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

Abstract

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.

• Authors: Marie Stampe Ostenfeld, Nicole Fehrenbacher, Maria Høyer-Hansen, Christian Thomsen, Thomas Farkas, Marja Jäättelä
• Journal: Cancer research (Cancer Res) Vol. 65 Issue 19 Pg. 8975-83 (Oct 01 2005) ISSN: 0008-5472 [Print] United States
• PMID: 16204071 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Ligands
• Lu 28-179
• Receptors, sigma
• Spiro Compounds
• Tumor Suppressor Protein p53
• sigma-2 receptor
• Cytochromes c
• Cathepsins
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Cathepsins (metabolism)
• Cell Line, Transformed
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Female
• Fibrosarcoma (drug therapy, metabolism, pathology)
• Humans
• Indoles (pharmacology)
• Ligands
• Lysosomes (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NIH 3T3 Cells
• Oxidative Stress (drug effects)
• Receptors, sigma (metabolism)
• Spiro Compounds (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays