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In the present study, we present evidence that the S100A8\/A9 also exerts its apoptotic effect by a zinc-independent mechanism. Treatment of the colon carcinoma cells with different concentrations of human S100A8\/A9 or the metal ion chelator diethylenetriaminepentacetic acid (DTPA) resulted in a significant increase of cell death. Annexin V\/phosphatidylinositol and Hoechst 33258 staining revealed that cell death was mainly of the apoptotic type. A significant increase in the activity of caspase-3 and -9 was observed in both cell lines after treatment. Caspase-8 activation was negligible in both cell lines. The cytotoxicity\/apoptotic effect of human S100A8\/A9 and DTPA was inhibited significantly (P&amp;lt;0.05) by Zn+2 and Cu+2, more effectively than by Ca2+ and Mg2+. The antioxidant N-acetyl-L-cysteine inhibited the cytotoxicity\/apoptotic effect of S100A8\/A9 and DTPA. However, as a result of the different time-courses of both agents and that the S100A8\/A9-induced apoptosis was not completely reversed, we conclude that S100A8\/A9 exerts its apoptotic effect on two colon carcinoma cell lines through a dual mechanism: one via zinc exclusion from the target cells and the other through a yet-undefined mechanism, probably relaying on the cell-surface receptor(s).<\/jats:p>","DOI":"10.1189\/jlb.0903435","type":"journal-article","created":{"date-parts":[[2004,4,6]],"date-time":"2004-04-06T00:33:27Z","timestamp":1081211607000},"page":"169-175","source":"Crossref","is-referenced-by-count":127,"title":["Mechanism of apoptosis induced by S100A8\/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions"],"prefix":"10.1093","volume":"76","author":[{"given":"Saeid","family":"Ghavami","sequence":"first","affiliation":[{"name":"Cancer Research Laboratory, Clinical Biochemistry Department, School of Medical Science, Tarbiat Modarres University , Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"Kerkhoff","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology , M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marek","family":"Los","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology , M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Hashemi","sequence":"additional","affiliation":[{"name":"Cancer Research Laboratory, Clinical Biochemistry Department, School of Medical Science, Tarbiat Modarres University , Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemens","family":"Sorg","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology , M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatemeh","family":"Karami-Tehrani","sequence":"additional","affiliation":[{"name":"Cancer Research Laboratory, Clinical Biochemistry Department, School of Medical Science, Tarbiat Modarres University , Tehran, Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2004,4,1]]},"reference":[{"key":"2023033100104457900_","doi-asserted-by":"crossref","first-page":"9496","DOI":"10.1074\/jbc.272.14.9496","article-title":"Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway","volume":"272","author":"Rammes","year":"1997","journal-title":"J. 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