Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RB)-dependent G1 block in cancer cells and is now in clinical trial. In breast cancer cells, G1 block is accompanied by differentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and lipid droplets. In cells lacking RB, neither G1 arrest nor differentiation occurs; instead, they undergo apoptosis in mitosis. Introduction of RB into these cells restores the differentiation response to 17-AAG. Inhibitors of the ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid droplets when associated with G1 arrest but do not cause morphological changes. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells induces RB-dependent morphological and functional mammary differentiation. G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug.
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PMID:Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. 1130 72

Interactions between the protein kinase C (PKC) and Chk1 inhibitor UCN-01 and the heat shock protein 90 (Hsp90) antagonist 17-AAG have been examined in human leukemia cells in relation to effects on signal transduction pathways and apoptosis. Simultaneous exposure (30 hours) of U937 monocytic leukemia cells to minimally toxic concentrations of 17-AAG (eg, 400 nM) and UCN-01 (eg, 75 nM) triggered a pronounced increase in mitochondrial injury (ie, loss of mitochondrial membrane potential [Deltapsim]; cytosolic release of cytochrome c), caspase activation, and apoptosis. Synergistic induction of apoptosis was also observed in other human leukemia cell types (eg, Jurkat, NB4). Coexposure of human leukemia cells to 17-AAG and the PKC inhibitor bisindolylmaleimide (GFX) did not result in enhanced lethality, arguing against the possibility that the PKC inhibitory actions of UCN-01 are responsible for synergistic interactions. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and marked down-regulation of Raf-1, MEK1/2, and mitogen-activated protein kinase (MAPK). Coadministration of 17-AAG and UCN-01 did not modify expression of Hsp90, Hsp27, phospho-JNK, or phospho-p38 MAPK, but was associated with further p34cdc2 dephosphorylation and diminished expression of Bcl-2, Mcl-1, and XIAP. In addition, inducible expression of both a constitutively active MEK1/2 or myristolated Akt construct, which overcame inhibition of ERK and Akt activation, respectively, significantly attenuated 17-AAG/UCN-01-mediated lethality. Together, these findings indicate that the Hsp90 antagonist 17-AAG potentiates UCN-01 cytotoxicity in a variety of human leukemia cell types and suggest that interference with both the Akt and Raf-1/MEK/MAP kinase cytoprotective signaling pathways contribute to this phenomenon.
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PMID:Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK- and AKT-related pathways. 1273 74

Several chaperone-binding drugs based on geldanamycin (GA) have been synthesized, and one of them, 17-allylamino-17-demethoxygeldanamycin (17-AAG), is being developed in the clinic. Interest in the use of 17-AAG in combination with cytotoxic drugs led us to study both GA and 17-AAG with cisplatin (DDP) in the human colon adenocarcinoma cell lines HT29 and HCT116. We performed isobologram analysis of combinations of DDP with GA or 17-AAG in these cell lines using the standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to evaluate cell survival. In HCT116, the effects of GA and 17-AAG with DDP were additive and schedule dependent. In HT29 both GA and 17-AAG antagonized DDP effects resulting in cytotoxicity less than expected. We hypothesized that the antagonism in HT29 cells might be a consequence of altered p53 function in this cell line. Accordingly, we tested GA/17-AAG and DDP in combination in the HCTp5.2 cell line, which expresses a dominant-negative form of p53. In these cells too, the GA analogues antagonized DDP, suggesting a role for p53 in the observed effects. Investigation of the DDP-induced signaling pathways revealed that ansamycins block the activation of mitogen-activated protein kinase and c-Jun NH(2)-terminal kinase pathways and c-Jun expression in HT29 cells while exerting incomplete inhibitory effects in HCT116 and HCTp5.2 cell lines. Therefore, effects on signaling are thought not to underlay the antagonism in the latter model. The ansamycins inhibited DDP-induced activation of caspases 8 and 3 in HT29 and HCTp5.2 but not in HCT116 cells, which we postulate to be the basis for higher survival of p53-deficient cells when treated with combinations of the two drugs.
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PMID:Geldanamycin and its 17-allylamino-17-demethoxy analogue antagonize the action of Cisplatin in human colon adenocarcinoma cells: differential caspase activation as a basis for interaction. 1281 Jun 54

