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

The combination of anticancer drugs used in the clinic has been based upon empiricism, and the potential permutations of currently available drugs overwhelm the clinical trials system. Recently, investigators have suggested that the combination of a blockade of vital signal transduction pathways in combination with more standard therapy might enhance anticancer effect. Using a panel of breast cancer cell lines and isobologram median effect analysis, a method of determining synergism or antagonism of drugs, we have investigated in vitro potentially clinically useful combinations of agents with the human cell lines MCF7/wt, MCF7/adr, BT474, and SK-BR-3 grown in log phase. Results were confirmed by curve shift analysis. Cells were exposed to the agent(s) for 72 h and then analyzed for cytotoxicity using a MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl-tetrazolium bromide) assay. Fluvastatin, an inhibitor of prenylation with excellent tolerability in man, was chosen to disrupt signal transduction pathways and thus potentially enhance the effect of more traditional anticancer agents. Anticancer agents tested were cytotoxics used in the treatment of breast cancer, trastuzumab, and rapamycin as an inhibitor of the AKT pathway. Fluvastatin combined with trastuzumab demonstrates global synergy of cytotoxic effect that is confirmed by apoptosis assay. These effects could only be partially reversed by adding farnesol or geranylgeraniol to restore prenylation. Epirubicin is also synergistic with fluvastatin in three of the four cell lines. Rapamycin, an inhibitor of MTOR, was synergistic with fluvastatin in two of the four cell lines and antagonistic in two other cell lines. The combination of fluvastatin or another inhibitor of prenylation and trastuzumab may be attractive for clinical development as the effect of trastuzumab in Her2/neu positive breast tumors is incomplete as a single agent.
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PMID:Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro. 1700 4

The expression and activity of Fatty Acid Synthase (FASN; the sole enzyme capable of the reductive de novo synthesis of long-chain fatty acids from acetyl-CoA, malonyl-CoA, and nicotinamide adenine dinucleotide phosphate -NADPH-) is extremely low in nearly all nonmalignant adult tissues, whereas it is significantly up-regulated or activated in many cancer types, thus creating the potential for a large therapeutic index. Since the pioneering observation that inhibition of FASN activity by the mycotoxin cerulenin preferentially kills cancer cells and retards the growth of tumors in xenografts models, numerous in vitro and in vivo studies have confirmed the potential of FASN as a target for antineoplastic intervention. Other FASN inhibitors such as the cerulenin derivative C75, the beta-lactone orlistat, the green tea polyphenol epigallocatechin-3-gallate (EGCG) and other naturally occurring flavonoids (i.e., luteolin, quercetin, and kaempferol), as well as the antibiotic triclosan, have been identified and have been shown to limit cancer cell growth by inducing apoptotic cell death. Though the exact mode of action of these FASN inhibitors is under discussion, it has been revealed that depletion of end-product fatty acids, toxic intracellular accumulation of supra-physiological concentrations of the FASN substrate malonyl-CoA and/or limited membrane synthesis and/or functioning by altered production of phospholipids partitioning into detergent-resistant membrane microdomains (lipid raft-aggregates), can explain, at least in part, the cytostatic, cytotoxic as well as the apoptotic effects occurring upon pharmacological inhibition of FASN activity in cancer cells. Moreover, several cancer-associated molecular features including nonfunctioning p53, overexpression of the Her-2/neu (erbB-2) oncogene, and hyperactivation of the PI-3'K down-stream effector protein kinase B (AKT), appear to determine an exacerbated sensitivity to FASN inhibition-induced cancer cell death. Although few of these inhibitors are expected to be "exclusively" selective for FASN, the potential of FASN as a target for antineoplastic intervention has eventually been confirmed by RNA interference (RNAi)-knockdown of FASN. Certainly, future studies should definitely elucidate the ultimate biochemical link between FASN inhibition and cancer cell death. Although the combination of FASN structural complexity and until recently the lack of X-ray crystallography data of mammalian FASN created a significant challenge in the exploitation of FASN as a valuable target for drug development, it is hoped that the improvement in the selectivity and potency of forthcoming novel FASN-targeted small molecule inhibitors by taking advantage, for instance, of the recent 4.5 A resolution X-ray crystallographic map of mammalian FASN, will direct the foundation of a new family of chemotherapeutic agents in cancer history.
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PMID:Pharmacological inhibitors of Fatty Acid Synthase (FASN)--catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? 1716 65

