interacts_with DB00379?
Dual ligands targeting dopamine D2 and serotonin P08908 receptors as new antipsychotical or anti-Parkinsonian agents . Psychiatric disorders like schizophrenia and neurodegenerative diseases like Parkinson 's disease are associated with poly-factorial pathogenic mechanisms , with several neurotransmitter systems closely involved . In addition to the cerebral dopaminergic ( DA ) system , the serotoninergic ( 5-HT ) system also plays a crucial role in regulating psychoemotional , cognitive and motor functions in the central nervous system ( CNS ) . Among the large 5-HT receptor family , accumulating data have revealed new insights into the therapeutic benefit of the P08908 receptor in treating various CNS disorders , especially schizophrenia and Parkinson 's disease . The present review discusses the advance of dual agents with mixed actions at the dopamine D2 and serotonin P08908 receptors in the treatment of these diseases . Aripiprazole was the only marketed drug with dual D2 and P08908 profile . It is a partial D2 and P08908 receptor agonist and has been prescribed as an atypical antipsychotical drug . Two other drugs DB06016 and Pardoprunox are being investigated in clinic . Most of the other candidate compounds , including DB04888 , Sarizotan , Mazapertine succinate , PF-217830 , and Adoprazine were discontinued due to either non-optimal pharmacokinetic properties or insufficient therapeutical efficacy . Although much effort has been done to highlight the advantages of the P08908 and D2 dual approach , it has to be pointed out that many of these drugs showed poly-pharmacological profile by targeting many other receptors and/or transporters besides the D2 and P08908 receptors . In this regard , ' pure ' compounds exclusively acting on the D2 and P08908 receptors are highly needed to further validate this approach . Meanwhile , safety concerns and in vivo pharmacokinetic alerts should also be implanted to the drug design art early . Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples in menopausal women . We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues . We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC . We measured serum P07202 -AB , DB00024 , FT4 , and estradiol , before and after surgery , and used immunohistochemistry to examine estrogen and progesterone receptors . BrC primary tissue cultures received the following treatments : ethanol , triiodothyronine , triiodothyronine plus 4-hydroxytamoxifen , 4-hydroxytamoxifen , estrogen , or estrogen plus 4-hydroxytamoxifen . Genes regulated by estrogen ( P01135 , P01137 , and P06401 ) and by triiodothyronine ( Q07011 , P22004 , and P10827 ) in vitro were evaluated . DB00024 levels in BrC patients did not differ from those of the control group ( 1.34 ± 0.60 versus 2.41 ± 1.10 μ U/mL ) , but FT4 levels of BrC patients were statistically higher than controls ( 1.78 ± 0.20 versus 0.95 ± 0.16 ng/dL ) . P01135 was upregulated and downregulated after estrogen and triiodothyronine treatment , respectively . DB00279 increased P06401 expression ; however 4-hydroxytamoxifen did not block triiodothyronine action on P06401 expression . DB04468 , alone or associated with triiodothyronine , modulated gene expression of Q07011 , P22004 , and P10827 , similar to triiodothyronine treatment . Thus , our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women . Cordycepin suppresses P01375 -α-induced NF-κB activation by reducing p65 transcriptional activity , inhibiting IκBα phosphorylation , and blocking IKKγ ubiquitination . Cordycepin is reported to participate in multiple pharmacological activities including anti-tumor and anti-inflammation , and is involved in the regulation of NF-κB signaling pathway . However , the detailed molecular mechanism of cordycepin in suppression of NF-κB signaling pathway remains ambiguous . In this study , we first analyzed the effect of cordycepin on NF-κB activity in P29320 -293T cells , and found that cordycepin resulted in a dose-dependent reduction in P01375 -α-induced NF-κB activation . Although cordycepin did not block P01375 -α-induced nuclear translocation of p65 , high concentration of cordycepin reduced the DNA-binding and transcriptional activities of NF-κB . Moreover , cordycepin also inhibited IκBα phosphorylation so as to suppress the degradation of IκBα . Further investigation