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A novel 7‐azaisoindigo derivative‐induced cancer cell apoptosis and mitochondrial dysfunction mediated by oxidative stress
Author(s) -
Xu Jingjing,
Dai Xiaomin,
Liu Hailiang,
Guo Wenjie,
Gao Jing,
Wang Chaohui,
Li Wenbin,
Yao Qizheng
Publication year - 2011
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1577
Subject(s) - mitochondrion , apoptosis , programmed cell death , cytosol , reactive oxygen species , microbiology and biotechnology , hela , cytochrome c , intracellular , oxidative stress , cancer cell , biology , cell , biochemistry , cancer , genetics , enzyme
This research focused on a novel 7‐azaisoindigo derivative [namely N 1 ‐( n ‐butyl)‐7‐azaisoindigo, 7‐AI‐b], and investigated its molecular antitumor mechanism by exploring the means of cell death and the effects on mitochondrial function. 7‐AI‐b inhibited cancer cell proliferation in a dose‐ and time‐dependent way. The morphological and nuclei changes in H 2 B‐GFP‐labeled HeLa cells were observed using a live cell system. The results suggested that cell death induced by 7‐AI‐b is closely related to apoptosis. 7‐AI‐b induced release of cytochrome C from mitochondria to cytosol and activation of caspase‐3, showing that the apoptosis is mediated by the mitochondrial pathway. Furthermore, our data indicated that 7‐AI‐b triggers apoptosis through reactive oxygen species (ROS): cellular ROS levels were increased after 3 h exposure of 7‐AI‐b, which was reversed by the ROS scavenger N ‐acetyl‐ l ‐cysteine. As a consequence, 7‐AI‐b‐mediated cell death, mitochondrial transmembrane potential collapse and ATP level were partly blocked by N ‐acetyl‐ l ‐cysteine. Further study showed that 7‐AI‐b could induce mitochondrial dysfunction: collapse of the mitochondrial transmembrane potential and reduction of intracellular ATP level. In summary, the novel synthesized 7‐AI‐b was demonstrated to be effective in killing cancer cells via an ROS‐promoted and mitochondria‐ and caspase‐dependent apoptotic pathway. Copyright © 2010 John Wiley & Sons, Ltd.