title: SMAC mimetic (JP1201) sensitizes non-small cell lung cancers to multiple chemotherapy agents in an IAP-dependent but TNF-α-independent manner.
abstract: Inhibitors of apoptosis proteins (IAP) are key regulators of apoptosis and are inhibited by the second mitocondrial activator of caspases (SMAC). Previously, a small subset of TNF-α-expressing non-small cell lung cancers (NSCLC) was found to be sensitive to SMAC mimetics alone. In this study, we determined if a SMAC mimetic (JP1201) could sensitize nonresponsive NSCLC cell lines to standard chemotherapy. We found that JP1201 sensitized NSCLCs to doxorubicin, erlotinib, gemcitabine, paclitaxel, vinorelbine, and the combination of carboplatin with paclitaxel in a synergistic manner at clinically achievable drug concentrations. Sensitization did not occur with platinum alone. Furthermore, sensitization was specific for tumor compared with normal lung epithelial cells, increased in NSCLCs harvested after chemotherapy treatment, and did not induce TNF-α secretion. Sensitization also was enhanced in vivo with increased tumor inhibition and increased survival of mice carrying xenografts. These effects were accompanied by caspase 3, 4, and 9 activation, indicating that both mitochondrial and endoplasmic reticulum stress-induced apoptotic pathways are activated by the combination of vinorelbine and JP1201. Chemotherapies that induce cell death through the mitochondrial pathway required only inhibition of X-linked IAP (XIAP) for sensitization, whereas chemotherapies that induce cell death through multiple apoptotic pathways required inhibition of cIAP1, cIAP2, and XIAP. Therefore, the data suggest that IAP-targeted therapy using a SMAC mimetic provides a new therapeutic strategy for synergistic sensitization of NSCLCs to standard chemotherapy agents, which seems to occur independently of TNF-α secretion.
authors: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Rachel M
authors: RM
authors: Greer
authors: Michael
authors: M
authors: Peyton
authors: Jill E
authors: JE
authors: Larsen
authors: Luc
authors: L
authors: Girard
authors: Yang
authors: Y
authors: Xie
authors: Adi F
authors: AF
authors: Gazdar
authors: Patrick
authors: P
authors: Harran
authors: Lai
authors: L
authors: Wang
authors: Rolf A
authors: RA
authors: Brekken
authors: Xiaodong
authors: X
authors: Wang
authors: John D
authors: JD
authors: Minna
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D024101:Mitochondrial Proteins / Q000378:metabolism; D018716:Molecular Mimicry; D017239:Paclitaxel / Q000008:administration & dosage; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D014747:Vinblastine; D016190:Carboplatin; D053148:Caspase 3; D053453:Caspase 9; D017239:Paclitaxel; D000077235:Vinorelbine; D000093542:Gemcitabine