US EPA

7463061 

Journal Article 

Sigma-2 receptor ligand as a novel method for delivering a SMAC mimetic drug for treating ovarian cancer 

Zeng, C; Vangveravong, S; Mcdunn, JE; Hawkins, WG; Mach, RH 

2013 

Yes 

British Journal of Cancer
ISSN: 0007-0920
EISSN: 1532-1827 

109 

9 

2368-2377 

English 

10.1038/bjc.2013.593 

Background:The sigma-2 receptor has been validated as a biomarker for proliferating tumours. Second mitochondria-derived activator of caspase (Smac) is a protein released from mitochondria into the cytosol, leading to apoptosis. In this study, we investigated a sigma-2 ligand as a tumour-targeting drug delivery agent for treating ovarian cancer.Methods:A sigma-2 ligand, SW 43, was conjugated with a Smac mimetic compound (SMC), SW IV-52s, to form SW III-123. The delivery function of the sigma-2 moiety and cell killing mechanisms of SW III-123 were examined in human ovarian cancer cell lines.Results:SW III-123 internalisation into ovarian cancer cells was mediated by sigma-2 receptors. SW III-123, but not SW IV-52s or SW 43, exhibited potent cytotoxicity in human ovarian cancer cell lines SKOV-3, CaOV-3 and BG-1 after 24-h treatment, suggesting that the sigma-2 ligand successfully delivered SMC into ovarian cancer cells. SW III-123 induced rapid degradation of inhibitor of apoptosis proteins (cIAP1 and cIAP2), accumulation of NF-κB-inducing kinase (NIK) and phosphorylation of NF-κB p65, suggesting that SW III-123 activated both canonical and noncanonical NF-κB pathways in SKOV-3 cells. SW III-123 cleaved caspase-8, -9 and -3. Tumour necrosis factor alpha (TNFα) antibody markedly blocked SW III-123-induced cell death and caspase-3 activity in SKOV-3 cells, indicating that SW III-123 activated both intrinsic and extrinsic apoptotic pathways and induced TNFα-dependent cell death in SKOV-3 cells.Conclusion:Sigma-2 ligands are a promising tumour-targeting drug delivery agent. Sigma-2-conjugated SMC exemplifies a novel class of therapeutic drugs for treating ovarian cancer. © 2013 Cancer Research UK. 

drug delivery; IAPs; ovarian cancer; sigma-2 receptor; Smac; 1 [3,3 dimethyl 2 [2 (methylamino)propanamido]butanoyl] n (1,2,3,4 terahydronaphthalen 1 yl)pyrrolidine 2 carboxamide oxalate; 9 [10 [[1 [[3,3 dimethyl 1 oxo 1 [2 [(1,2,3,4 tetrahydronaphthalen 1 yl)carbamoyl]pyrrolidin 1 yl]butan 2 yl]amino] 1 oxopropan 2 yl]amino]decyl] 9 azabicyclo[3.3.1]nonan 3 yl (2 methoxy 5 methylphenyl)carbamate; caspase 3; caspase 8; caspase 9; immunoglobulin enhancer binding protein; inhibitor of apoptosis protein 1; inhibitor of apoptosis protein 2; second mitochondrial activator of caspase; sigma 2 opiate receptor; transcription factor RelA; tumor necrosis factor alpha; tumor necrosis factor alpha antibody; unclassified drug; apoptosis; article; cytotoxicity; female; human; human cell; ovary cancer; priority journal; protein cleavage; protein degradation; protein phosphorylation