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

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.

[1]  A. Cartmell,et al.  Bortezomib, ascorbic acid and melphalan (BAM) therapy for patients with newly diagnosed multiple myeloma: an effective and well‐tolerated frontline regimen , 2009, European journal of haematology.

[2]  O. Sezer.  Myeloma bone disease: recent advances in biology, diagnosis, and treatment. , 2009, The oncologist.

[3]  M. Boccadoro,et al.  Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. , 2008, Blood.

[4]  J. Bradner,et al.  HDAC6 inhibition enhances 17-AAG--mediated abrogation of hsp90 chaperone function in human leukemia cells. , 2008, Blood.

[5]  Bin Jiang,et al.  Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. , 2008, The New England journal of medicine.

[6]  H. Einsele,et al.  Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma , 2008, Leukemia.

[7]  Lisa L. Smith,et al.  Rituximab and 17‐allylamino‐17‐demethoxygeldanamycin induce synergistic apoptosis in B‐cell chronic lymphocytic leukaemia , 2007, British journal of haematology.

[8]  O. Sezer,et al.  Bortezomib inhibits human osteoclastogenesis , 2007, Leukemia.

[9]  O. Sezer,et al.  Osteoblasts promote migration and invasion of myeloma cells through upregulation of matrix metalloproteinases, urokinase plasminogen activator, hepatocyte growth factor and activation of p38 MAPK , 2007, British journal of haematology.

[10]  M. Dimopoulos,et al.  The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma , 2007, Leukemia.

[11]  R. Hájek,et al.  An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. , 2007, European journal of cancer.

[12]  J. Kersey,et al.  Synergism between Etoposide and 17-AAG in Leukemia Cells: Critical Roles for Hsp90, FLT3, Topoisomerase II, Chk1, and Rad51 , 2007, Clinical Cancer Research.

[13]  G. Kroemer,et al.  Heat Shock Proteins 27 and 70: Anti-Apoptotic Proteins with Tumorigenic Properties , 2006, Cell cycle.

[14]  P. Atadja,et al.  The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. , 2006, Cancer research.

[15]  Vincenzo Callea,et al.  Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial , 2006, The Lancet.

[16]  S. Alkan,et al.  Analysis of expression of heat shock protein-90 (HSP90) and the effects of HSP90 inhibitor (17-AAG) in multiple myeloma , 2006, Leukemia & lymphoma.

[17]  P. Marks,et al.  Histone deacetylase inhibitors: discovery and development as anticancer agents , 2005, Expert opinion on investigational drugs.

[18]  T. Libermann,et al.  Antimyeloma activity of heat shock protein-90 inhibition. , 2005, Blood.

[19]  S. Lindquist,et al.  HSP90 and the chaperoning of cancer , 2005, Nature Reviews Cancer.

[20]  R. Mesa,et al.  Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. , 2005, Blood.

[21]  S Fruehauf,et al.  Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL – Inhibition of P-glycoprotein function by 17-AAG , 2005, Leukemia.

[22]  Srinivas Annavarapu,et al.  Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. , 2005, Blood.

[23]  O. Sezer,et al.  Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion , 2003, Journal of Cancer Research and Clinical Oncology.

[24]  A. Olshen,et al.  Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. , 2003, Cancer research.

[25]  L. Norton,et al.  Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. See: E. A. Sausville, Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters, Clin. Cancer Res., 7: 2155- , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  E. Sausville,et al.  Combining cytotoxics and 17-allylamino, 17-demethoxygeldanamycin: sequence and tumor biology matters. Commentary re: P. Münster et al., Modulation of Hsp90 function by ansamycins sensitizes breast cancer cells to chemotherapy-induced apoptosis in an RB- and schedule-dependent manner. Clin. Cancer Re , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  A I Pick,et al.  THE TREATMENT OF MULTIPLE MYELOMA , 1948, Harefuah.

[28]  O. Sezer,et al.  Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma , 2008, Leukemia.

[29]  P. Kloetzel,et al.  The effects of the histone deacetylase inhibitor valproic acid on cell cycle, growth suppression and apoptosis in multiple myeloma. , 2006, Haematologica.

[30]  J. Bradner,et al.  INHIBITION OF HISTONE DEACETYLASE 6 ACETYLATES AND DISRUPTS THE CHAPERONE FUNCTION OF HEAT SHOCK PROTEIN 90: A NOVEL BASIS OF ANTILEUKEMIA ACTIVITY OF HISTONE DEACETYLASE INHIBITORS , 2005 .

[31]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.

[32]  O. Cope,et al.  Multiple myeloma. , 1948, The New England journal of medicine.