Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of EGFR inhibitors has influenced the field of targeted therapeutics significantly. Unfortunately, the benefits of EGFR inhibitors are limited by several mechanisms of drug resistance, which include KRAS mutations. Mutations in this gene result in constitutive activation of the Ras/Raf/MEK/ERK pathway, with loss of EGFR signaling control, rendering inhibitors of EGFR ineffective. Several strategies are being developed to overcome this mechanism of resistance, including MEK inhibitors, Braf inhibitors, Hsp90 inhibitors, K-Ras-directed immunotherapy, mTOR inhibitors and several combination approaches.
 ...
PMID:The role of KRAS mutations in resistance to EGFR inhibition in the treatment of cancer. 1994 2

Curcumin, a natural polyphenol, has been described to exhibit effects on signaling pathways, leading to induction of apoptosis. In this study, we observed that curcumin inhibited Hsp90 activity causing depletion of client proteins implicated in survival pathways. Based on this observation, this study was designed to investigate the cellular effects of curcumin combination with the pan-HDAC inhibitors, vorinostat and panobinostat, which induce hyperacetylation of Hsp90, resulting in inhibition of its chaperone function. The results showed that, at subtoxic concentrations, curcumin markedly sensitized tumor cells to vorinostat- and panobinostat-induced growth inhibition and apoptosis. The sensitization was associated with persistent depletion of Hsp90 client proteins (EGFR, Raf-1, Akt, and survivin). In conclusion, our findings document a novel mechanism of action of curcumin and support the therapeutic potential of curcumin/HDAC inhibitors combination, because the synergistic interaction was observed at pharmacologically achievable concentrations, which were ineffective when each drug was used alone.
 ...
PMID:The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. 2003 95

In mammals, CpG mediated immune activation is initiated through toll-like receptor (TLR) 9 and Hsp90 via activation of MAPK/ERK and PI3K/AKT pathways. However, in the absence of TLR9 ortholog in chicken genome, the role of Hsp90 and kinase (MAPK/ERK and PI3K/AKT) pathways in initiating CpG ODN(2007) induced immune activation in chicken is not clear. Using electrophoretic mobility shift assay (EMSA) and selective inhibitors of signal transduction pathways, we determined the role of these pathways in the production of Th1 cytokines/chemokines and nitric oxide (NO) in CpG ODN(2007) treated avian macrophage cells. Hsp90alpha but not Hsp90beta is bound to CpG ODN(2007). Inhibition of Hsp90 with geldanamycin resulted in the inactivation of MAPK/ERK and PI3K/AKT pathways leading to significantly reduced levels of IFN-gamma, IL-6 and NO mRNAs in CpG ODN(2007) stimulated cells. Moreover, inhibition of ERK1/2 and PI3/AKT kinase pathways with PD985009 and LY294002, respectively, suppresses the phosphorylation of ERK2 and AKT leading to the production of decreased amounts of IFN-gamma, IL-6 and NO mRNAs in CpG ODN(2007) stimulated cells. Our results demonstrate that binding of CpG ODN(2007) to Hsp90 induces activation of ERK2 and AKT phosphorylation leading to the production of high levels of IFN-gamma, IL-6, MIP-3alpha and nitric oxide (NO). In contrast to mammals, our results suggest that Hsp90alpha but not Hsp90beta binds with the CpG ODN(2007) and may play a major role in CpG ODN(2007) induced immunoactivation in avian macrophage cells. To our knowledge, this is the first report evaluating the involvement of Hsp90 and kinase (MAPK/ERK and PI3K/AKT) pathways in CpG mediated immunostimulation in avian macrophage cells.
 ...
PMID:Role of Hsp90 in CpG ODN mediated immunostimulation in avian macrophages. 2009 33

