The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis

Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL.

[1]  P. Elliott,et al.  The proteasome: a new target for novel drug therapies. , 2001, American journal of clinical pathology.

[2]  E. Estey,et al.  Phase I Study of Bortezomib in Refractory or Relapsed Acute Leukemias , 2004, Clinical Cancer Research.

[3]  Zhijian J. Chen.  Ubiquitin signalling in the NF-kappaB pathway. , 2005, Nature cell biology.

[4]  M. Weber,et al.  Increased IkappaB kinase activity is associated with activated NF-kappaB in acute myeloid blasts. , 2002, Leukemia.

[5]  Y. Rustum,et al.  Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients' colon tumors grown in SCID mice. , 2002, Cancer research.

[6]  S. Montoto,et al.  Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia , 2010, British journal of haematology.

[7]  A. Hershko,et al.  The ubiquitin system for protein degradation and some of its roles in the control of the cell division cycle* , 2005, Cell Death and Differentiation.

[8]  G. Melino.  Discovery of the ubiquitin proteasome system and its involvement in apoptosis , 2005, Cell Death and Differentiation.

[9]  Stephen W. Fesik,et al.  Promoting apoptosis as a strategy for cancer drug discovery , 2005, Nature Reviews Cancer.

[10]  S. Gibson,et al.  The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells , 2006, Apoptosis.

[11]  B. Dörken,et al.  High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. , 1996, Blood.

[12]  H. Wajant,et al.  Selective inhibition of FLICE-like inhibitory protein expression with small interfering RNA oligonucleotides is sufficient to sensitize tumor cells for TRAIL-induced apoptosis. , 2002, Molecular medicine.

[13]  B. Monsarrat,et al.  Proteasome inhibitor-induced apoptosis in acute myeloid leukemia: a correlation with the proteasome status. , 2010, Leukemia research.

[14]  J. Adams.  The development of proteasome inhibitors as anticancer drugs. , 2004, Cancer cell.

[15]  Xinyu Zhao,et al.  Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. , 2008, Leukemia research.

[16]  P. Elliott,et al.  Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  F. Khuri,et al.  The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. , 2007, Cancer research.

[18]  E. Gelmann,et al.  The ubiquitin-proteasome pathway and its role in cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  S. Soignet,et al.  A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  R. Kurzrock,et al.  Nuclear factor-κB maintains TRAIL resistance in human pancreatic cancer cells , 2006, Molecular Cancer Therapeutics.

[21]  D. Howard,et al.  Preferential induction of apoptosis for primary human leukemic stem cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Wajant,et al.  Selective Inhibition of FLICE-like Inhibitory Protein (FLIP) Expression With Small Interfering RNA Oligonucleotides (siRNAs) Is Sufficient to Sensitize Tumor Cells for TRAIL-Induced Apoptosis , 2002 .

[23]  R. Brunning,et al.  Classification of 358 Cases of Acute Myeloid Leukemia by FAB Criteria: Analysis of Clinical and Morphologic Features , 1985 .

[24]  Zhijian J. Chen.  Ubiquitin signalling in the NF-κB pathway , 2005, Nature Cell Biology.

[25]  O. Sezer,et al.  The potential of proteasome inhibitors in cancer therapy. , 2008, Expert opinion on investigational drugs.

[26]  E. Sausville,et al.  Proteasome inhibitors: a novel class of potent and effective antitumor agents. , 1999, Cancer research.

[27]  M. Smyth,et al.  TRAIL and its receptors as targets for cancer therapy , 2004, Cancer science.

[28]  G. Gores,et al.  TRAIL resistance results in cancer progression: a TRAIL to perdition? , 2006, Oncogene.

[29]  J. Adams.  Proteasome inhibition in cancer: development of PS-341. , 2001, Seminars in oncology.

[30]  A. Ciechanover,et al.  The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. , 2002, Physiological reviews.

[31]  P. Crooks,et al.  Nuclear factor‐κB as a potential therapeutic target for the novel cytotoxic agent LC‐1 in acute myeloid leukaemia , 2008, British journal of haematology.

