Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells

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Abstract
Arsenic trioxide (As2O3), an effective drug for the treatment of acute promyelocytic leukemia (APL), can induce apoptosis and partial differentiation in APL cells in vitro and in vivo. However, As2O3 also induces apoptosis in cancer cells other than APL with complex mechanisms, which seem to be cell type dependent. In this study, we report that APL cells (NB4 cell line) are arrested at early mitotic phase before the collapse of mitochondrial transmembrane potential (Δϕm) and apoptosis after treatment with pharmacological concentrations (1.0–2.0 μM) of As2O3. We have also made the following new discoveries: (1) 0.5 μM As2O3 that fails to induce apoptosis has no effects on cell cycle distribution. (2) With inhibition of As2O3-induced Δϕm collapse and apoptosis, dithiothreitol also effectively inhibits As2O3-induced mitotic arrest, suggesting that both As2O3-induced apoptosis and mitotic arrest involve proteins with thiol groups. (3) 1.5 mM caffeine that relieves cells from G2/M arrest also inhibits As2O3-induced Δϕm collapse and apoptosis, (4) 1.0 μM As2O3 increases the expression of both cyclin B1 and hCDC20 whereas it inhibits Tyr15 phosphorylation of p34cdc2. In conclusion, our results strongly support that there is a tight link between As2O3-induced apoptosis and mitotic arrest, the latter being one of common mechanisms for As2O3-induced apoptosis in cancer cells.