective action , including lowering of plasma low density lipoprotein ( LDL ) cholesterol . Using an in vitro system exhibiting normal regulation of P01130 ( P01130 ) gene transcription , we show that 17beta-estradiol activates the P01130 promoter in transiently transfected HepG2 cells . P01130 activation by estrogen in HepG2 cells is dependent on the presence of exogenous estrogen receptor , and the estrogen-responsive region of the P01130 promoter colocalizes with the sterol response element previously identified . The estrogen response is concentration dependent , saturable , and sensitive to antagonism by estrogen receptor antagonists . Further , we show that compounds with androgen receptor agonist activity attenuate the estrogen-induced up-regulation of P01130 in our model system . Progestins with androgen receptor agonist activity , such as medroxyprogesterone acetate , also suppress estrogen 's effects on P01130 expression through their androgenic properties . Characterization of the interplay between these hormone receptors on the P01130 in vitro system may allow a better understanding of the actions of sex steroids on P01130 gene expression and their roles in cardiovascular disease . Autophagy is induced through the ROS- P04637 - Q8N682 pathway in response to mitochondrial protein synthesis inhibition . Mitoribosome in mammalian cells is responsible for synthesis of 13 mtDNA-encoded proteins , which are integral parts of four mitochondrial respiratory chain complexes ( I , III , IV and V ) . O75616 is a nuclear-encoded GTPase important for the formation of the 28S small mitoribosomal subunit . Here , we demonstrate that knockdown of O75616 by RNA interference inhibits mitochondrial protein synthesis and promotes reactive oxygen species ( ROS ) generation , leading to autophagic vacuolization in HeLa cells . Cells that lack O75616 expression showed a significant conversion of LC3-I to LC3-II and an enhanced accumulation of autophagic vacuoles carrying the LC3 marker , all of which were blocked by the autophagy inhibitor 3-MA as well as by the ROS scavenger Q9C000 . Inhibition of mitochondrial protein synthesis either by O75616 siRNA or chloramphenicol ( CAP ) , a specific inhibitor of mitoribosomes , induced autophagy in HTC-116 P04637 ( +/+ ) cells , but not in HTC-116 P04637 ( -/- ) cells , indicating that tumor protein 53 ( P04637 ) is essential for the autophagy induction . The ROS elevation resulting from mitochondrial protein synthesis inhibition induced P04637 expression at transcriptional levels by enhancing P04637 promoter activity , and increased P04637 protein stability by suppressing P04637 ubiquitination through Q16539 /p38 MAPK-mediated P04637 phosphorylation . Upregulation of P04637 and its downstream target gene Q8N682 , but not P38936 / P38936 , was required for the autophagy induction in O75616 siRNA or CAP-treated cells . Altogether , these data indicate that autophagy is induced through the ROS- P04637 - Q8N682 pathway in response to mitochondrial protein synthesis inhibition . PP2Cdelta ( Ppm1d , O15297 ) , an endogenous inhibitor of p38 MAPK , is regulated along with Trp53 and Cdkn2a following p38 MAPK inhibition during mouse preimplantation development . Preimplantation embryos utilize mitogen-activated protein kinase signaling ( MAPK ) pathways to relay signals from the external environment to prepare appropriate responses and adaptations to a changing milieu . It is therefore important to investigate how MAPK pathways are regulated during preimplantation development . This study was conducted to investigate whether PP2Cdelta ( Ppm1d , O15297 ) is expressed during mouse preimplantation development and to determine the influences of p38 MAPK inhibition on expression of Trp53 ( p53 ) , Ppm1d , ( O15297 ) , and Cdkn2a ( p16 ) during mouse preimplantation development . Our results indicate that Trp53 , Ppm1d , and Cdkn2a mRNAs and TRP53 and PP2Cdelta proteins are expressed throughout mouse preimplantation development . Treatment of 2-cell embryos with DB04338 ( potent inhibitor of p38 MAPK alpha/beta/ Q16539 /11 ) significantly increased Trp53 , Ppm1d and Cdkn2a and Mapk14 mRNA levels at 12 and 24 hr . Treatment of 8-cell embryos with DB04338 for 12 hr increased Trp53 , Ppm1d , and Cdkn2a mRNA levels , but not Mapk14 mRNA levels . Treatment of 8-cell embryos for 24 hr increased Trp53 , and Ppm1d mRNA levels , but decreased Cdkn2a and Mapk14 mRNA levels . Therefore , blockade of p38 MAPK activity is associated with embryo stage specific influences on Trp53 , Ppm1d , Cdkn2a , and Mapk14 expression during mouse preimplantation development . These results define downstream targets of p38 MAPK during preimplantation development and indicate that the p38 MAPK pathway regulates Trp53 , Ppm1d , and Cdkn2a expression . This study increases our understanding of the mechanisms controlling preimplantation development and of the interactions between preimplantation embryos and their culture environments . Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines/patients ' bone marrow samples ) untreated/treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 /proteosome dependent fragmentation ) ( WB , DB00266 , qPCR ) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 /proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 /ERα/HIF1α/c-Myc ) . Finally , we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention . Activity and potential role of licofelone in the management of osteoarthritis . Osteoarthritis is the most common form of arthritis . It is a progressive joint disease associated with aging . It may be found in the knees , hips , or other joints . It is estimated that costs associated with osteoarthritis exceed 2 % of the gross national product in developed countries . Nonsteroidal anti-inflammatory drugs ( NSAIDs ) are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide . The main limitation in using NSAIDs consists in their side-effects , including gastrointestinal ulcerogenic activity and bronchospasm . The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase ( P36551 ) , and , consequently , the conversion of arachidonic acid into prostaglandins . It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of P23219 ( constitutive isoform ) , whereas the beneficial effects are related to the inhibition of P35354 ( inducible isoform ) . Arachidonic acid can also be converted to leukotrienes ( LTs ) by the action of P09917 ( 5- P28300 ) . DB04725 , a P28300 / P36551 competitive inhibitor , decreases the production ofproinflammatory leukotrienes and prostaglandins ( which are involved in the pathophysiology of osteoarthritis and in gastrointestinal ( GI ) damage induced by NSAIDs ) and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability . Preliminary data with this drug seem promising , but further well-designed clinical trials of this agent in the elderly will be necessary before a final evaluation is possible . Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins . Low-density lipoprotein-cholesterol ( LDL-C ) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk . P04035 inhibitors ( statins ) are currently the most effective LDL-C-lowering drugs . However , a substantial number of patients do not reach treatment targets with statins . Therefore , an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels , either by monotherapy or combination therapy . Upregulation of the P01130 with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat ( DB05317 ) has recently been discontinued . DB00973 combined with statins allowed significantly more patients to reach their LDL-C targets . Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate ( DB05449 ) and bile acid transport inhibitors have shown positive results in early development trials , whereas the prospect of acyl coenzyme A : cholesterol acyltransferase inhibition in cardiovascular prevention is dire . Selective inhibition of messenger RNA ( mRNA ) by antisense oligonucleotides is a new approach to modify cholesterol levels . The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium ( ISIS 301012 ) has shown striking results in phase II studies both as monotherapy as well as in combination with statins . Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation . Head and neck squamous cell carcinoma ( HNSCC ) is the sixth leading cancer in the world ; the main risk factors are alcohol and tobacco use . Advancements in therapies have yet to improve the prognosis of HNSCC . The connection between diabetes and cancer is being recognized , and metformin has been shown to decrease cancer incidence in diabetic patients . Accordingly , here , for the first time , we investigated metformin 's efficacy on the growth and viability of human HNSCC FaDU and Detroit cells . Our results show that metformin treatment ( 5-20 mM ) dose-dependently inhibits the growth of both cell lines . In FaDU cells , metformin caused 18-57 % and 35-81 % growth inhibition after 48 and 72 h treatments , respectively . Similarly , in Detroit 562 cells , 48 and 72 h metformin treatment resulted in 20-57 % and 33-82 % inhibition , respectively . Mechanistically , metformin caused G 1 arrest , which coincided with a decrease in the protein levels of CDKs ( 2 , 4 and 6 ) , cyclins ( D1 and E ) and CDK inhibitors ( p15 , p16 , p18 and p27 ) , but no change in p19 and P38936 . Metformin also decreased the levels of oncogenic proteins Skp2 and β-Trcp . In other studies , metformin decreased the phosphorylation of Q13541 at Ser65 , Thr37/46 and Thr70 sites , but drastically increased the phosphorylation of P13639 at Thr56 and AMPK at Thr172 , which results in global translational inhibition . In summary , the observed wide spectrum of mechanistic effects of metformin on HNSCC cells provides support for the anticancer capability of the drug and its potential use in future therapies .