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Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma

Kaiser, M and Lamottke, B and Mieth, M and Jensen, Michael Rugaard and Quadt, Cornelia and Garcia-Echeverria, Carlos and Atadja, Peter and Heider, U and von Metzler, I and Turkmen, S and Sezer, O (2009) Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma. European Journal of Haematology, 84 (4). pp. 337-344. ISSN 0902-4441

Abstract

Abstract Heat shock protein 90 (HSP90) is a promising target for tumor therapy. The novel HSP90 inhibitor NVP-AUY922 has preclinical activity in multiple myeloma, however, little is known about effective combination partners to design clinical studies. Multiple myeloma cell lines, OPM-2, RPMI-8226, U-266, LP-1, MM1.S and primary myeloma cells were exposed to NVP-AUY922 and one of the combination partners histone deacetylase inhibitor NVP-LBH589, SAHA, melphalan or doxorubicin, either simultaneously or in sequential patterns. Effects on cell proliferation and apoptosis were determined. Synergistic effects were evaluated using the method of Chou and Talalay. Combined sequential incubation with NVP-AUY922 and SAHA showed that best synergistic effects were achieved with 24 hours pre-incubation with SAHA followed by another 48 hours of combination treatment. Combination of NVP-AUY922 with SAHA, NVP-LBH589, melphalan or doxorubicin resulted in synergistic inhibition of viability, with strong synergy (combination index < 0.3) in the case of melphalan. Importantly, resistance of the RPMI-8226 cell line and relative resistance of some primary myeloma cells against NVP-AUY922 could be overcome by combination treatment. These data show impressive synergistic action of the novel HSP90 inhibitor NVP-AUY922 with melphalan, doxorubicin, NVP-LBH589 and SAHA in multiple myeloma and build the frame work for clinical trials.

Item Type: Article
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Additional Information: Archiving not allowed on institutional repository
Keywords: multiple myeloma; heat shock protein; histone deacetylase; melphalan; doxorubicin
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2292

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