Bryostatin 1-induced modulation of nucleoside transporters and 2-chlorodeoxyadenosine influx in WSU-CLL cells

WSU-CLL cells, a fludarabine resistant B-cell chronic lymphocytic leukemia cell line, has been shown to exhibit enhanced sensitivity to 2-chlorodeoxya denosine (2-CdA) following 48-72 h exposure to bryostatin 1. For 2-CdA to m anifest its chemotherapeutic activity, it must first enter the cell through one of several specific nucleoside transporter systems. We present data to show that bryostatin 1-induced enhanced influx of 2-CdA is in part the res ult of bryostatin 1-induced modulation of nucleoside transporters in WSU-CL L cells. The bi-directional equilibrative NBMPR sensitive transporters in W SU-CLL cells were significantly down-regulated 90 min post-exposure to 1-20 0 nM bryostatin 1. This down-regulation was evident up to 144 h. In contras t, WSU-CLL cells exhibited a transient increase in Na+-dependent concentrat ive 2-CdA influx from 48 to 96 h after bryostatin 1 exposure which was evid ent for a longer duration than that accounted for by the increase in deocyc ytidine kinase activity. These data may, in part, explain the enhanced effi cacy of 2-CdA seen in WSU-CLL cells following 48-72 h exposure to bryostati n 1. It may raise questions as to the importance of the bi-directional tran sporters in determining the resistance or sensitivity of CLL cells to 2-CdA or other nucleoside analogues.