Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date, clinical studies combining the new generation of targeted therapies and chemotherapy have had mixed results. Preclinical studies can be used to identify potential antagonism/synergy between certain agents, with the potential to predict the most efficacious combinations for further investigation in the clinical setting. In this study, we investigated the sequence-dependent interactions of ZD6474 with oxaliplatin in two human colon cell lines in vitro. We evaluated the in vitro antitumor activity of ZD6474, an inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and RET tyrosine kinase activity, and oxaliplatin using three combination schedules: ZD6474 before oxaliplatin, oxaliplatin before ZD6474, and concurrent exposure. Cell proliferation studies showed that treatment with oxaliplatin followed by ZD6474 was highly synergistic, whereas the reverse sequence was clearly antagonistic as was concurrent exposure. Oxaliplatin induced a G(2)-M arrest, which was antagonized if the cells were previously or concurrently treated with ZD6474. ZD6474 enhanced oxaliplatin-induced apoptosis but only when added after oxaliplatin. The sequence-dependent antitumor effects appeared, in part, to be based on modulation of compensatory prosurvival pathways. Thus, expression of total and active phosphorylated EGFR, as well as AKT and extracellular signal-regulated kinase, was markedly increased by oxaliplatin. This increase was blocked by subsequent treatment with ZD6474. Furthermore, the synergistic sequence resulted in reduced expression of insulin-like growth factor-I receptor and a marked reduction in secretion of vascular endothelial growth factor protein. ZD6474 in combination with oxaliplatin has synergistic antiproliferative properties in human colorectal cancer cell lines in vitro when oxaliplatin is administered before ZD6474.
 ...
PMID:Sequence-dependent inhibition of human colon cancer cell growth and of prosurvival pathways by oxaliplatin in combination with ZD6474 (Zactima), an inhibitor of VEGFR and EGFR tyrosine kinases. 1689 75

HER-2/neu in breast cancer is associated with tamoxifen resistance, but little data exist on its interaction with estrogen deprivation or fulvestrant. Here, we used an in vivo xenograft model of estrogen receptor (ER)-positive breast cancer with HER-2/neu overexpression (MCF7/HER-2/neu-18) to investigate mechanisms of growth inhibition and treatment resistance. MCF7/HER-2/neu-18 tumors were growth inhibited by estrogen deprivation and with fulvestrant, but resistance developed in 2 to 3 months. Inhibited tumors had reductions in ER, insulin-like growth factor-I receptor (IGF-IR), phosphorylated HER-2/neu (p-HER-2/neu), and phosphorylated p42/44 mitogen-activated protein kinase (p-MAPK). p27 was increased especially in tumors sensitive to estrogen deprivation. Tumors with acquired resistance to these therapies had complete loss of ER, increased p-HER-2/neu, increased p-MAPK, and reduced p27. In contrast, IGF-IR and phosphorylated AKT (p-AKT) levels were markedly reduced in these resistant tumors. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib, which can block EGFR/HER-2/neu signaling, significantly delayed the emergence of resistance to both estrogen deprivation and fulvestrant. Levels of p-MAPK and p-AKT decreased with gefitinib, whereas high ER levels were restored. Eventually, however, tumors progressed in mice treated with gefitinib combined with estrogen deprivation or fulvestrant accompanied again by loss of ER and IGF-IR, increased p-HER-2/neu, high p-MAPK, and now increased p-AKT. Thus, estrogen deprivation and fulvestrant can effectively inhibit HER-2/neu-overexpressing tumors but resistance develops quickly. EGFR/HER-2/neu inhibitors can delay resistance, but reactivation of HER-2/neu and signaling through AKT leads to tumor regrowth. Combining endocrine therapy with EGFR/HER-2/neu inhibitors should be tested in clinical breast cancer, but a more complete blockade of EGFR/HER-2/neu may be optimal.
 ...
PMID:Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. 1691 7

