A novel 7-azaisoindigo derivative-induced cancer cell apoptosis and mitochondrial dysfunction mediated by oxidative stress.
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.
Xu
Jing-jing
JJ
School of Pharmacy, Jiangsu University, Zhenjiang, People's Republic of China.
Dai
Xiao-min
XM
Liu
Hai-liang
HL
Guo
Wen-jie
WJ
Gao
Jing
J
Wang
Chao-hui
CH
Li
Wen-bin
WB
Yao
Qi-zheng
QZ
D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D016166:Free Radical Scavengers; D007211:Indoles; C558729:N1-(n-butyl)-7-azaisoindigo; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; C505407:CASP3 protein, human; D053148:Caspase 3; D000111:Acetylcysteine