Multiple signal transduction pathways are involved in G₂/M growth arrest and apoptosis induced by the immunomodulator AS101 in multiple myeloma

The organotellurium compound, AS101, induces G2/M growth arrest and apoptosis in multiple myeloma (MM) cell lines. To characterize the mechanism by which AS101 promotes these effects, an antibody microarray analysis was performed, comparing levels of proteins and phosphoproteins in untreated versus AS101-treated mouse 5T33 MM cells. We found that AS101 down-regulated Ilk-1, Cdc25C and phosphorylation of Plk-1 on Thr210, all of which can affect the onset of mitosis or cell survival. In addition, AS101 inhibited the activity of a high molecular weight matrix metalloproteinase complex corresponding to the MMP-9/NGAL complex. Another signaling pathway that was affected by AS101 involves p53 and p65/RelA. Levels of both proteins were elevated upon treatment with AS101. Thus, multiple signaling pathways are involved in the G2/M growth arrest and apoptosis induced by AS101 in multiple myeloma, suggesting that if one pathway becomes unresponsive, the therapeutic effect of AS101 might persist through alternative pathways.