revealed that cordycepin suppressed IKKs-mediated NF-κB activation and inhibited the ubiquitination of IKKγ . In conclusion , cordycepin effectively inhibits NF-κB signaling through suppressing the activities of NF-κB , IκB and IKK . Thus , cordycepin may provide some potential therapeutic application in inflammation-associated disorders and cancer . P01286 as an agonist of the ghrelin receptor GHS-R1a . Ghrelin synergizes with growth hormone-releasing hormone ( P01286 ) to potentiate growth hormone ( GH ) response through a mechanism not yet fully characterized . This study was conducted to analyze the role of P01286 as a potential ligand of the ghrelin receptor , GHS-R1a . The results show that hGHRH(1-29)NH(2) ( P01286 ) induces a dose-dependent calcium mobilization in P29320 293 cells stably transfected with GHS-R1a an effect not observed in wild-type P29320 293 cells . This calcium rise is also observed using the Q02643 agonists JI-34 and JI-36 . Radioligand binding and cross-linking studies revealed that calcium response to P01286 is mediated by the ghrelin receptor GHS-R1a . P01286 activates the signaling route of inositol phosphate and potentiates the maximal response to ghrelin measured in inositol phosphate turnover . The presence of P01286 increases the binding capacity of (125)I-ghrelin in a dose dependent-fashion showing a positive binding cooperativity . In addition , confocal microscopy in CHO cells transfected with GHS-R1a tagged with enhanced green fluorescent protein shows that P01286 activates the GHS-R1a endocytosis . Furthermore , the selective P01286 -R antagonists , JV-1-42 and JMR-132 , act also as antagonists of the ghrelin receptor GHS-R1a . Our findings suggest that P01286 interacts with ghrelin receptor GHS-R1a , and , in consequence , modifies the ghrelin-associated intracellular signaling pathway . This interaction may represent a form of regulation , which could play a putative role in the physiology of GH regulation and appetite control . DB00233 inhibits O15111 alpha phosphorylation of P25963 in mouse intestinal epithelial cells . P01375 alpha ( TNFalpha ) -stimulated nuclear factor ( NF ) kappaB activation plays a key role in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Phosphorylation of NFkappaB inhibitory protein ( IkappaB ) leading to its degradation and NFkappaB activation , is regulated by the multimeric O15111 complex , including IKKalpha and IKKbeta . We recently reported that DB00244 ( DB00244 ) inhibits TNFalpha-regulated IkappaB degradation and NFkappaB activation . To determine the mechanism of DB00244 inhibition of IkappaB degradation , we studied young adult mouse colon ( YAMC ) cells by immunodetection and in vitro kinase assays . We show DB00244 inhibits TNFalpha-stimulated phosphorylation of P25963 in intact YAMC cells . Phosphorylation of a glutathione S-transferase- P25963 fusion protein by cellular extracts or immunoprecipitated IKKalpha isolated from cells treated with TNFalpha is inhibited by DB00244 . Recombinant IKKalpha and IKKbeta autophosphorylation and their phosphorylation of glutathione S-transferase- P25963 are inhibited by DB00244 . However , IKKalpha serine phosphorylation by its upstream kinase in either intact cells or cellular extracts is not blocked by DB00244 . Surprisingly , immunodepletion of cellular extracts suggests IKKalpha is predominantly responsible for P25963 phosphorylation in intestinal epithelial cells . In summary , DB00244 inhibits TNFalpha-stimulated IKKalpha kinase activity toward P25963 in intestinal epithelial cells . These findings suggest a novel role for DB00244 in the management of Q9UKU7 by disrupting TNFalpha activation of NFkappaB . DB01645 potentiates the P01160 effect on a K(+)-conductance in P29320 -293 cells . P29320 -293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT-PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 -specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V(m) ) were monitored and P29320 -293 cells depolarized by 2.3 +/- 0.5 mV ( n=14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3.9 +/- 0.8 mV ( n=14 ) . After removal of genistein the P01160 -mediated depolarization further increased by 147 % to 5.7 +/- 1.0 mV ( n=14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 -293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba(2+) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K(+)-conductance