Effective tumor cell death by σ-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress

Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel sigma-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Sir...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-10, Vol.65 (19), p.8975-8983
Main Authors: OSTENFELD, Marie Stampe, FEHRENBACHER, Nicole, HØYER-HANSEN, Maria, THOMSEN, Christian, FARKAS, Thomas, JÄÄTTELÄ, Marja
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Biological and medical sciences
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Caspases - metabolism
Cathepsins - metabolism
Cell Line, Transformed
Cell Line, Tumor
Cytochromes c - metabolism
Female
Fibrosarcoma - drug therapy
Fibrosarcoma - metabolism
Fibrosarcoma - pathology
General aspects
Humans
Indoles - pharmacology
Ligands
Lysosomes - drug effects
Lysosomes - metabolism
Medical sciences
Mice
Mice, Inbred BALB C
NIH 3T3 Cells
Oxidative Stress - drug effects
Pharmacology. Drug treatments
Receptors, sigma - metabolism
Spiro Compounds - pharmacology
Tumor Suppressor Protein p53 - metabolism
Xenograft Model Antitumor Assays
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Summary:Acquired resistance to classic caspase-mediated apoptosis is a common problem for the treatment of human cancer. Here, we show that siramesine, a novel sigma-2 receptor ligand, effectively induces caspase-independent programmed cell death in immortalized and transformed cells of various origins. Siramesine-treated tumor cells displayed increased levels of reactive oxygen species, lysosomal membrane permeabilization, chromatin condensation, and shrinkage and detachment of cells. Lipid antioxidants (alpha-tocopherol and gamma-tocopherol), but not other tested antioxidants (butylated hydroxyanisol or N-acetyl cysteine), effectively inhibited siramesine-induced morphologic changes and cell death. Cathepsin B inhibitors (CA-074-Me and R-2525) conferred similar, but less pronounced protection, whereas ectopic expression of antiapoptotic protein Bcl-2, lack of wild-type p53 as well as pharmacologic inhibitors of caspases (zVAD-fmk, DEVD-CHO, and LEHD-CHO), calpains (PD150606), and serine proteases (N-tosyl-L-phenylalanine chloromethyl ketone and pefabloc) failed to protect cells against siramesine-induced death. Importantly, transformation of murine embryonic fibroblasts with activated c-src or v-Ha-ras oncogenes greatly sensitized them to siramesine-induced cytotoxicity. Furthermore, p.o. administration of well-tolerated doses of siramesine had a significant antitumorigenic effect in orthotopic breast cancer and s.c. fibrosarcoma models in mice. These results present siramesine as a promising new drug for the treatment of tumors resistant to traditional therapies.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-05-0269