Open AccessInvolvement of mitochondrial aggregation in arsenic trioxide (As 2 O 3 )‐induced apoptosis in human glioblastoma cells
Author(s) -
Haga Naomi,
Fujita Naoya,
Tsuruo Takashi
Publication year - 2005
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2005.00114.x
Subject(s) - arsenic trioxide , apoptosis , arsenic , glioblastoma , mitochondrion , cancer research , chemistry , trioxide , microbiology and biotechnology , biology , biochemistry , sulfur , organic chemistry
Arsenic trioxide (As 2 O 3 ) is effective against acute promyelocytic leukemia and has potential as a novel treatment against malignant solid tumors. As 2 O 3 induces differentiation and inhibits growth. It also causes mitochondrial damage mediated by the production of reactive oxygen species (ROS) and the dissipation of mitochondrial transmembrane potential (ΔΨ m ), leading to apoptosis. Mitochondria might be the key target of antitumor activity by As 2 O 3 ; however, its mechanisms have not been completely elucidated. Using two human glioblastoma cell lines, A172 and T98G, we found that As 2 O 3 induced apoptosis in A172 cells but not in T98G cells. As 2 O 3 ‐induced ROS production was observed in both cell lines; however, the dissipation of ΔΨ m , Bax oligomerization and caspase activation occurred only in As 2 O 3 ‐sensitive A172 cells. To determine the mechanisms of As 2 O 3 ‐induced apoptosis after ROS generation, we examined the change of mitochondrial morphology. As we reported previously, mitochondrial aggregation occurs before cytochrome c release during apoptosis, thus playing a role in cell death progression. We observed mitochondrial aggregation in As 2 O 3 ‐sensitive A172 cells but not in T98G cells treated with As 2 O 3 . Using laser scanning cytometry, we quantitatively confirmed the results, which indicate that mitochondrial aggregation plays an important role in regulating sensitivity to As 2 O 3 ‐induced apoptosis. We propose a sequential process involving ROS generation, mitochondrial aggregation, Bax oligomerization and ΔΨ m dissipation, and caspase activation during As 2 O 3 ‐induced apoptosis. ( Cancer Sci 2005; 96: 825–833)