via a cGMP-dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 -293 cells by -3.9 +/- 0.6 mV ( n=11 ) and this effect could also be fully blocked by Ba(2+) ( -0.3 +/- 0.1 mV , n=5 ) , indicating that genistein activates a K(+)-conductance which contributes significantly to the membrane potential of P29320 -293 cells . DB05692 , a thrombin receptor ( P25116 ) antagonist for the prevention and treatment of atherothrombosis . DB05692 is a novel antiplatelet agent undergoing development by Schering-Plough Corp for the treatment and prevention of atherothrombosis . The compound is an orally administered himbacine analog that potently antagonizes the platelet thrombin receptor protease-activated receptor 1 ( P25116 ) , which leaves the procoagulant function of thrombin intact . In preclinical studies , DB05692 demonstrated no effect on bleed time or coagulation parameters . In both cynomolgus monkeys and humans , the compound had high bioavailability and inhibited ex vivo TRAP ( thrombin receptor-activating peptide ) -stimulated platelet aggregation in a potent and long-lasting manner . In a phase II clinical trial of patients undergoing percutaneous coronary intervention , DB05692 added to standard therapy with aspirin and clopidogrel did not increase major or minor thrombolysis in myocardial infarction bleeding , and demonstrated a trend toward decreased major adverse cardiovascular events versus placebo . At the time of publication , three phase III trials were underway to assess the efficacy and safety of DB05692 for at least 1 year in up to 35,000 patients with acute coronary syndromes or atherosclerosis . The distinct mechanism of action of DB05692 allows for cardiovascular protection without the liability of increased bleeding associated with other antiplatelet therapies . Phase III trials in high-risk patients will determine the use of DB05692 in cardiological practice . The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas : preclinical investigations and results of a phase I dose-escalation clinical trial . PURPOSE : Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas . DB03496 is a pan-CDK inhibitor that has been shown to potentiate chemotherapy . As such , we explored the potentiation of doxorubicin by flavopiridol in sarcoma , in vitro and in vivo , and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas . EXPERIMENTAL DESIGN : Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin . In the phase I study , doxorubicin and flavopiridol were administered on two flavopiridol schedules ; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion . RESULTS : Preclinically , flavopiridol potentiated doxorubicin . In vivo , doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone . Clinically , 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules ( 90 mg/m(2) bolus ; 50 mg/m(2) bolus + 40 mg/m(2) infusion ) both in combination with doxorubicin ( 60 mg/m(2) ) . Dose-limiting toxicities were neutropenia , leukopenia , and febrile neutropenia but no maximum tolerated dose was defined . DB03496 pharmacokinetics showed increasing C(max) with increasing dose . Response Evaluation Criteria in Solid Tumors ( RECIST ) responses included two partial responses , however , stable disease was seen in 16 patients . Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma , eight had stable disease greater than 12 weeks . CONCLUSIONS : The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules . Disease control was observed in well- and dedifferentiated liposarcoma specifically , a disease in which P11802 is known to be amplified . Rat peroxisome proliferator-activated receptors and brown adipose tissue function during cold acclimatization . Brown adipose tissue ( Q14032 ) hyperplasia is a fundamental physiological response to cold ; it involves an acute phase of mitotic cell growth followed by a prolonged differentiation phase . Peroxisome proliferator-activated receptors ( PPARs ) are key regulators of fatty acid metabolism and adipocyte differentiation and may therefore mediate important metabolic changes during non-shivering thermogenesis . In the present study we have investigated Q07869 mRNA expression in relation to peroxisome proliferation in rat Q14032 during cold acclimatization . By immunoelectron microscopy we show that the number of peroxisomes per cytoplasmic