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Sci. STKE, 11 January 2005
Vol. 2005, Issue 266, p. tw17
[DOI: 10.1126/stke.2662005tw17]



Many antineoplastic drugs elicit DNA damage, thereby activating p53-dependent apoptotic pathways. The existence of p53 mutations in many cancers thus likely contributes to drug resistance. Erdal et al. exposed p53 wild-type and p53–/– cultured HCT116 colon carcinoma cell lines to each of 879 compounds (the National Cancer Institute mechanistic diversity set, known to cause growth inhibition through different mechanisms) in an effort to identify drugs that elicited apoptosis independently of p53. Of these, 175 compounds elicited apoptosis [assessed with an enzyme-linked immunosorbent assay (ELISA) for caspase-cleaved cytokeratin-18] at a concentration of 5 μM or less. Further analysis of 15 compounds that induced apoptosis with little or no dependence on p53 expression indicated that Bax was required for apoptosis with all 15 and that 11 of them activated caspase-3 (assessed by flow cytometry) in enucleated cells, suggesting a cytoplasmic target. Vital staining with Acridine Orange indicated that seven of the drugs with cytoplasmic targets caused permeabilization of lysosomal membranes; moreover, these seven compounds stimulated translocation of the proteases cathepsin B and cathepsin D from lysosomes to cytoplasm. Pepstatin A, a cathepsin D inhibitor, partially inhibited apoptosis in response to these seven compounds. The authors concluded that these drugs stimulated a p53-independent pathway to apoptosis that involved lysosomal permeabilization and that drugs using such a mechanism might be useful in cancer therapy.

H. Erdal, M. Berndtsson, J. Castro, U. Brunk, M. C. Shoshan, S. Linder, Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Proc. Natl. Acad. Sci. U.S.A. 102, 192-197 (2005). [Abstract] [Full Text]

Citation: Bypassing p53. Sci. STKE 2005, tw17 (2005).

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