Epidermal growth factor receptor (EGFR) is a critical mediator of several types of epithelial cancers. Skin cancer arising from exposure to ultraviolet B irradiation (UVB) from the sun is a prominent form of human cancer. Recent data indicate that in addition to cognate ligands, EGFR is activated by UVB irradiation. We used pharmacological and genetic approaches to investigate the function of EGFR in mediating UVB-induced signal transduction in human skin keratinocyte HaCaT cells. Pharmacological inhibition of EGFR tyrosine kinase significantly inhibited UVB-mediated induction of ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of UVB activation of EGFR also suppressed activation of AKT-, PKC-, and PKA-dependent signal transduction pathways. B82 mouse L cells devoid of EGFR were used to further investigate EGFR dependence of UVB-induced signal transduction. UVB failed to induce ERK, and JNK activation was reduced 60% in B82 cells compared to B82K+ cells, which express EGFR. In addition, UVB induced both c-Fos and c-Jun proteins in B82K+ cells, whereas neither were induced in B82 cells. Taken together, these data demonstrate that EGFR is required for UVB-mediated induction of multiple signaling pathways that are known to mediate tumor formation in skin.
 ...
PMID:Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. 1693 59

Hepatocyte growth factor (HGF) and its tyrosine kinase receptor Met play a pivotal role in the tumor metastatic phenotype and represent attractive therapeutic targets. We investigated the biochemical and biological effects of the tyrosine kinase inhibitor RPI-1 on the human lung cancer cell lines H460 and N592, which express constitutively active Met. RPI-1-treated cells showed down-regulation of Met activation and expression, inhibition of HGF/Met-dependent downstream signaling involving AKT, signal transducers and activators of transcription 3 and paxillin, as well as a reduced expression of the proangiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Cell growth in soft agar of H460 cells was strongly reduced in the presence of the drug. Furthermore, RPI-1 inhibited both spontaneous and HGF-induced motility/invasiveness of both H460 and human endothelial cells. Targeting of Met signaling by alternative methods (Met small interfering RNA and anti-phosphorylated Met antibody intracellular transfer) produced comparable biochemical and biological effects. Using the spontaneously metastasizing lung carcinoma xenograft H460, daily oral treatment with well-tolerated doses of RPI-1 produced a significant reduction of spontaneous lung metastases (-75%; P < 0.001, compared with control mice). In addition, a significant inhibition of angiogenesis in primary s.c. tumors of treated mice was observed, possibly contributing to limit the development of metastases. The results provide preclinical evidence in support of Met targeting pharmacologic approach as a new option for the control of tumor metastatic dissemination.
 ...
PMID:Inhibition of c-Met and prevention of spontaneous metastatic spreading by the 2-indolinone RPI-1. 1698 73

AKT and MAPK signaling are involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. RAS proteins are upstream mediators that transfer messages from surface receptors to intracellular signal transducers including MAPK and AKT pathways. AZD3409 is a novel prenyl inhibitor that has shown activity against both farnesyl transferase and geranylgeranyl transferase in isolated enzyme studies. We explored the activity of AZD3409 on breast cancer cell lines with high (SK-Br-3), intermediate (MDA-MB-361) or low (MDA-MB-468) sensitivity to gefitinib. We found that AZD3409 inhibits the growth of breast cancer cells in a dose-dependent manner, with the MDA-MB-468 and MDA-MB-361 cell lines showing higher sensitivity as compared with SK-Br-3 cells. Treatment with AZD3409 produced a significant reduction in the levels of activation of AKT in the three cell lines. AZD3409 also induced an increase in the expression of p27kip-1 and of hypophosphorylated forms of pRb2 in MDA-MB-468 cells that was associated with accumulation of cells in G0/G1 and the appearance of a sub-G1 peak suggestive of apoptosis. In contrast, AZD3409 produced a G2 arrest associated with reduced expression of pRb2 in MDA-MB-361 cells. A synergistic anti-tumor effect was observed when MDA-MB-468 or MDA-MB-361 cells were treated with both AZD3409 and gefitinib, whereas this combination was only additive in SK-Br-3 cells. However, treatment of breast cancer cells with AZD3409 and gefitinib did not produce a more significant blockade of AKT signaling as compared with gefitinib alone. These data suggest that AZD3409 might be active in gefitinib-resistant breast carcinoma.
 ...
PMID:AZD3409 inhibits the growth of breast cancer cells with intrinsic resistance to the EGFR tyrosine kinase inhibitor gefitinib. 1700 12