Protein microarrays allow highly accurate comparison and quantification of numerous biological samples in parallel while requiring only little material. This qualifies protein arrays for systems biology and clinical research where only limited sample material is available, but a precise readout is required. With the introduction of signal normalization steps to monitor the drop size of manually contact-spotted RP protein arrays, the usefulness of normalizer proteins to ensure a high-throughput but inexpensive protein analysis was demonstrated. This approach was applied for the analysis of signaling through ERBB receptor activated kinases in the breast cancer cell line MCF-7. Activation of ERK1/2 and AKT by ERBB1 (EGFR), ERRB2 (HER2/neu), and ERBB3-4 was monitored in a time-resolved manner. Analysis of pathway activation by stimulation with epidermal growth factor and heregulin, or inhibition by blocking with gefitinib or herceptin allowed a characterization of the distinct signaling properties of the different ERBB receptor subtypes.
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PMID:Contact spotting of protein microarrays coupled with spike-in of normalizer protein permits time-resolved analysis of ERBB receptor signaling. 1835 92

Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3(+/-) mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3(wt) mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH(2) kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3(+/-) tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer.
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PMID:The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice. 1848 52

Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT-PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P=0.006), non-serous tumour type (P=0.042) and in multivariate analysis with a longer progression-free survival (P=0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P=0.011). Positive pAKT staining was associated with advanced-stage disease (P=0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.
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PMID:The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer. 1862 64

Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux (cetuximab) on human tumor cells expressing both EGFR and HER2. Investigation of the effect of cetuximab on the activation of EGFR-EGFR, EGFR-HER2 and HER2-HER2 homodimers and heterodimers was conducted using the NCI-N87 human gastric carcinoma cell line. Treatment of NCI-N87 cells with cetuximab completely inhibited formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. Activation of HER2-HER2 homodimers was not appreciably stimulated by exogenous ligand and was not inhibited by cetuximab treatment. Furthermore, cetuximab inhibited EGF-induced EGFR and HER2 phosphorylation in CAL27, NCI-H226 and NCI-N87 cells. The activation of downstream signaling molecules such as AKT, MAPK and STAT-3 were also inhibited by cetuximab in these cells. To examine the effect of cetuximab on the growth of tumors in vivo, athymic mice bearing established NCI-N87 or CAL27 xenografts were treated with cetuximab (1 mg, i.p., q3d). The growth of NCI-N87 and CAL27 tumors was significantly inhibited with cetuximab therapy compared to the control groups (p<0.0001 in both cases). In the CAL27 xenograft model, tumor growth inhibition by cetuximab treatment was similar to that by cetuximab and trastuzumab combination treatment. Immunohistological analysis of cetuximab-treated tumors showed a decrease in EGFR-HER2 signaling and reduced tumor cell proliferation. These results suggest that cetuximab may be useful in the treatment of carcinomas co-expressing EGFR and HER2.
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PMID:Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. 1908 74

ErbB-2 gene encodes tyrosine kinase receptor p185(neu). Overexpression of erbB-2 plays a key role in tumorigenesis or progression such as breast cancer and ovarian cancer. Our previous study showed that ON-III (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) extracted from Traditional Chinese Medicine Cleistocaly xoperculatus dry flower could inhibit KDR tyrosine kinase phosphorylation and tumor growth in vivo. In this study, we reported that ON-III repressed tyrosine phosphorylation of erbB-2 without reduced erbB-2 receptor expression in MDA-MB-453 cells. Activation of mitogen-activated protein kinase (MAPK) and AKT, downstream molecules of erbB-2-mediated signal transduction pathway, was inhibited following exposure to ON-III. ON-III induced apoptosis in breast cancer cells as determined by caspase-3 and PARP cleavage. Also, ON-III upregulated the expression of proapoptotic BH3-only Bcl-2 family member Bim. Bim siRNA could inhibit ON-III-mediated apoptosis in MDA-MB-453 cells. It concludes that ON-III inhibits erbB-2 tyrosine kinase phosphorylation, shuts down its downstream pathway and triggered apoptosis via induction of Bim. These results suggest that ON-III is a potential novel anti-cancer agent for erbB-2-overexpressing cancer.
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PMID:ON-III inhibits erbB-2 tyrosine kinase receptor signal pathway and triggers apoptosis through induction of Bim in breast cancer cells. 1924 12