Interactions between the histone deacetylase inhibitors (HDACIs) suberoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino-17-demethoxygeldanamycin (17-AAG) have been examined in human leukemia cells (U937). Coadministration of marginally toxic concentrations of 17-AAG with sublethal concentrations of SB or SAHA resulted in highly synergistic induction of mitochondrial damage (i.e., cytochrome c release), caspase-3 and -8 activation, and apoptosis. Similar interactions were noted in human promyelocytic (HL-60) and lymphoblastic (Jurkat) leukemia cells. These events were accompanied by multiple perturbations in signal transduction, cell cycle, and survival-related pathways, including early down-regulation of Raf-1, inactivation of extracellular signal-regulated kinase (ERK) 1/2 and mitogen-activated protein/ERK kinase (MEK) 1/2, diminished expression of phospho-Akt, and late activation of c-Jun-NH(2)-terminal kinase, but no changes in expression of phospho-p38 mitogen-activated protein kinase. Coadministration of 17-AAG blocked SAHA-mediated induction of the cyclin-dependent kinase inhibitor p21(CIP1) and resulted in reduced expression of p27(KIP1) and p34(cdc2). 17-AAG/SAHA-treated cells also displayed down-regulation of the antiapoptotic protein Mcl-1 and evidence of Bcl-2 cleavage. Enforced expression of doxycycline-inducible p21(CIP1) or constitutively active MEK1 significantly diminished 17-AAG/SAHA-mediated lethality, indicating that interference with ERK activation and p21(CIP1) induction play important functional roles in the lethal effects of this regimen. In contrast, enforced expression of constitutively active Akt failed to exert cytoprotective actions. Together, these findings indicate that coadministration of SAHA or SB with the Hsp90 antagonist 17-AAG in human leukemia cells leads to multiple perturbations in signaling, cell cycle, and survival pathways that culminate in mitochondrial injury and apoptosis. They also raise the possibility that combining such agents with Hsp90 antagonists may represent a novel antileukemic strategy.
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PMID:Coadministration of the heat shock protein 90 antagonist 17-allylamino- 17-demethoxygeldanamycin with suberoylanilide hydroxamic acid or sodium butyrate synergistically induces apoptosis in human leukemia cells. 1467 5

Elucidation of the mechanism by which oxaliplatin induces cell death is essential to enhancing its action. We investigated the effects of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin (17-AAG) in a panel of four colon adenocarcinoma cell lines. Cytotoxicity assays demonstrated at least additivity in three of the cell lines. Activation of the c-Jun NH(2)-terminal kinase pathway by oxaliplatin does not determine cytotoxicity. Activation of p38 was shown to be a key proapoptotic mediator of oxaliplatin-induced cell death. Modulation of extracellular signal-regulated kinase and AKT signaling had no impact on oxaliplatin toxicity in these cells. Nuclear factor (NF)-kappaB was constitutively active in all of the cell lines and was inhibited by 17-AAG. Down-regulation of NF-kappaB transactivation by pharmacological inhibitors enhanced oxaliplatin cytotoxicity. These data support an interaction between 17-AAG and components of the NF-kappaB pathway in the modulation of oxaliplatin sensitivity in colon cancer cells.
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PMID:Additive interaction of oxaliplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines results from inhibition of nuclear factor kappaB signaling. 1469 70