Inhibition of the JAK2/STAT pathway has been implicated recently in cytoprotective mechanisms in both vascular smooth muscle cells and astrocytes. The advent of JAK2-specific inhibitors provides a practical tool for the study of this pathway in different cellular types. An interest in finding methods to improve endothelial cell (EC) resistance to injury led us to examine the effect of JAK2/STAT inhibition on EC protection. Furthermore, the signaling pathways involved in JAK2/STAT inhibition-related actions were examined. Our results reveal, for the first time, that blockade of JAK2 with the tyrosine kinase inhibitor AG490 strongly protects cultured EC against cell detachment-dependent death and serum deprivation and increases reseeding efficiency. Confirmation of the specificity of the effects of JAK2 inhibition was attained by finding protective effects on transfection with a dominant negative JAK2. Furthermore, AG490 blocked serum deprivation-induced phosphorylation of JAK2. In terms of mechanism, treatment with AG490 induces several relevant responses, both in monolayer and detached cells. These mechanisms include the following: 1) Increase and nuclear translocation of the active, dephosphorylated form of beta-catenin. In functional terms, this translocation is transcriptionally active, and its protective effect is further supported by the stimulation of EC cytoprotection by transfectionally induced excess of beta-catenin. 2) Increase of platelet endothelial cell adhesion molecule (PECAM)/CD31 levels. 3) Increase in total and phosphorylated AKT. 4) Increase in phosphorylated glycogen synthase kinase (GSK)3alpha/beta. The present findings imply potential practical applications of JAK2 inhibition on EC. These applications affect not only EC in the monolayer but also circulating detached cells and involve mechanistic interactions not previously described.
 ...
PMID:Mechanisms of endothelial cell protection by blockade of the JAK2 pathway. 1703 97

Protein kinase B (PKB/Akt) is a member of the second-messenger regulated subfamily of protein kinases. It is implicated in signaling downstream of growth factors, insulin receptor tyrosine kinases and phosphoinositide 3-kinase (PI3K). Current studies indicate that nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and PI3K help mediate inflammatory hyperalgesia. However, little is known about the role of PKB/Akt in the nociceptive system. In this study, we investigated whether PKB/Akt in primary sensory neurons is activated after noxious stimulation and contributes to pain behavior induced in rats by capsaicin. We demonstrated that phospho-PKB/Akt (p-PKB/Akt) is increased in dorsal root ganglia (DRG) at 5 min after intradermal injection of capsaicin. p-PKB/Akt is distributed predominantly in small- and medium-sized DRG cells. After capsaicin injection, p-PKB/Akt (473) is colocalized with isotectin-B4 (IB4), tyrosine kinase A (TrkA), and calcitonin gene-related peptide (CGRP). Furthermore, most transient receptor potential vanilloid type 1 (TRPV1) positive DRG neurons double label for p-PKB/Akt. Behavioral experiments show that intradermal injection of a PI3K (upstream of PKB/Akt) inhibitor, wortmannin, dose-dependently inhibits the changes in exploratory behavior evoked by capsaicin injection. The PKB/Akt inhibitor, Akt inhibitor IV, has the same effect. The results suggest that the PKB/Akt signaling pathway in the periphery is activated by noxious stimulation and contributes to pain behavior.
 ...
PMID:Activation of protein kinase B/Akt in the periphery contributes to pain behavior induced by capsaicin in rats. 1708 39

The Flt3 receptor tyrosine kinase is a critical mediator in the pathogenesis of acute myeloid leukaemia (AML). Flt3-activating mutations have been associated with poor prognosis and decreased overall survival of AML patients, thus Flt3 constitutes an ideal target for drug treatment of such disease. Unfortunately, the monotherapy with small-molecule tyrosine kinase inhibitors in clinical trials shows that remission is not permanent, presumably by resistance of Flt3 mutants to inhibitors. An alternative approach for treatment is based on the cooperation between Flt3 and additional intracellular pathways for AML transformation in some patients. Thus, the inhibition of both Flt3 and such pathways may be exploited for successful treatment of the disease. We investigated the importance of Flt3-activating mutations for the constitutive activation of intracellular pathways in primary AML cells, and their effect on cell survival. We found that the main compounds involved in the differentiation, proliferation and survival of AML (MAPK/AKT/STAT) were constitutively activated. However, only four samples showed internal tandem duplications (ITDs) for Flt3. Surprisingly, contrary to previous reports, we found that inhibition of ITD/Flt3 activity did not prevent the phosphorylation of ERK, STAT5 or Akt in some primary AML cells. In parallel, we found that in these cells, Flt3 and ERK or Akt cooperate to regulate cell survival. Our results support the hypothesis that the optimal therapeutic treatment of AML may require not only the oncogenic tyrosine kinase, but also the appropriate combination of different specific inhibitors, thus providing a more effective approach to reverse leukaemogenesis. Thus, we propose that each AML patient should have an individually tailored combination treatment.
 ...
PMID:Inhibition of Flt3-activating mutations does not prevent constitutive activation of ERK/Akt/STAT pathways in some AML cells: a possible cause for the limited effectiveness of monotherapy with small-molecule inhibitors. 1712 18

