Arsenic trioxide induces G2/M growth arrest and apoptosis after caspase-3 activation and bcl-2 phosphorylation in promonocytic U937 cells

Arsenic trioxide has recently been shown to inhibit growth and induce apopt osis in acute promyelocytic leukemia (APL), but little is known about the m olecular mechanisms mediating these effects. Here we demonstrate that treat ment of promonocytic U937 cells with arsenic trioxide leads to G2/M arrest which was associated with a dramatic increase in the levels of cyclin B and cyclin B-dependent kinase and apoptosis. We further show that apoptosis oc curs after bcl-2 phosphorylation and caspase-3 activation followed by cleav age of PARP and PLC-gamma1 degradation and DNA fragmentation. The arsenic t rioxide-induced apoptosis could be blocked by the protein synthesis inhibit or cycloheximide. In addition, pretreatment of U937 cells with the DNA poly merase inhibitor aphidicolin also blocked apoptosis, but did not cause the arrest of cells in the G2/M phase. The findings suggest that arsenic trioxi de exerts its growth-inhibitory effects by modulating expression and/or act ivity of several key G2/M regulatory proteins. Furthermore, arsenic trioxid e-mediated G2/M arrest correlates with the onset of apoptosis. (C) 2001 Aca demic Press.