Substituted quinolines (PQ code number), which reduce colony formation and increase gap junctional intercellular communication, were tested for their ability to interact with various molecular targets in murine and human tumor cell lines in vitro. Various markers of tumor cell metabolism, DNA fragmentation, mitotic disruption, apoptosis induction and growth factor receptor signaling pathways were assayed in vitro to evaluate drug cytotoxicity. Based on its ability to inhibit the metabolic activity of suspension cultures of leukemic L1210 cells at days 2 and 4 in vitro, PQ1 succinic acid salt is the most effective antiproliferative agent among the synthetic quinoline analogs tested. Moreover, antiproliferative PQ1 is effective across a spectrum of monolayer cultures of pancreatic Pan02, epidermoid A-431 and mammary SK-BR-3 and BT-474 tumor cells. PQ1 also blocks Ki-67 expression, a marker of tumor cell proliferation. A 1.5- to 3-h treatment with PQ1 is sufficient to inhibit the incorporations of [3H]-thymidine into DNA, [3H]-uridine into RNA and [3H]-leucine into protein used to assess the rates of macromolecule syntheses over a 0.5- or 1-h period of pulse-labeling in L1210 tumor cells. A 15-min pretreatment with PQ1 inhibits the cellular transport of both purine and pyrimidine nucleosides over a 30-sec period in vitro, suggesting that PQ1 may prevent the incorporation of [3H]-adenosine and [3H]-thymidine into DNA because it rapidly blocks the uptake of these nucleosides by the tumor cells. Since PQ1 does not reduce the fluorescence of the ethidium bromide-DNA complex, it does not directly bind to or destabilize double-stranded DNA. Over a 6- to -48-h period, PQ1 has very little effect on the mitotic index of L1210 cells but stimulates the formation of many binucleated cells and a few micronuclei, suggesting that this compound might increase mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis. The fact that PQ1 induces initiator caspase-2 and effector caspase-3 activities and poly(ADP-ribose) polymerase-1 cleavage within 1-4 h and internucleosomal DNA fragmentation within 24 h in L1210 cells suggests that this antitumor drug can trigger the early and late events required for cells to undergo apotosis. Whole-cell immunodetection and Western blot analysis indicate that, in contrast to 17-(allylamino)-17-demethoxygeldanamycin and radicicol, PQ1 fails to down-regulate the protein level at 24 h and autophosphorylation at 3 h of membrane-anchored HER1 in A-431 cells and HER2 in SK-BR-3 cells, suggesting that this antitumor compound is unlikely to interact with and inhibit Hsp90 and the epidermal growth factor (EGF) receptor signaling pathways. In conclusion, antiproliferative PQ1 is effective against a spectrum of tumor cells and might interact with various membrane and nuclear targets to enhance gap junctions, inhibit nucleoside transport and block cytokinesis but does not appear to disrupt the EGF receptor-mediated signaling pathways to induce growth arrest and apoptosis.
 ...
PMID:Bioactivity and molecular targets of novel substituted quinolines in murine and human tumor cell lines in vitro. 2012 88

The Hsp90 chaperone is a master regulator of the stability and activity of multiple oncoproteins such as Her2, Akt, Bcr-Abl, c-Kit, EGFR and mutant BRAF. The promise of inhibition of such a master regulator for cancer therapy is the potential to cause combinatorial inhibition of multiple oncogenic signaling pathways simultaneously. With the recent discovery of feedback loops that effectively negate the efficacy of selectively targeted anti-cancer agents, there is renewed interest in such a multi-pronged approach. There are now 14 drug candidates that target Hsp90 undergoing clinical trials in multiple indications as single agents or combination therapy. These compounds represent a diverse array of chemical matter stemming from natural product scaffolds to synthetic structure-based design. Although the compounds fall into distinct classes with unique properties, each inhibitor binds in the N-terminal ATP pocket and accumulates in tumor tissue while being rapidly cleared from circulation and normal tissue. The most advanced candidates are now in Phase 2 clinical trials and defining the therapeutic window, dosing schedule, and indication are the primary challenges for these potential first-in-class inhibitors.
 ...
PMID:Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. 2040 45

