Involvement of mitochondrial aggregation in arsenic trioxide (As2O3)-induced apoptosis in human glioblastoma cells

Arsenic trioxide (As2O3) is effective against acute promyelocytic leukemia and has potential as a novel treatment against malignant solid tumors. As2O3 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 (Delta Psi(m)), leading to apoptosis. Mitochondria might be the key target of antitumor activity by As2O3; however, its mechanisms have not been completely elucidated. Using two human glioblastoma cell lines, A172 and T98G, we found that As2O3 induced apoptosis in A172 cells but not in T98G cells. As2O3-induced ROS production was observed in both cell lines; however, the dissipation of Delta Psi(m) Bax oligomerization and caspase activation occurred only in As2O3-sensitive A172 cells. To determine the mechanisms of As2O3-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 As2O3. Using laser scanning cytometry, we quantitatively confirmed the results, which indicate that mitochondrial aggregation plays an important role in regulating sensitivity to As2O3-induced apoptosis. We propose a sequential process involving ROS generation, mitochondrial aggregation, Bax oligomerization and Delta Psi(m) dissipation, and caspase activation during As2O3-induced apoptosis.