The role of mitochondrial targeting in arsenic trioxide‐induced apoptosis in myeloid cell lines

Abstract

Summary Data regarding the role of mitochondria in arsenic trioxide (As2O3)‐induced apoptosis are controversial. We investigated the contribution of caspases and mitochondrial depolarization to As2O3‐induced apoptosis in the myeloid cell lines NB‐4, HL‐60 and U‐937. Caspase inhibition reduced the amount of cells with As2O3 (20 μmol/l)‐induced mitochondrial depolarization by about 50% in all cell lines. As2O3 also induced dose‐dependent phosphatidylserine exposure in cells without depolarized mitochondria. We conclude that caspase activation is of similar importance in As2O3‐induced apoptosis in myeloid cell lines as direct mitochondrial targeting and mitochondria are not necessary for caspase activation downstream of mitochondria.

Cytotoxic effects induced by combination of heliantriol B2 and dequalinium against human leukemic cell lines

“…It is well known that mitochondria play a critical role in initiating apoptotic cell death (Körper et al ., 2004). Therefore, we searched for HB2‐induced mitochondrial alterations related to Δ Ψ m and O 2 •− accumulation either in the absence or presence of DQA.…”

The effect of intracellular ascorbate on the susceptibility of HL60 and Jurkat cells to chemotherapy agents

“…As 2 O 3 has been shown to down-regulate the levels of the oncogene fusion protein bcr-abl, and this is thought to contribute to its ability to act against promyelocytic leukaemia [42]. Its toxicity has also been shown to depend upon the cellular reduced glutathione levels, and agents that deplete GSH can enhance As 2 O 3 toxicity [43,44]. A synergistic effect of extracellular ascorbate has been documented, and this is now thought to be due to the depletion of intracellular GSH by high extracellular concentrations of ascorbate via the production of H 2 O 2 in the culture medium, leading to apoptosis [19,45].…”

Antimony-trioxide- and arsenic-trioxide-induced apoptosis in myelogenic and lymphatic cell lines, recruitment of caspases, and loss of mitochondrial membrane potential are enhanced by modulators of the cellular glutathione redox system

“…Decrease of Ψ m was shown to play a crucial role in As 2 O 3 therapy-relevant effects [15,17]. These effects are most probably based on inhibition of enzymes of the intracellular glutathione redox system, such as glutathione peroxidase GPx [57,58], glutathione reductase GR and glutathione-S-transferase [58], resulting in an increase of ROS.…”

“…Lately, we showed that induction of apoptosis by As 2 O 3 in 22 myeloid and non-myeloid malignant cell lines of different sensitivity for cytostatic drugs, is based on breakdown of the mitochondrial membrane potential (Ψ m ) and therefore the redox system of the cell is one of the primary targets of As 2 O 3 . Activation of caspases is a downstream effect occurring after the breakdown of Ψ m [15][16][17] and release of radical oxygen species (ROS) [18][19][20][21].…”

“…As far as data were achievable and tolerable concentrations of the different substances in vivo were available (BSO, NaAsc, NaSal), we have chosen concentrations within this range. For As 2 O 3 and Sb 2 O 3 we have chosen incubation times and concentrations as we previously published for As 2 O 3 [15,17,22]. The As 2 O 3 concentrations are in the range of peak values of clinically achievable As 2 O 3 plasma levels as shown by pharmacokinetic analysis [10].…”