volume and acyl- DB01992 oxidase immunolabeling density remained constant ( thus increasing in parallel with tissue mass and cell number ) during the initial proliferative phase and the acute thermogenic response but increased after 14 days of cold exposure , correlating with terminal differentiation of Q14032 . A pronounced decrease in Q14032 PPARalpha and PPARgamma mRNA levels was found within hours of exposure to cold , which was reversed after 14 days , suggesting a role for either or both of these subtypes in the proliferation and induction of peroxisomes and peroxisomal beta-oxidation enzymes . In contrast , PPARdelta mRNA levels increased progressively during cold exposure . Transactivation assays in HIB 1B and P29320 -293 cells demonstrated an adrenergic stimulation of peroxisome proliferator response element reporter activity via Q07869 , establishing a role for these nuclear receptors in hormonal regulation of gene transcription in Q14032 . PEGylation of growth hormone-releasing hormone ( P01286 ) analogues . Synthetically produced GRF1-29 ( DB00010 ) has an amino acid composition identical to the N-terminal 29 amino acids sequence of the natural hypothalamic GHRH1-44 ( Figure 1 ) . It maintains bioactivity in vitro and is almost equally effective in eliciting secretion of endogenous growth hormone in vivo . The main drawbacks associated with the pharmaceutical use of hGRF1-29 relate to its short half-life in plasma , about 10-20 min in humans , which is caused mostly by renal ultrafiltration and enzymatic degradation at the N terminus . PEGylation has been considered as one valid approach to obtain more stable forms of the peptide , with a longer in vivo half-life and ultimately with increased pharmacodynamic response along the somatotropic axis ( endogenous GH , DB01277 levels ) . Different PEGylated P01286 conjugates were obtained and their bioactivity was tested in vitro and in vivo by monitoring endogenous growth hormone ( GH ) serum levels after intravenous ( i.v. ) injection in rats , and intravenous and subcutaneous ( s.c. ) injection in pigs . It was found that P01286 -PEG conjugates are able to bind and activate the human Q02643 , although with different potency . The effect of PEG molecular weight , number of PEG chains bound and position of PEGylation site on P01286 activity were investigated . Mono-PEGylated isomers with a PEG5000 polymer chain linked to Lys 12 or Lys 21 residues , showed high biological activity in vitro , which is similar to that of hGRF1-29 , and a higher pharmacodynamic response as compared to unmodified P01286 molecule . Q08462 selectively couples to E prostanoid type 2 receptors , whereas adenylyl cyclase 3 is not receptor-regulated in airway smooth muscle . Adenylyl cyclases ( ACs ) are important regulators of airway smooth muscle function , because β-adrenergic receptor ( βAR ) agonists stimulate AC activity and DB02527 production . We have previously shown in a number of cell types that AC6 selectively couples to βAR and these proteins are coexpressed in lipid rafts . We overexpressed AC2 , O60266 , and AC6 in mouse bronchial smooth muscle cells ( mBSMCs ) and human embryonic kidney ( P29320 ) -293 cells by using recombinant adenoviruses and assessed their localization and regulation by various G protein-coupled receptors ( GPCRs ) . O60266 and AC6 were expressed primarily in caveolin-rich fractions , whereas AC2 expression was excluded from these domains . AC6 expression enhanced DB02527 production in response to isoproterenol but did not increase responses to butaprost , reflecting the colocalization of AC6 with β(2)AR but not E prostanoid type 2 receptor ( EP(2)R ) in lipid raft fractions . AC2 expression enhanced butaprost-stimulated DB02527 production but had no effect on the β(2)AR-mediated response . O60266 did not couple to any GPCR tested . DB02587 -induced arborization of mBSMCs was assessed as a functional readout of DB02527 signaling . Arborization was enhanced by overexpression of AC6 and O60266 , but AC2 had no effect . GPCR-stimulated arborization mirrored the selective coupling observed for DB02527 production . With the addition of the phosphodiesterase 4 ( DB05876 ) inhibitor rolipram AC2 accelerated forskolin-stimulated arborization . Thus , AC2 selectively couples to EP(2)R , but signals from this complex are limited by DB05876 activity . O60266 does not seem to couple to GPCR in either mBSMCs or P29320 -293 cells , so it probably exists in a distinct signaling domain in these cells . Q03135 interacts with 5- Q13049 serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors . 5-Hydroxytryptamine 2A ( 5-HT(2A) ) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction , platelet aggregation , and the modulation of perception , cognition , and emotion . In a search for 5-HT(2A) receptor-interacting proteins , we discovered that caveolin-1 ( Cav-1 ) , a scaffolding protein enriched in caveolae , complexes with 5-HT(2A) receptors in a number of cell types including P13671 glioma cells , transfected P29320 -293 cells , and rat brain synaptic membrane preparations . To address the functional significance of this interaction , we performed RNA interference-mediated knockdown of Cav-1 in P13671 glioma cells , a cell type that endogenously expresses both 5-HT(2A) receptors and Cav-1 . We discovered that the in vitro knockdown of Cav-1 in P13671 glioma cells nearly abolished 5-HT(2A) receptor-mediated signal transduction as measured by calcium flux assays . RNA interference-mediated knockdown of Cav-1 also greatly attenuated endogenous Galpha(q)-coupled P2Y purinergic receptor-mediated signaling without altering the signaling of P25116 thrombin receptors . Cav-1 appeared to modulate 5-HT(2A) signaling by facilitating the interaction of 5-HT(2A) receptors with Galpha(q) . These studies provide compelling evidence for a prominent role of Cav-1 in regulating the functional activity of not only 5-HT(2A) serotonin receptors but also selected Galpha(q)-coupled receptors . Functional characterization of a novel serotonin receptor ( 5-HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full-length cDNA , coding for a novel serotonin receptor ( 5-HTap2 ) . The receptor protein bears the characteristics of G protein-coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5-HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5-HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [3H]LSD binding was : methiothepin > metergoline > 5-CT > PAPP > 5-HT > ketanserin > NAN-190 > 8-OH-DPAT > clozapine . RT-PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5-HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5-HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg-laying behavior . DuOx2 Promoter Regulation by Hormones , Transcriptional Factors and the Coactivator TAZ . The production of H2O2 , which is essential to thyroid hormone synthesis , involves two NADPH oxidases : dual oxidases 1 and 2 ( DuOx1 and DuOx2 ) . A functional study with human DuOx genes and their 5'-flanking regions showed that DuOx1 and -2 promoters are different from thyroid-specific gene promoters . Furthermore , their transcriptional activities are not restricted to thyroid cells . While regulation of Tg ( thyroglobulin ) and P07202 ( thyroperoxidase ) expression have been extensively studied , DuOx2 promoter regulation by hormones and transcriptional factors need to be more explored . Herein we investigated the role of DB00024 , insulin and insulin-like growth factor 1 ( DB01277 ) , as well as the DB02527 effect on DuOx2 promoter ( ptx41 ) activity in transfected rat thyroid cell lines ( PCCL3 ) . We also assessed DuOx2 promoter activity in the presence of transcriptional factors crucial to thyroid development such as Q15669 -1 ( thyroid transcription factor 1 ) , Q06710 , CREB , Q9Y2W7 , Nkx2.5 and the coactivator TAZ in HeLa and P29320 293T-transfected cells . Our results show that DB00024 and forskolin , which increase DB02527 in thyroid cells , stimulated DuOx2 promoter activity . DB01277 led to pronounced stimulation , while insulin induction was not statistically different from DuOx2 promoter basal activity . All transcriptional factors selected for this work and coactivator TAZ , except Q9Y2W7 , stimulated DuOx2 promoter activity . Moreover , Nkx2.5 and TAZ synergistically increased DuOx2 promoter activity . In conclusion , we show that DuOx2 expression is regulated by hormones and transcription factors involved in thyroid organogenesis and carcinogenesis , reinforcing the importance of the control of H2O2 generation in the thyroid . Emerging small molecule drugs . Dyslipidaemia is a major risk factor for cardiovascular diseases . Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk . However , a substantial residual risk persists especially in patients with type 2 diabetes mellitus . Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases , novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases . However , until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits . This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new P11597 inhibitors ( anacetrapib , evacetrapib ) , novel Q07869 agonists ( K-877 , CER-002 , P15924 -8658 , INT131 and DB05187 ) , LXR agonists ( ATI-111 , LXR-623 , XL-652 ) and RVX-208 . The zinc-finger protein Q9P0J7 is overexpressed during pancreatic cancer development and downregulation of Q9P0J7 inhibits pancreatic cancer development in mice . Q9P0J7 1 ( Q9P0J7 ) was found upregulated in a differential screen in the metaplastic epithelium in the pancreas of transforming growth factor ( TGF ) -alpha transgenic mice . Expression analysis indicated broad overexpression in human cancer tissues . Therefore , we investigated the hypothesis that Q9P0J7 promotes metaplastic changes and tumor development . Q9P0J7 represents an evolutionarily highly conserved protein with a 95 % identity between human and zebrafish . Q9P0J7 is expressed during embryonic development and in the majority of adult tissues investigated . Upregulation of nuclear Q9P0J7 expression is evident in preneoplastic lesions and in several epithelial malignancies , such as pancreatic cancer in mice and humans . In cell culture and in the chicken chorioallantoic membrane model , Q9P0J7 enhances proliferation , migration and invasion of P29320 -293 and Panc1 cells . In crossbreeding experiments , Q9P0J7 -knockdown gene trap mice showed a reduced number and size of premalignant lesions and absence of pancreatic cancer formation in TGF-alpha transgenic mice . This effect is related to the decreased expression of P55008 to S cell-cycle regulators such as cyclin D and cyclin-dependent kinase ( CDK ) 4 . Our data support the hypothesis that Q9P0J7 mediates pro-oncogenic functions in vitro and in vivo and downregulation of Q9P0J7 results in the inhibition of pancreatic cancer formation in mice . These effects are mediated through downregulation of cell-cycle control genes such as cyclin D and P11802 . Gating properties of Q14524 mutations and the response to mexiletine in long-QT syndrome type 3 patients . BACKGROUND : DB00379 ( Mex ) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg(-1) . d(-1) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na(+) current from P29320 293 cells transfected with wild-type ( WT ) or mutant Nav1.5 . All mutations showed impaired inactivation of Na(+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V(1/2) of steady-state inactivation . Furthermore , Mex produced use-dependent block with the order R1626P=P1332L > S941N=WT > M1652R , suggesting that Mex-sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V(1/2) of steady-state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 . The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor . Local anesthetics suppress proliferation in several cancer cells . The mechanism of the suppression , however , is unknown . Our previous study shows that lidocaine , at the level of tissue concentration under topical or local administration , has a direct inhibitory effect on the activity of epidermal growth factor receptor ( P00533 ) , which is a potential target for antiproliferation in cancer cells . Therefore , we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of P00533 activity . We investigated the effects of lidocaine ( 40-4000 microM ) on proliferation of a human tongue cancer cell line , CAL27 , which has a high level of P00533 expression , and also examined the effect of lidocaine on epidermal growth factor ( P01133 ) -stimulated autophosphorylation of P00533 in CAL27 cells . A clinical concentration of lidocaine ( 400 microM ) suppressed both serum-induced and P01133 -induced proliferation of CAL27 cells and inhibited P01133 -stimulated tyrosine kinase activity of P00533 without cytotoxicity . A larger concentration of lidocaine ( 4000 microM ) showed cytotoxicity with an antiproliferative effect . We suggest that the inhibition of P01133 -stimulated P00533 activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells . DB00281 administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells .