title: Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma.
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, suberoylanilide hydroxamic acid (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 h preincubation with SAHA followed by another 48 h 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.
authors.affiliation: Department of Hematology and Oncology, Charité- Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.forename: Britta
authors.initials: B
authors.lastname: Lamottke
authors.forename: Maren
authors.initials: M
authors.lastname: Mieth
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Peter
authors.initials: P
authors.lastname: Atadja
authors.forename: Ulrike
authors.initials: U
authors.lastname: Heider
authors.forename: Ivana
authors.initials: I
authors.lastname: von Metzler
authors.forename: Seval
authors.initials: S
authors.lastname: Türkmen
authors.forename: Orhan
authors.initials: O
authors.lastname: Sezer
mesh_terms: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000819:agonists / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000819:agonists / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D008558:Melphalan / Q000819:agonists / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D012118:Resorcinols / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D007555:Isoxazoles; D012118:Resorcinols; D004317:Doxorubicin; D006655:Histone Deacetylases; D008558:Melphalan