FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2009561809> ?p ?o ?g. }

• W2009561809 abstract "Heat shock protein 90 (HSP90) is a molecular chaperone that regulates the functional stability of client oncoproteins, which is driven by the binding and hydrolysis of ATP. The geldanamycin analog, 17-AAG, binds to the ATP pocket of HSP90 leading to the degradation of client proteins such as Akt, p53, STAT3, Bcr-Abl, and Pim-1. Pim (Pim-1, -2, -3) kinases are constitutively active serine/threonine kinases overexpressed in hematological malignancies such as chronic lymphocytic leukemia (CLL). Pim kinases have several substrates which are involved in gene transcription, protein translation, cell proliferation, and apoptosis. AZD1208 is a small molecule Pim kinase inhibitor currently in clinical trials. The PI3K-dependent activation of AKT (a client protein of HSP90) and the JAK/STAT-dependent induction of PIM are partially overlapping kinase pathways. Therefore, we hypothesized that the mechanism-based combination of 17-AAG (to decrease AKT levels) with AZD1208 (to inhibit Pim kinases) will result in an increase in cytotoxicity in CLL cells. An AZD1208 dose-response experiment was performed in 4 CLL patient samples to determine the optimal cytotoxic concentrations. AZD1208 concentrations of 3 μM and 10 μM were selected to treat 22 additional CLL patient samples for 24 hours. Cell death ranged from 0-30% and 2-45%, respectively, as determined by Annexin-V/PI staining after subtraction of endogenous cell death. All CLL patient samples were sensitive to AZD1208 regardless of their prognostic markers such as IgVH mutation and ZAP70 positivity or cytogenetics such as 17p del (p53 locus) or 11q del (ATM locus). Similarly, prior treatment history or Rai stage did not influence the biological response of AZD1208 in CLL cells. Based on published data, 0.5 μM and 2 μM 17-AAG were selected for the combination treatments with AZD1208 for 24 and 48 hours. Cytotoxicity for these combinations was assessed in 13 CLL blood samples, resulting in additive (n=8) or more than additive (n=3) cell death when using the fractional two-drug combination analysis. Immunoblot analysis was performed in 3 CLL samples probing for HSP90, HSP70, Akt, Pim-1, Mcl-1, Bcl-2, Phospho-4E-BP1 (Thr37/46), 4E-BP1, and β-actin. In agreement with previous work, 17-AAG treatment resulted in an increase of HSP90 and HSP70 protein levels while Akt levels were markedly decreased. In these preliminary immunoblots, Pim-1 and Bcl-2 levels remained unchanged; however, Mcl-1 protein levels decreased in the combination treatments at 24 and 48 hours. Levels for total and phospho-4E-BP1 also declined. Taken together, these preliminary data indicate that AZD1208 (at 3 and 10 μM) has a modest cytotoxic effect in CLL cells. However, when combined with 17-AAG for 24 and 48 hours there was an additive or more than additive effect in majority of CLL samples, with the possible mechanisms of action being through the Akt and 4E-BP1 pathways. Citation Format: Fabiola Gomez, Lisa Chen, William Wierda, Varsha Gandhi. In vitro effect of AZD1208 (Pim Kinase Inhibitor) and 17-AAG (HSP90 Inhibitor) combination in CLL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2057. doi:10.1158/1538-7445.AM2013-2057" @default.
• W2009561809 created "2016-06-24" @default.
• W2009561809 creator A5009161783 @default.
• W2009561809 creator A5024454882 @default.
• W2009561809 creator A5087082314 @default.
• W2009561809 creator A5089428686 @default.
• W2009561809 date "2013-04-15" @default.
• W2009561809 modified "2023-09-26" @default.
• W2009561809 title "Abstract 2057: In vitro effect of AZD1208 (Pim Kinase Inhibitor) and 17-AAG (HSP90 Inhibitor) combination in CLL." @default.
• W2009561809 doi "https://doi.org/10.1158/1538-7445.am2013-2057" @default.
• W2009561809 hasPublicationYear "2013" @default.
• W2009561809 type Work @default.
• W2009561809 sameAs 2009561809 @default.
• W2009561809 citedByCount "0" @default.
• W2009561809 crossrefType "proceedings-article" @default.
• W2009561809 hasAuthorship W2009561809A5009161783 @default.
• W2009561809 hasAuthorship W2009561809A5024454882 @default.
• W2009561809 hasAuthorship W2009561809A5087082314 @default.
• W2009561809 hasAuthorship W2009561809A5089428686 @default.
• W2009561809 hasConcept C104317684 @default.
• W2009561809 hasConcept C11960822 @default.
• W2009561809 hasConcept C184235292 @default.
• W2009561809 hasConcept C185592680 @default.
• W2009561809 hasConcept C205260736 @default.
• W2009561809 hasConcept C2775932338 @default.
• W2009561809 hasConcept C2780297055 @default.
• W2009561809 hasConcept C502942594 @default.
• W2009561809 hasConcept C55493867 @default.
• W2009561809 hasConcept C62478195 @default.
• W2009561809 hasConcept C75217442 @default.
• W2009561809 hasConcept C86554907 @default.
• W2009561809 hasConcept C86803240 @default.
• W2009561809 hasConcept C95444343 @default.
• W2009561809 hasConceptScore W2009561809C104317684 @default.
• W2009561809 hasConceptScore W2009561809C11960822 @default.
• W2009561809 hasConceptScore W2009561809C184235292 @default.
• W2009561809 hasConceptScore W2009561809C185592680 @default.
• W2009561809 hasConceptScore W2009561809C205260736 @default.
• W2009561809 hasConceptScore W2009561809C2775932338 @default.
• W2009561809 hasConceptScore W2009561809C2780297055 @default.
• W2009561809 hasConceptScore W2009561809C502942594 @default.
• W2009561809 hasConceptScore W2009561809C55493867 @default.
• W2009561809 hasConceptScore W2009561809C62478195 @default.
• W2009561809 hasConceptScore W2009561809C75217442 @default.
• W2009561809 hasConceptScore W2009561809C86554907 @default.
• W2009561809 hasConceptScore W2009561809C86803240 @default.
• W2009561809 hasConceptScore W2009561809C95444343 @default.
• W2009561809 hasLocation W20095618091 @default.
• W2009561809 hasOpenAccess W2009561809 @default.
• W2009561809 hasPrimaryLocation W20095618091 @default.
• W2009561809 hasRelatedWork W1442691200 @default.
• W2009561809 hasRelatedWork W144793029 @default.
• W2009561809 hasRelatedWork W2017597339 @default.
• W2009561809 hasRelatedWork W2026076652 @default.
• W2009561809 hasRelatedWork W2289079909 @default.
• W2009561809 hasRelatedWork W2318778072 @default.
• W2009561809 hasRelatedWork W2550174857 @default.
• W2009561809 hasRelatedWork W2558173458 @default.
• W2009561809 hasRelatedWork W2558511132 @default.
• W2009561809 hasRelatedWork W2561541746 @default.
• W2009561809 hasRelatedWork W2571045122 @default.
• W2009561809 hasRelatedWork W2575767755 @default.
• W2009561809 hasRelatedWork W2581287880 @default.
• W2009561809 hasRelatedWork W2593084911 @default.
• W2009561809 hasRelatedWork W2887762323 @default.
• W2009561809 hasRelatedWork W2919286019 @default.
• W2009561809 hasRelatedWork W2980093462 @default.
• W2009561809 hasRelatedWork W2984976086 @default.
• W2009561809 hasRelatedWork W3161908308 @default.
• W2009561809 hasRelatedWork W386996490 @default.
• W2009561809 isParatext "false" @default.
• W2009561809 isRetracted "false" @default.
• W2009561809 magId "2009561809" @default.
• W2009561809 workType "article" @default.