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In present study, the molecular apoptotic mechanisms induced by two kinds of TCNAs, designated as DOXY and COL\u20103 (chemically modified tetracycline\u20103; 6\u2010demethyl, 6\u2010deoxy, 4\u2010dedimethylamino tetracycline), were evaluated in cultured HT29 cells. Both TCNAs inhibited the proliferation of 6 different colorectal cancer cell lines in a dose\u2010dependent manner. Especially, COL\u20103 had a stronger effect on cancer cells than DOXY. Apoptotic changes were actually observed by 10 \u03bcg\/ml COL\u20103 and 20 \u03bcg\/ml DOXY in a time\u2010dependent manner. COL\u20103 produced the increase in cytosolic cytochrome <jats:italic>c<\/jats:italic> and the loss of mitochondrial membrane potential after 3 hr treatment, and thereafter activated caspases. In case of DOXY, these changes were observed after 24 hr. Bax translocation was not a prerequisite for cytochrome <jats:italic>c<\/jats:italic> releasing in COL\u20103 treatment. Pretreated pancaspase inhibitor (Z\u2010VAD\u2010FMK) reduced COL\u20103 and DOXY mediated apoptosis up to 81.3 and 35.3%, as compared with nontreated cells, respectively. These data indicated that TCNAs could induce mitochondria\u2010mediated apoptosis through both caspase\u2010dependent and \u2010independent pathway. In fact, endonuclease G and apoptosis\u2010inducing factor were released into cytosol after the treatment of TCNAs, which indicated that caspase\u2010independent apoptotic pathway is also one of the key mechanisms for the treatment of TCNAs. Taken together, we believe that TCNAs could have strong potentials for clinical application in treating colorectal cancers and improve cancer chemotherapy. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.21447","type":"journal-article","created":{"date-parts":[[2005,9,8]],"date-time":"2005-09-08T17:19:01Z","timestamp":1126199941000},"page":"1309-1315","source":"Crossref","is-referenced-by-count":81,"title":["Tetracycline analogues (doxycycline and COL\u20103) induce caspase\u2010dependent and \u2010independent apoptosis in human colon cancer cells"],"prefix":"10.1002","volume":"118","author":[{"given":"Toshinao","family":"Onoda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipok 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