Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma.
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Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma. / Kaiser, Martin; Lamottke, Britta; Mieth, Maren; Jensen, Michael R; Quadt, Cornelia; Garcia-Echeverria, Carlos; Atadja, Peter; Heider, Ulrike; von Metzler, Ivana; Türkmen, Seval; Sezer, Orhan.
in: EUR J HAEMATOL, Jahrgang 84, Nr. 4, 4, 2010, S. 337-344.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Synergistic action of the novel HSP90 inhibitor NVP-AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma.
AU - Kaiser, Martin
AU - Lamottke, Britta
AU - Mieth, Maren
AU - Jensen, Michael R
AU - Quadt, Cornelia
AU - Garcia-Echeverria, Carlos
AU - Atadja, Peter
AU - Heider, Ulrike
AU - von Metzler, Ivana
AU - Türkmen, Seval
AU - Sezer, Orhan
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Humans
KW - inhibitors
KW - Cell Line, Tumor
KW - Apoptosis drug effects
KW - Multiple Myeloma drug therapy
KW - Antibiotics, Antineoplastic
KW - Antineoplastic Agents, Alkylating
KW - Cell Proliferation drug effects
KW - Cell Survival drug effects
KW - Doxorubicin agonists
KW - Drug Evaluation, Preclinical
KW - Drug Synergism
KW - HSP90 Heat-Shock Proteins antagonists
KW - Histone Deacetylase Inhibitors agonists
KW - Histone Deacetylases metabolism
KW - Isoxazoles agonists
KW - Melphalan agonists
KW - Resorcinols agonists
KW - Humans
KW - inhibitors
KW - Cell Line, Tumor
KW - Apoptosis drug effects
KW - Multiple Myeloma drug therapy
KW - Antibiotics, Antineoplastic
KW - Antineoplastic Agents, Alkylating
KW - Cell Proliferation drug effects
KW - Cell Survival drug effects
KW - Doxorubicin agonists
KW - Drug Evaluation, Preclinical
KW - Drug Synergism
KW - HSP90 Heat-Shock Proteins antagonists
KW - Histone Deacetylase Inhibitors agonists
KW - Histone Deacetylases metabolism
KW - Isoxazoles agonists
KW - Melphalan agonists
KW - Resorcinols agonists
M3 - SCORING: Zeitschriftenaufsatz
VL - 84
SP - 337
EP - 344
JO - EUR J HAEMATOL
JF - EUR J HAEMATOL
SN - 0902-4441
IS - 4
M1 - 4
ER -
