Comparison of Uptake and Intracellular Induced Structural Changes of Arsenic Trioxide, an Inorganic Compound, and Organic Arsenic Derivative S-Dimethylarsino-Glutathione (SGLU; ZIO-101) in NB4 Acute Promyelocytic Leukemia (APL) Cells.

Arsenic trioxide (As₂O₃; ATO) inhibits proliferation and induces apoptosis of APL cells. However, little is known about the intracellular structural changes associated with arsenic exposure. We studied effects of 2 arsenic compounds, ATO and S-dimethylarsino-glutathione (SGLU; ZIO-101) on NB4 APL cells. ZIO-101 is novel water-soluble organic arsenic derivative currently in Phase I clinical studies. Exposure of cancer cells to ZIO-101 results in G2/M cell cycle arrest and apoptosis. NB4 cells were exposed to 10, 50, 100 and 250 μM ZIO-101 or ATO for 1 h and intracellular arsenic content was determined by inductively coupled plasma mass spectrometry (ICP/MS). ZIO-101-treated cells contained 5–8 fold more arsenic then ATO-treated cells. Electron microscopy of NB4 cells exposed to 1 μM ZIO-101 or ATO for 24–72 h revealed different structural changes. ATO treated cells showed time-dependent mitochondrial hypotrophy and apoptosis, including cytoplasmic vacuolization, nuclear condensation and cell blebs. In contrast, ZIO-101 treated cells showed time-dependent mitochondrial atrophy, mitochondrial matrix condensation, and apoptosis. These data suggest that ZIO-101 is more specific mitochondrial toxin than ATO. Studies are in progress to understand the exact mechanism through which ZIO-101 affects mitochondria. Because these arsenic derivatives have different mechanism of action they may have different spectrums of activity against cancers; this should be tested in clinical trials.