TY - JOUR
T1 - SMAC mimetic (JP1201) sensitizes non-small cell lung cancers to multiple chemotherapy agents in an IAP-dependent but TNF-α-independent manner
AU - Greer, Rachel M.
AU - Peyton, Michael
AU - Larsen, Jill E.
AU - Girard, Luc
AU - Xie, Yang
AU - Gazdar, Adi F.
AU - Harran, Patrick
AU - Wang, Lai
AU - Brekken, Rolf A.
AU - Wang, Xiaodong
AU - Minna, John D.
PY - 2011/12/15
Y1 - 2011/12/15
N2 - 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-αsecretion. 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.
AB - 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-αsecretion. 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.
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U2 - 10.1158/0008-5472.CAN-10-3947
DO - 10.1158/0008-5472.CAN-10-3947
M3 - Article
C2 - 22049529
AN - SCOPUS:84255192023
SN - 0008-5472
VL - 71
SP - 7640
EP - 7648
JO - Cancer research
JF - Cancer research
IS - 24
ER -