Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis

被引:114
作者
Kitamura, K
Minami, Y
Yamamoto, K
Akao, Y
Kiyoi, H
Saito, H
Naoe, T
机构
[1] Nagoya Univ, Sch Med, Dept Infect Dis, Showa Ku, Nagoya, Aichi 4668550, Japan
[2] Nagoya Univ, Sch Med, Dept Internal Med 1, Showa Ku, Nagoya, Aichi 4668550, Japan
[3] Gifu Int Inst Biotechnol, Gifu, Japan
关键词
acute promyelocytic leukemia; apoptosis; arsenic trioxide; caspase; 8;
D O I
10.1038/sj.leu.2401900
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Arsenic trioxide (As2O3)-treatment is effective in acute promyelocytic leukemia (APL) patients with t(15;17). Clinically achievable concentrations of As2O3 induce apoptosis in NB4, an APL cell line, in vitro. Here, to study the mechanism of As2O3-induced apoptosis, we established an As2O3-resistant subline, NB4/As. Growth of NB4/As was inhibited by 50% after 2 day-treatment (IC50) at 1.6 mu M As2O3, whereas IC50 of NB4 was 0.3 mu M. Degradation of PML-RAR alpha and change of the PML-subcellular localization were similarly induced by As2O3 in NB4 and NB4/As, suggesting that their contribution to apoptosis is small. Treatment with 1 mu M As2O3 induced the activation of caspase 3 as well as a loss of mitochondrial transmembrane potential (Delta Psi m) in NB4 but not in NB4/As. Caspase 8 and Bid were also activated by As2O3 in NB4 but not in NB4/As. In NB4, an inhibitor of caspase 8 blocked not only the activation of caspase 3 but also the loss of Delta Psi m. Neither cell line expressed CD95/Fas, and agonistic anti-Fas antibody (CH-11) failed to cause apoptosis. Neither antagonistic anti-CD95/Fas antibody nor anti-fas ligand antibodies influenced the As2O3-induced apoptosis. NB4/As had a higher concentration of intracellular glutathione (GSH) than NB4 (96 vs 32 nmol/mg). Reduction of the GSH level by buthionine sulfoxide (BSO) completely restored the sensitivity to As2O3 in NB4/As. Furthermore, caspase activation and the loss of Delta Psi m were recovered by combination treatment with BSO. These findings suggest that the As2O3 treatment activates caspase 8 in a CD95-independent but GSH concentration-dependent manner. In combination with BSO, As2O3 might be applied to therapy of leukemia/cancers which are insensitive to the clinically achievable concentrations of As2O3.
引用
收藏
页码:1743 / 1750
页数:8
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