Fatty acid synthase (FASN) represents a metabolic oncogene. It produces phospholipids for membrane microdomains that accommodate receptor tyrosine kinases including Epidermal Growth Factor-Receptor (EGFR, ErbB1) and ErbB2 (HER2/neu). FASN and ErbBs are overexpressed in ovarian cancer. We examined the effect of FASN and ErbB inhibition on A2780 and SKOV3 ovarian cancer cells. Growth assays reveal that FASN inhibitor C75 sensitizes tumor cells against anti-ErbB drugs (pelitinib [EKB-569], canertinib [CI-1033], erlotinib, cetuximab, matuzumab, trastuzumab) suggesting FASN/ErbB cooperation. qRT-PCR and Western blotting revealed that C75 represses FASN, EGFR, ErbB2, and AKT suggesting that FASN-induced membrane microdomains accommodate/stabilize ErbBs and facilitate AKT recruitment/activation. Our data indicate that AKT is crucial for ErbB/FASN interaction, AKT cross-inhibits ERK and feeds loops that boost FASN and EGFR transcription, and EGFR and ErbB2 must be co-silenced for maximal FASN downregulation. Taken together, interference with FASN and ErbB abrogates their oncogenicity and should be exploited for ovarian cancer treatment.
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PMID:Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. 1946 22

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. To enhance its potency, we tested the efficacy of synthetic curcumin analogues, known as FLLL11 and FLLL12, in cancer cells. We examined the impact of FLLL11 and FLLL12 on cell viability in eight different breast and prostate cancer cell lines. FLLL11 and FLLL12 (IC(50) values 0.3-5.7 and 0.3-3.8 micromol/L, respectively) were substantially more potent than curcumin (IC(50) values between 14.4-50 micromol/L). FLLL11 and FLLL12 were also found to inhibit AKT phosphorylation and downregulate the expression of HER2/neu. In addition, we demonstrate for the first time that FLLL11 and FLLL12 inhibit phosphorylation of signal transducer and activator of transcription (STAT) 3, an oncogene frequently found to be persistently active in many cancer types. The inhibition of STAT3 signaling was confirmed by the inhibition of STAT3 DNA binding and STAT3 transcriptional activity. Furthermore, FLLL11 and FLLL12 were more effective than curcumin in inhibiting cell migration and colony formation in soft agar as well as inducing apoptosis in cancer cells. These results indicate that FLLL11 and FLLL12 exhibit more potent activities than curcumin on the inhibition of STAT3, AKT, and HER-2/neu, as well as inhibit cancer cell growth and migration, and may thus have translational potential as chemopreventive or therapeutic agents for breast and prostate cancers.
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PMID:New curcumin analogues exhibit enhanced growth-suppressive activity and inhibit AKT and signal transducer and activator of transcription 3 phosphorylation in breast and prostate cancer cells. 1955 77

Many inhibitors of the epidermal growth factor receptor (EGFR)-RAS-phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway are in clinical use or under development for cancer therapy. Here, we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3K, or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion, and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results, as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target, as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor but did respond with vascular alterations to RAS or PI3K inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3K inhibition with decreased tumor hypoxia, increased vascular flow, and morphologic alterations of their vessels, including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after the antiangiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy.
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PMID:Tumor vascular changes mediated by inhibition of oncogenic signaling. 1962 66


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