Pituitary adenomas usually occur as sporadic tumors, but familial cases are now increasingly identified. As opposed to multiple endocrine neoplasia type 1 and Carney complex, in familial isolated pituitary adenoma (FIPA) syndrome no other disease is associated with the familial occurrence of pituitary adenomas. It is an autosomal dominant disease with incomplete variable penetrance. Approximately 20% of patients with FIPA harbour germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene located on 11q13. Patients with AIP mutations have an overwhelming predominance of somatotroph and lactotroph adenomas, which often present in childhood or young adulthood. AIP, originally identified as a molecular co-chaperone of several nuclear receptors, is thought to act as a tumor suppressor gene; overexpression of wild-type, but not mutant AIP, reduces cell proliferation while knockdown of AIP stimulates it. AIP is shown to bind various proteins, including the aryl hydrocarbon receptor, Hsp90, phosphodiesterases, survivin, RET and the glucocorticoid receptor, but currently it is not clear which interaction has the leading role in pituitary tumorigenesis. This chapter summarizes the available clinical and molecular data regarding the role of AIP in the pituitary gland.
 ...
PMID:Molecular genetics of the aip gene in familial pituitary tumorigenesis. 2054 68

A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.
 ...
PMID:Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors. 2065 37

The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in pancreatic cancer cells. Western blotting showed that 17-AAG caused a 2- to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment. Moreover, U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins. Although 17-AAG downregulated cyclin D1, cyclin E, CDK4 and CDK6, it led to cyclin A and CDK2 accumulation, which was reversed by the addition of U0126. Antiproliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect. More importantly, 17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer.
 ...
PMID:MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. 2066 73

The 32nd National Medicinal Chemistry Symposium, held in Minneapolis, MN, USA, included topics covering new developments in the field of medicinal chemistry. This conference report highlights selected presentations on Hsp90 inhibitors and Hsp70 inducers, such as KU-32 and KU-174 (University of Kansas); natural products in drug design, such as minnelide (University of Minnesota) and tylocrebrine; novel compounds from Merck for metabolic and cardiovascular diseases, such as MK-7725, a series of DDP4 inhibitors and KV1.5 ion channel antagonists; and the discovery of the VEGFR2 kinase inhibitor AMG-429 (Amgen Inc).
 ...
PMID:32nd National Medicinal Chemistry Symposium--medicinal chemistry developments for cancer, and cardiovascular, metabolic and psychiatric disorders. 2072 18

Although metastasis accounts for >90% of cancer-related deaths, no therapeutic that targets this process has yet been approved. Because the chemokine receptor CXCR4 is one of the targets closely linked with tumor metastasis, inhibitors of this receptor have the potential to abrogate metastasis. In the current report, we demonstrate that celastrol can downregulate the CXCR4 expression on breast cancer MCF-7 cells stably transfected with HER2, an oncogene known to induce the chemokine receptor. Downregulation of CXCR4 by the triterpenoid was not cell type-specific as downregulation occurred in colon cancer, squamous cell carcinoma, and pancreatic cancer cells. Decrease in CXCR4 expression was not due to proteolysis as neither proteasome inhibitors nor lysosomal stabilization had any effect. Quantitative reverse transcription polymerase chain reaction analysis revealed that downregulation of CXCR4 messenger RNA (mRNA) by celastrol occurred at the translational level. Chromatin immunoprecipitation analysis revealed regulation at the transcriptional level as well. Abrogation of the chemokine receptor by celastrol or by gene-silencing was accompanied by suppression of invasiveness of colon cancer cells induced by CXCL12, the ligand for CXCR4. This effect was not cell type-specific as celastrol also abolished invasiveness of pancreatic tumor cells, and this effect again correlated with the disappearance of both the CXCR4 mRNA and CXCR4 protein. Other triterpenes, such as withaferin A and gedunin, which are known to inhibit Hsp90, did not downregulate CXCR4 expression, indicating that the effects were specific to celastrol. Overall, these results show that celastrol has potential in suppressing invasion and metastasis of cancer cells by down-modulation of CXCR4 expression.
 ...
PMID:Celastrol suppresses invasion of colon and pancreatic cancer cells through the downregulation of expression of CXCR4 chemokine receptor. 2079 12


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