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Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis
Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
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2005 (Engelska)Ingår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, nr 1, s. 192-197Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set, 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at ≤5 μM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.

Ort, förlag, år, upplaga, sidor
2005. Vol. 102, nr 1, s. 192-197
Nyckelord [en]
anticancer drugs, cathepsin D, M30 antibody
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Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-24638DOI: 10.1073/pnas.0408592102Lokalt ID: 6824OAI: oai:DiVA.org:liu-24638DiVA, id: diva2:244960
Tillgänglig från: 2009-10-07 Skapad: 2009-10-07 Senast uppdaterad: 2017-12-13

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Brunk, Ulf

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Brunk, Ulf
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HälsouniversitetetFarmakologi
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Proceedings of the National Academy of Sciences of the United States of America
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