期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 346, 期 1, 页码 242-251出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2006.05.106
关键词
quinols; glutathione; BSO; apoptosis induction
Novel heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(7-benzenesulfonyl-1H-indol-2-yl)-4hydroxycyclohexa-2,5-dienone (2) are promising novel anticancer agents. They exhibit in vitro antiproliferative activity against colon, renal, and breast carcinoma cell lines as well as in vivo antitumor activity in colon, renal, and breast tumor xenografts. Elucidation of the mechanism of antitumor action of these compounds is of great importance. We show in this study that the compounds induced apoptosis as demonstrated by caspase 3 and PARP cleavage at doses causing G(2)/M cell cycle arrest. Glutathione was found to play an important role in modulating quinol-mediated cytotoxicity. In HCT 116 cells, treatment with 1 and 2 caused a 2- to 3-fold increase in the total glutathione content, suggestive of a glutathione-mediated antioxidant response. Indeed, buthionine sulfoximine (BSO)-induced glutathione depleted cells were 6-10 times more sensitive to 1 and 2, while glutathione monoethyl ester supplementation decreased the antitumor potencies by 2-3 times. In further studies we determined other cellular proteins which bind to an immobilized quinol analog, and identified several proteins including beta-tubulin, heat shock protein 60, and peroxiredoxin l as potential molecular targets of quinols that may contribute to their proapoptotic and antiproliferative effects. 2006 Elsevier Inc. All rights reserved.
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