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[Cancer Research 65, 8975-8983, October 1, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Effective Tumor Cell Death by {sigma}-2 Receptor Ligand Siramesine Involves Lysosomal Leakage and Oxidative Stress

Marie Stampe Ostenfeld1, Nicole Fehrenbacher1, Maria Høyer-Hansen1, Christian Thomsen2, Thomas Farkas1 and Marja Jäättelä1

1 Apoptosis Department, Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark and 2 Molecular Pharmacology and Neurochemistry, H. Lundbeck A/S, Valby, Denmark

Requests for reprints: Marja Jäättelä, Apoptosis Department, Institute for Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Phone: 45-35257318; Fax: 45-35257721; E-mail: mj{at}cancer.dk.

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.




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Copyright © 2005 by the American Association for Cancer Research.