Genomes and Genes
Summary: LACTAMS forming compounds with a ring size of approximately 1-3 dozen atoms.
- Lang S, Klein D, Moser C, Gaumann A, Glockzin G, Dahlke M, et al. Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Mol Cancer Ther. 2007;6:1123-32 pubmed..Hence, gastric cancer harbors attractive molecular targets for therapy with Hsp90 inhibitors, which could lead to improved efficacy of antineoplastic therapy regimens. ..
- Tse A, Klimstra D, Gonen M, Shah M, Sheikh T, Sikorski R, et al. A phase 1 dose-escalation study of irinotecan in combination with 17-allylamino-17-demethoxygeldanamycin in patients with solid tumors. Clin Cancer Res. 2008;14:6704-11 pubmed publisher..The combination of irinotecan and 17AAG can be given to patients with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m(2) irinotecan and 300 mg/m(2) 17AAG. ..
- Harrison E, Sharpe E, Bellamy C, McNally S, Devey L, Garden O, et al. Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2008;295:F397-405 pubmed publisher..Therefore, HBAs mediate upregulation of protective Hsps in mouse kidneys which are associated with reduced I/R injury and may be useful in reducing transplant-associated kidney injury. ..
- Oda T, Hayano T, Miyaso H, Takahashi N, Yamashita T. Hsp90 regulates the Fanconi anemia DNA damage response pathway. Blood. 2007;109:5016-26 pubmed
- Powers M, Workman P. Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. Endocr Relat Cancer. 2006;13 Suppl 1:S125-35 pubmed..We also review the discovery and development of novel small-molecule inhibitors and discuss alternative approaches to inhibit HSP90 activity, both of which offer exciting prospects for the future. ..
- Herbst M, Wanker E. Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation. A possible therapeutic strategy. Neurodegener Dis. 2007;4:254-60 pubmed..We suggest that geldanamycin derivatives such as 17-DMAG should be considered for the development of a drug treatment for polyQ disorders and other neurodegenerative diseases involving protein aggregation. ..
- Wetzler M, Earp J, Brady M, Keng M, Jusko W. Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity--pharmacodynamic drug-drug interaction modeling. Clin Cancer Res. 2007;13:2261-70 pubmed..These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity. ..
- Ramanathan R, Egorin M, Eiseman J, Ramalingam S, Friedland D, Agarwala S, et al. Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers. Clin Cancer Res. 2007;13:1769-74 pubmed..The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70. ..
- Burkitt M, Magee C, O Connor D, Campbell F, Cornford P, Greenhalf W. Potentiation of chemotherapeutics by the Hsp90 antagonist geldanamycin requires a steady serum condition. Mol Carcinog. 2007;46:466-75 pubmed
- Yamano T, Mizukami S, Murata S, Chiba T, Tanaka K, Udono H. Hsp90-mediated assembly of the 26 S proteasome is involved in major histocompatibility complex class I antigen processing. J Biol Chem. 2008;283:28060-5 pubmed publisher..Our results indicate that hsp90 facilitates MHC class I antigen processing through epitope production in a complex of the 26 S proteasome. ..
- Modi S, Stopeck A, Gordon M, Mendelson D, Solit D, Bagatell R, et al. Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study. J Clin Oncol. 2007;25:5410-7 pubmed..These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth. ..
- Lang S, Moser C, Gaumann A, Klein D, Glockzin G, Popp F, et al. Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1alpha autocrine loop, and reduces ort. Clin Cancer Res. 2007;13:6459-68 pubmed..Therefore, we suggest that Hsp90 inhibitors could prove to be valuable in the treatment of pancreatic cancer. ..
- Holmes J, Sharp S, Hobbs S, Workman P. Silencing of HSP90 cochaperone AHA1 expression decreases client protein activation and increases cellular sensitivity to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 2008;68:1188-97 pubmed publisher..Furthermore, AHA1 knockdown could sensitize cancer cells to 17-AAG. We conclude that modulation of AHA1 might be a potential therapeutic strategy to increase sensitivity to HSP90 inhibitors. ..
