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

• 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
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-0269

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.