title: Inhibitor of apoptosis proteins as therapeutic targets in multiple myeloma.
abstract: The inhibitor of apoptosis (IAP) proteins have a critical role in the control of apoptotic machinery, and has been explored as a therapeutic target. Here, we have examined the functional importance of IAPs in multiple myeloma (MM) by using a Smac (second mitochondria-derived activator of caspases)-mimetic LCL161. We observed that LCL161 was able to potently induce apoptosis in some MM cell lines but not in others. Examining the levels of X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein 1 (cIAP1) and cellular inhibitor of apoptosis protein 2 (cIAP2) post LCL161 treatment indicated clear downregulation of both XIAP activity and cIAP1 levels in both the sensitive and less sensitive (resistant) cell lines. cIAP2, however, was not downregulated in the cell line resistant to the drug. Small interfering RNA-mediated silencing of cIAP2 significantly enhanced the effect of LCL161, indicating the importance of downregulation of all IAPs simultaneously for induction of apoptosis in MM cells. LCL161 induced marked up regulation of the Jak2/Stat3 pathway in the resistant MM cell lines. Combining LCL161 with a Jak2-specific inhibitor resulted in synergistic cell death in MM cell lines and patient cells. In addition, combining LCL161 with death-inducing ligands clearly showed that LCL161 sensitized MM cells to both Fas-ligand and TRAIL.
authors.affiliation: Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ramakrishnan
authors.affiliation: 1] Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA [2] 4th Department of Internal Medicine, Hematology University Hospital Hradec Kralove and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.
authors.forename: U
authors.initials: U
authors.lastname: Painuly
authors.affiliation: Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kimlinger
authors.affiliation: Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Haug
authors.affiliation: Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Rajkumar
authors.affiliation: Division of Hematology, Mayo Clinic and Foundation, Rochester, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology / Q000633:toxicity; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; C574246:LCL161; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D013844:Thiazoles; D053614:Janus Kinase 2; D020169:Caspases