- Pare J, Tahbaz N, López Orozco J, LaPointe P, Lasko P, Hobman T. Hsp90 regulates the function of argonaute 2 and its recruitment to stress granules and P-bodies. Mol Biol Cell. 2009;20:3273-84 pubmed publisher..Together, our data suggest that Hsp90 is a critical modulator of Argonaute function. Moreover, we propose that Ago2 and PACT form a complex that functions at the level of SGs. ..
- Gaspar N, Sharp S, Pacey S, Jones C, Walton M, Vassal G, et al. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res. 2009;69:1966-75 pubmed publisher..In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in GB, melanoma, and, possibly, other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. ..
- Clark C, Rane M, El Mehdi D, Miller C, Sachleben L, Gozal E. Role of oxidative stress in geldanamycin-induced cytotoxicity and disruption of Hsp90 signaling complex. Free Radic Biol Med. 2009;47:1440-9 pubmed publisher..These differences between MEN- and GA-induced cytotoxicity may allow more specific targeting of cancer cells. ..
- Caplan A, Mandal A, Theodoraki M. Molecular chaperones and protein kinase quality control. Trends Cell Biol. 2007;17:87-92 pubmed..This requirement might relate to conformational changes that take place during the protein kinase activity cycle. ..
- Liu Y, Baek J, Zhang H, Diez R, Cole R, Semenza G. RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. Mol Cell. 2007;25:207-17 pubmed..Thus, RACK1 is an essential component of an O(2)/PHD/VHL-independent mechanism for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex. ..
- Ryhanen T, Mannermaa E, Oksala N, Viiri J, Paimela T, Salminen A, et al. Radicicol but not geldanamycin evokes oxidative stress response and efflux protein inhibition in ARPE-19 human retinal pigment epithelial cells. Eur J Pharmacol. 2008;584:229-36 pubmed publisher..05) radicicol, but not in geldanamycin-treated RPE cells. These novel findings help in understanding the influence of HSP90 inhibition and regulatory mechanisms of drug delivery to retinal cells. ..
- Kabakov A, Makarova Y, Malyutina Y. Radiosensitization of human vascular endothelial cells through Hsp90 inhibition with 17-N-allilamino-17-demethoxygeldanamycin. Int J Radiat Oncol Biol Phys. 2008;71:858-65 pubmed publisher..These findings characterize 17AAG as a promising radiosensitizer for the tumor vasculature. ..
- Babchia N, Calipel A, Mouriaux F, Faussat A, Mascarelli F. 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci. 2008;49:2348-56 pubmed publisher..Uveal melanoma cells express WT B-Raf and only rarely express V600E B-Raf. This study was conducted to investigate the effects of HSP90 inhibition on uveal melanoma cell lines...
- Solit D, Ivy S, Kopil C, Sikorski R, Morris M, Slovin S, et al. Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res. 2007;13:1775-82 pubmed..The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies. ..
- Schumacher J, Crockett D, Elenitoba Johnson K, Lim M. Proteome-wide changes induced by the Hsp90 inhibitor, geldanamycin in anaplastic large cell lymphoma cells. Proteomics. 2007;7:2603-16 pubmed..Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects. ..
- Banerji U, Affolter A, Judson I, Marais R, Workman P. BRAF and NRAS mutations in melanoma: potential relationships to clinical response to HSP90 inhibitors. Mol Cancer Ther. 2008;7:737-9 pubmed publisher..These preliminary results suggest that BRAF and NRAS mutation status should be determined in prospective phase II studies of HSP90 inhibitors in melanoma. ..