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 30% of breast tumor cases and its overexpression correlates with an unfavorable prognosis. A major contributor for this course of the disease is the insensitivity of these tumors toward chemotherapy. Monoclonal antibodies, inhibiting the ligand-induced activation of the receptor and tyrosine kinase inhibitors acting on the intrinsic enzymatic activity of the intracellular domain, have been developed as targeted drugs. Both have been shown to be beneficial for breast cancer patients. We targeted a third aspect of receptor function: its association with intracellular signaling components. For this purpose, we selected peptide aptamers, which specifically interact with defined domains of the intracellular part of the receptor. The peptide aptamers were selected from a random peptide library using a yeast two-hybrid system with the intracellular tyrosine kinase domain of ErbB2 as a bait construct. The peptide aptamer AII-7 interacts with high specificity with the ErbB2 receptor in vitro and in vivo. The aptamers colocalized with the intracellular domain of ErbB2 within cells. We investigated the functional consequences of the aptamer interaction with the ErbB2 receptor within tumor cells. The aptamer sequences were either expressed intracellularly or introduced into the cells as recombinant aptamer proteins. The phosphorylation of p42/44 mitogen-activated protein kinase was nearly unaffected and the activation of signal transducers and activators of transcription-3 was only modestly reduced. In contrast, they strongly inhibited the induction of AKT kinase in MCF7 breast cancer cells treated with heregulin, whereas AKT activation downstream of insulin-like growth factor I or epidermal growth factor receptor was not or only slightly affected. High AKT activity is responsible for the enhanced resistance of ErbB2-overexpressing cancer cells toward chemotherapeutic agents. Peptide aptamer interference with AKT activation resulted in the restoration of regular sensitivity of breast cancer cells toward Taxol.
 ...
PMID:Peptide aptamers with binding specificity for the intracellular domain of the ErbB2 receptor interfere with AKT signaling and sensitize breast cancer cells to Taxol. 1718 88

In renal cell carcinoma (RCC) models, maximal cytotoxicity of the proteasome inhibitor bortezomib is dependent on efficient blockade of constitutive nuclear factor kappaB (NF-kappaB) activity. Signaling through the epidermal growth factor receptor (EGFR) has been shown to result in NF-kappaB activation. Thus, we sought to investigate whether inhibition of the EGFR sensitizes RCC cells to the cytotoxic effects of bortezomib. We first established that constitutive NF-kappaB activity is dependent on signaling through the EGFR in RCC cells. Indeed, blockade of EGFR signaling with an EGFR tyrosine kinase inhibitor (TKI) resulted in inhibition of NF-kappaB activity. Using pharmacologic and genetic approaches, we also showed that EGFR-mediated NF-kappaB activation occurs through the phosphotidylinositol-3-OH kinase/AKT pathway. Combinations of the EGFR-TKI and bortezomib resulted in synergistic cytotoxic effects when RCC cells were pretreated with the EGFR-TKI, but an antagonistic interaction was observed with bortezomib pretreatment. Evaluation of the effects of drug sequencing on inhibition of NF-kappaB activity revealed that EGFR-TKI pretreatment markedly augmented the NF-kappaB inhibitory effect of bortezomib, whereas bortezomib preexposure resulted in suboptimal NF-kappaB blockade and thus provides a biochemical explanation for the drug interaction results. We conclude that the constitutive NF-kappaB activity observed in RCC cells is mediated, at least in part, through an EGFR/phosphotidylinositol-3-OH kinase/AKT signaling cascade. Pretreatment with an EGFR-TKI sensitizes to bortezomib-mediated cytotoxicity by inhibiting constitutive NF-kappaB activity. The combination of bortezomib and a currently approved EGFR inhibitor warrants clinical investigation.
 ...
PMID:Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib. 1723 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>