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

Abstract

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 microM As2O3, whereas IC50 of NB4 was 0.3 microM. Degradation of PML-RARalpha 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 microM As2O3 induced the activation of caspase 3 as well as a loss of mitochondrial transmembrane potential (deltapsim) 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 deltapsim. 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 deltapsim 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.

• Authors: K Kitamura, Y Minami, K Yamamoto, Y Akao, H Kiyoi, H Saito, T Naoe
• Journal: Leukemia (Leukemia) Vol. 14 Issue 10 Pg. 1743-50 (Oct 2000) ISSN: 0887-6924 [Print] England
• PMID: 11021749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arsenicals
• Oxides
• fas Receptor
• CASP8 protein, human
• CASP9 protein, human
• Caspase 8
• Caspase 9
• Caspases
• Glutathione
• Arsenic Trioxide

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology, therapeutic use)
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Enzyme Activation
• Glutathione (metabolism)
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy, pathology)
• Oxides (pharmacology, therapeutic use)
• Tumor Cells, Cultured
• fas Receptor (immunology)