- Siegelin M, Habel A, Gaiser T. 17-AAG sensitized malignant glioma cells to death-receptor mediated apoptosis. Neurobiol Dis. 2009;33:243-9 pubmed publisher..In addition, over-expression of survivin attenuated cytotoxicity induced by the combination of 17-AAG and TRAIL. In summary, survivin is a key regulator of TRAIL-17-AAG mediated cell death in malignant glioma. ..
- Wu X, Wanders A, Wardega P, Tinge B, Gedda L, Bergstrom S, et al. Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin. Br J Cancer. 2009;100:334-43 pubmed publisher..Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy. ..
- Koll T, Feis S, Wright M, Teniola M, Richardson M, Robles A, et al. HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair. Mol Cancer Ther. 2008;7:1985-92 pubmed publisher..Thus, administration of HSP90 inhibitors before radiation is critical for optimizing their use as radiosensitizers. ..
- Song D, Chaerkady R, Tan A, Garcia Garcia E, Nalli A, Suarez Gauthier A, et al. Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol Cancer Ther. 2008;7:3275-84 pubmed publisher..In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling. ..
- Gooljarsingh L, Fernandes C, Yan K, Zhang H, Grooms M, Johanson K, et al. A biochemical rationale for the anticancer effects of Hsp90 inhibitors: slow, tight binding inhibition by geldanamycin and its analogues. Proc Natl Acad Sci U S A. 2006;103:7625-30 pubmed..In the broader context, these studies highlight the essentiality of detailed biochemical characterization of drug-target interactions for the effective translation of in vitro pharmacology to cellular and in vivo efficacy. ..
- Guo W, Reigan P, Siegel D, Zirrolli J, Gustafson D, Ross D. Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res. 2005;65:10006-15 pubmed..In conclusion, these studies have shown that reduction of 17-AAG by NQO1 generates 17-AAGH2, a relatively stable hydroquinone that exhibits superior Hsp90 inhibition. ..
- da Rocha Dias S, Friedlos F, Light Y, Springer C, Workman P, Marais R. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res. 2005;65:10686-91 pubmed..Our data show that B-RAF is an important target for 17-AAG in human cancer. ..
- Grbovic O, Basso A, Sawai A, Ye Q, Friedlander P, Solit D, et al. V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc Natl Acad Sci U S A. 2006;103:57-62 pubmed..Hsp90 inhibition represents a therapeutic strategy for the treatment of melanoma. ..
- Dey A, Cederbaum A. Geldanamycin, an inhibitor of Hsp90, potentiates cytochrome P4502E1-mediated toxicity in HepG2 cells. J Pharmacol Exp Ther. 2006;317:1391-9 pubmed..These results suggest that Hsp90 is protective against CYP2E1-dependent oxidant stress and loss of cell viability in HepG2 cells. ..
- Keppler B, Grady A, Jarstfer M. The biochemical role of the heat shock protein 90 chaperone complex in establishing human telomerase activity. J Biol Chem. 2006;281:19840-8 pubmed..We propose that the hsp90-p23 complex fine tunes and stabilizes a functional telomerase structure, allowing primer loading and extension. ..
- Wang K, Ma Q, Ren Y, He J, Zhang Y, Zhang Y, et al. Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/beta-catenin signaling in HER2 overexpressing human breast cancer cells. Oncol Rep. 2007;17:89-96 pubmed..These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast cancers. ..
- Robles A, Wright M, Gandhi B, Feis S, Hanigan C, Wiestner A, et al. Schedule-dependent synergy between the heat shock protein 90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin and doxorubicin restores apoptosis to p53-mutant lymphoma cell lines. Clin Cancer Res. 2006;12:6547-56 pubmed
- Mitsiades C, Mitsiades N, McMullan C, Poulaki V, Kung A, Davies F, et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood. 2006;107:1092-100 pubmed
- Guo F, Rocha K, Bali P, Pranpat M, Fiskus W, Boyapalle S, et al. Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res. 2005;65:10536-44 pubmed..Collectively, these data indicate that induction of hsp70 attenuates the apoptotic effects of 17-AAG, and abrogation of hsp70 induction significantly enhances the antileukemia activity of 17-AAG. ..
- Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland L, Valenti M, et al. Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino, 17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res. 2005;11:7023-32 pubmed..Pharmacokinetic-pharmacodynamic relationships were established for 17-AAG. This information formed the basis of a pharmacokinetic-pharmacodynamic-driven phase I trial. ..
- Zsebik B, Citri A, Isola J, Yarden Y, Szollosi J, Vereb G. Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1. Immunol Lett. 2006;104:146-55 pubmed
- Paduano F, Villa R, Pennati M, Folini M, Binda M, Daidone M, et al. Silencing of survivin gene by small interfering RNAs produces supra-additive growth suppression in combination with 17-allylamino-17-demethoxygeldanamycin in human prostate cancer cells. Mol Cancer Ther. 2006;5:179-86 pubmed..These findings suggest that combined strategies aimed at interfering with the survivin-Hsp90 connection may provide novel approaches for treatment of androgen-independent prostate cancer. ..
- Bauer S, Yu L, Demetri G, Fletcher J. Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res. 2006;66:9153-61 pubmed..The dramatic inactivation of imatinib-resistant KIT oncoproteins suggests that HSP90 inhibition provides a therapeutic solution to the challenge of heterogeneous imatinib resistance mutations in GIST patients. ..
- Niikura Y, Ohta S, Vandenbeldt K, Abdulle R, McEwen B, Kitagawa K. 17-AAG, an Hsp90 inhibitor, causes kinetochore defects: a novel mechanism by which 17-AAG inhibits cell proliferation. Oncogene. 2006;25:4133-46 pubmed
- Waza M, Adachi H, Katsuno M, Minamiyama M, Tanaka F, Doyu M, et al. Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein. J Mol Med (Berl). 2006;84:635-46 pubmed..This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases...
- Noguchi M, Yu D, Hirayama R, Ninomiya Y, Sekine E, Kubota N, et al. Inhibition of homologous recombination repair in irradiated tumor cells pretreated with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Biochem Biophys Res Commun. 2006;351:658-63 pubmed..Our data demonstrate for the first time that 17-AAG inhibits the HR repair process and could provide a new therapeutic strategy to selectively result in higher tumor cell killing. ..
- Moulick K, Clement C, Aguirre J, Kim J, Kang Y, Felts S, et al. Synthesis of a red-shifted fluorescence polarization probe for Hsp90. Bioorg Med Chem Lett. 2006;16:4515-8 pubmed..The synthesis of a red-shifted cy3B-GM ligand and its evaluation as a fluorescence polarization probe for Hsp90 is presented. ..
- Machida H, Nakajima S, Shikano N, Nishio J, Okada S, Asayama M, et al. Heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin potentiates the radiation response of tumor cells grown as monolayer cultures and spheroids by inducing apoptosis. Cancer Sci. 2005;96:911-7 pubmed..The findings suggest that 17AAG effectively sensitizes radioresistant cells to radiation by inhibiting the PI3K-Akt pathway. Targeting the PI3K-Akt pathway with 17AAG could be a useful strategy for radiosensitization of carcinomas. ..
- Georgakis G, Li Y, Rassidakis G, Martinez Valdez H, Medeiros L, Younes A. Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death. Clin Cancer Res. 2006;12:584-90 pubmed
- Yocum A, Busch C, Felix C, Blair I. Proteomics-based strategy to identify biomarkers and pharmacological targets in leukemias with t(4;11) translocations. J Proteome Res. 2006;5:2743-53 pubmed..This work represents one of the most comprehensive proteomics screens of MLL leukemias that have been conducted to date. ..
- Hieronymus H, Lamb J, Ross K, Peng X, Clement C, Rodina A, et al. Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006;10:321-30 pubmed..Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy. ..