[32]  F. Jin,et al.  Bortezomib Sensitizes Non–Hodgkin's Lymphoma Cells to Apoptosis Induced by Antibodies to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) Receptors TRAIL-R1 and TRAIL-R2 , 2007, Clinical Cancer Research.

[33]  E. Campo,et al.  Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level1 , 2007, The Journal of Immunology.

[34]  Christian Stehlik,et al.  Nuclear Factor (NF)-κB–regulated X-chromosome–linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor α–induced Apoptosis , 1998, The Journal of experimental medicine.

[35]  D. Howard,et al.  Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. , 2001, Blood.

[36]  K. McIntyre,et al.  BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. , 2003, The Journal of biological chemistry.

[37]  C. Scheidereit,et al.  Transcription factor NF-κB is constitutively activated in acute lymphoblastic leukemia cells , 2000, Leukemia.

[38]  H. Ovaa,et al.  Activity patterns of proteasome subunits reflect bortezomib sensitivity of hematologic malignancies and are variable in primary human leukemia cells , 2007, Leukemia.

[39]  E. D. de Vries,et al.  P-glycoprotein and multidrug resistance protein activities in relation to treatment outcome in acute myeloid leukemia. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  M. Weber,et al.  Increased IκB kinase activity is associated with activated NF-κB in acute myeloid blasts , 2002, Leukemia.

[41]  A. Seth,et al.  The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. , 2004, European journal of cancer.

[42]  P. Richardson,et al.  TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. , 2001, Blood.

[43]  Michael Lübbert,et al.  Acute myeloid leukemia: Epidemiology and etiology , 2006, Cancer.

[44]  B. Hylander,et al.  The anti-tumor effect of Apo2L/TRAIL on patient pancreatic adenocarcinomas grown as xenografts in SCID mice , 2005, Journal of Translational Medicine.

[45]  James R. Burke,et al.  BMS-345541 Is a Highly Selective Inhibitor of IκB Kinase That Binds at an Allosteric Site of the Enzyme and Blocks NF-κB-dependent Transcription in Mice* , 2003, The Journal of Biological Chemistry.

[46]  T. Haferlach,et al.  XIAP expression correlates with monocytic differentiation in adult de novo AML: impact on prognosis. , 2004, The hematology journal : the official journal of the European Haematology Association.

[47]  R. Kurzrock,et al.  Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. , 2006, Molecular cancer therapeutics.

[48]  P. Elliott,et al.  The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. , 2003, Blood.

[49]  A. Kolb,et al.  TRAIL/bortezomib cotreatment is potentially hepatotoxic but induces cancer‐specific apoptosis within a therapeutic window , 2007, Hepatology.

[50]  R. Millikan,et al.  Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  M. Gulisano,et al.  Antitumor Activity of Bortezomib Alone and in Combination with Trail in Human Acute Myeloid Leukemia , 2008, Acta Haematologica.

[52]  J. Meixensberger,et al.  Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis , 2007, Clinical Cancer Research.

[53]  T. Robak,et al.  Current and emerging therapies for acute myeloid leukemia. , 2009, Clinical therapeutics.

[54]  Francis J Giles,et al.  Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. , 2010, Blood.

[55]  E. Colado,et al.  The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype , 2008, Haematologica.

[56]  K. Tanaka,et al.  Abnormally high expression of proteasomes in human leukemic cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[57]  K. Shiraki,et al.  Cellular FLICE/Caspase-8–Inhibitory Protein as a Principal Regulator of Cell Death and Survival in Human Hepatocellular Carcinoma , 2003, Laboratory Investigation.

[58]  A. Ballestrero,et al.  Cooperative Cytotoxicity of Proteasome Inhibitors and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand in Chemoresistant Bcl-2-Overexpressing Cells , 2005, Clinical Cancer Research.

[59]  C. Peschle,et al.  M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib‐mediated apoptosis , 2007, British journal of haematology.

[60]  D. Neuberg,et al.  Phase I and Pharmacokinetic Study of Bortezomib in Combination with Idarubicin and Cytarabine in Patients with Acute Myelogenous Leukemia , 2008, Clinical Cancer Research.