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Anti-Cancer Agent Siramesine Induces Selective Cathepsin Induced Cell Death

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The putative anticancer drug siramesine selectively kills cancer cells via a caspase independent programmed cell death pathway involving the lysosomes. Siramesine is accumulated in the lysosomes where it induces a rapid rise in lysosomal pH followed by a release of lysosomal proteases (cathepsins), lysosomal accumulation of lipid, and subsequently cell death (Ostenfeld et al., 2005; Ostenfeld et al., 2008). The background for the selectivity against cancer cells however remains unknown. Here we investigated the differences in uptake of the drug, timeframe- and amount of effects on Src transformed murine embryonic fibroblasts and the non-transformed counterparts. Src transformed cells had increased bulk endocytosis but they did not accumulate higher amounts of siramesine indicating another uptake mechanism of the drug. Studies on model membranes showed that siramesine could permeabilize lipid membranes. These two results combined with knowledge about the chemical structure of siramesine as an amphiphilic weak base indicated that siramesine passively diffused across cellular membranes and was trapped in the acidic lysosomes. The action of siramesine on lysosomal pH and release of cathepsins was similar for the transformed and non-transformed cells, but the Src transformed cells had larger amounts of cathepsins, which, when released could prove fatal for the cells.

Ostenfeld, M., Fehrenbacher, N., Høyer-Hansen, M., Thomsen, C., Farkas, T., Jäättelä, M. (2005). Effective Tumor Cell Death by ó-2 Receptor Ligand Siramesine Involves Lysosomal Leakage and Oxidative Stress. Cancer Res. 65, 8975–8983.

Ostenfeld, M., Høyer-Hansen, M., Bastholm, L., Fehrenbacher N., Olsen, O., Groth-Pedersen, L., Puustinen, P., Kirkegaard-Sørensen, T., Nylandsted, J., Farkas, T., Jäättelä, M. (2008) Anti-Cancer Agent Siramesine is a Lysosomotropic Detergent that Induces Cytoprotective Autophagosome Accumulation. Unpublished.
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Document Type: Abstract

Affiliations: 1: Apoptosis Department, Kræftens Bekæmpelse, 2100 København Ø 2: MEMPHYS, Syddansk Universitet, Campusvej 55, 5230 Odense M

Publication date: 2008-05-01

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