Ansamycin antibiotics inhibit function of the heat shock protein (HSP) 90, causing selective degradation of several intracellular proteins regulating such processes as proliferation, cell cycle regulation, and prosurvival signaling cascades. HSP90 has been identified previously as a molecular target for anticancer agents, including ionizing radiation (IR). Therefore, we hypothesized that the ansamycin geldanamycin and its 17-allylamino-17-demethoxy analog (17-AAG), which inhibit HSP90, would enhance tumor cell susceptibility to the cytotoxicity of IR. Treatment of two human cervical carcinoma cell lines (HeLa and SiHa) with geldanamycin and 17-AAG resulted in cytotoxicity and, when combined with IR, enhanced the radiation response, each effect with a temporal range from 6 to 48 h after drug exposure. In addition, mouse in vivo models using 17-AAG at clinically achievable concentrations yielded results that paralleled the in vitro radiosensitization studies of both single and fractioned courses of irradiation. The increase in IR-induced cell death appears to be attributable to a combination of both programmed and nonprogrammed cell death. We also measured total levels of several prosurvival and apoptotic signaling proteins. Akt1, extracellular signal-regulated kinase-1, Glut-1, HER-2/neu, Lyn, cAMP-dependent protein kinase, Raf-1, and vascular endothelial growth factor expression were down-regulated in 17-AAG-treated cells, identifying these factors as molecular markers and potential therapeutic targets. Finally, a series of immortalized and human papillomavirus-transformed cell lines were used to demonstrate that the radiosensitizing effects of 17-AAG were limited to transformed cells, suggesting a possible differential cytotoxic effect. This work shows that altered HSP90 function induces significant tumor cytotoxicity and radiosensitization, suggesting a potential therapeutic utility.
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PMID:Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. 1469 17

We investigated the effects of cisplatin and the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination in a panel of human colon adenocarcinoma cell lines that differ in their p53 and mismatch repair status. Analysis of cytotoxicity after combined treatment revealed additive effects of cisplatin and 17-AAG in the HCT 116, DLD1, and SW480 cell lines and antagonism in HT-29 cells. Clonogenic assays demonstrated antagonism in HT-29, an additive effect in SW480, and synergism in HCT 116 and DLD1 cell lines. Analysis of signaling pathways revealed that cisplatin-induced activation of c-Jun N-terminal kinase (JNK) was fully blocked by 17-AAG in HT-29 and SW480 cells, whereas in HCT 116 and DLD1 cells it was inhibited only partially. The activation of caspases was also more pronounced in DLD1 and HCT 116 cell lines. These data suggested that a minimal level of apoptotic signaling through JNK was required for synergism with this combination. To test this hypothesis, we used the specific JNK inhibitor SP600125; when JNK was inhibited pharmacologically in HCT 116 and DLD1 cells, they demonstrated increased survival in clonogenic assays. Alternatively, sustained activation of JNK pathway led to an increase of the cytotoxicity of the cisplatin/17-AAG combination in HT-29 cells. Taken together, these data suggest that the synergistic interaction of this combination in colon cancer cell lines depends on the effect exerted by 17-AAG on cisplatin-induced signaling through JNK and associated pathways leading to cell death. An implication of that finding is that quantitative effects of signaling inhibitors may be critical for their ability to reverse cisplatin resistance.
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PMID:Quantitative effects on c-Jun N-terminal protein kinase signaling determine synergistic interaction of cisplatin and 17-allylamino-17-demethoxygeldanamycin in colon cancer cell lines. 1472 56

Presence of the activating length mutation (LM) in the juxtamembrane domain or point mutation in the kinase domain of FMS-like tyrosine kinase-3 (FLT-3) mediates ligand-independent progrowth and prosurvival signaling in approximately one-third of acute myelogenous leukemia (AML). PKC412, an inhibitor of FLT-3 kinase activity, is being clinically evaluated in AML. Present studies demonstrate that treatment of human acute leukemia MV4-11 cells (containing a FLT-3 LM) with the heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin (17-AAG) attenuated the levels of FLT-3 by inhibiting its chaperone association with heat shock protein 90, which induced the poly-ubiquitylation and proteasomal degradation of FLT-3. Treatment with 17-AAG induced cell cycle G(1) phase accumulation and apoptosis of MV4-11 cells. 17-AAG-mediated attenuation of FLT-3 and p-FLT-3 in MV4-11 cells was associated with decrease in the levels of p-AKT, p-ERK1/2, and p-STAT5, as well as attenuation of the DNA binding activity of STAT-5. Treatment with 17-AAG, downstream of STAT5, reduced the levels of c-Myc and oncostatin M, which are transactivated by STAT5. Cotreatment with 17-AAG and PKC412 markedly down-regulated the levels of FLT-3, p-FLT-3, p-AKT, p-ERK1/2, and p-STAT5, as well as induced more apoptosis of MV4-11 cells than either agent alone. Furthermore, the combination of 17-AAG and PKC412 exerted synergistic cytotoxic effects against MV4-11 cells. Importantly, 17-AAG and PKC412 induced more loss of cell viability of primary AML blasts containing FLT-3 LM, as compared with those that contained wild-type FLT-3. Collectively, these in vitro findings indicate that the combination of 17-AAG and PKC412 has high level of activity against AML cells with FLT-3 mutations.
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PMID:Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. 1515 Jan 24

Heat shock protein 90 (Hsp90) is a molecular chaperone that stabilizes growth factor receptors and signaling molecules. Disruption of this action inhibits the MAPK and phosphatidylinositol-3 kinase cascades and can induce cancer cell death. The goal of this study was to determine whether thyroid cancer cells are sensitive to the cytotoxic effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor in clinical trials, and to determine predictors of this response. Papillary (NPA), follicular (WRO), and anaplastic (ARO) thyroid cancers were incubated with 17-AAG in vitro. Surprisingly, the ARO cells were most sensitive to the cytotoxic effects of this agent. Conversely, all cell lines displayed similar responses to specific blockers of phosphatidylinositol-3 kinase and MAPK kinase (LY294002 and U0126, respectively). Western blot demonstrated that the NPA cells that were most resistant to 17AAG-induced cytotoxicity had the lowest levels of Hsp90 and were the only cells with persistent levels of Akt protein. Interestingly, even the WRO and ARO cell lines that were sensitive to 17-AAG-induced cell death did not undergo apoptosis. These data suggest that sensitivity of thyroid cancer cells to 17-AAG-induced cytotoxicity relates to Hsp90 levels rather than histological subtype and that thyroid cancer cells have a reduced apoptotic response to 17-AAG.
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PMID:17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlates with heat shock protein 90 levels. 1518 Oct 88

Present studies show that LBH589, a novel cinnamic hydroxamic acid analog histone deacetylase inhibitor, induces acetylation of histone H3 and H4 and of heat shock protein 90 (hsp90), increases p21 levels, as well as induces cell-cycle G(1) phase accumulation and apoptosis of the human chronic myeloid leukemia blast crisis (CML-BC) K562 cells and acute leukemia MV4-11 cells with the activating length mutation of FLT-3. In MV4-11 cells, this was associated with marked attenuation of the protein levels of p-FLT-3, FLT-3, p-AKT, and p-ERK1/2. In K562 cells, exposure to LBH589 attenuated Bcr-Abl, p-AKT, and p-ERK1/2. Treatment with LBH589 inhibited the DNA binding activity of signal transducers and activators of transcription 5 (STAT5) in both K562 and MV4-11 cells. The hsp90 inhibitor 17-allyl-amino-demethoxy geldanamycin (17-AAG) also induced polyubiquitylation and proteasomal degradation of FLT-3 and Bcr-Abl by reducing their chaperone association with hsp90. Cotreatment with LBH589 and 17-AAG exerted synergistic apoptosis of MV4-11 and K562 cells. In the imatinib mesylate (IM)-refractory leukemia cells expressing Bcr-Abl with the T315I mutation, treatment with the combination attenuated the levels of the mutant Bcr-Abl and induced apoptosis. Finally, cotreatment with LBH589 and 17-AAG also induced more apoptosis of IM-resistant primary CML-BC and acute myeloid leukemia (AML) cells (with activating mutation of FLT-3) than treatment with either agent alone.
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PMID:Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. 1551 6


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