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

Abstract

WSU-CLL cells, a fludarabine resistant B-cell chronic lymphocytic leukemia cell line, has been shown to exhibit enhanced sensitivity to 2-chlorodeoxyadenosine (2-CdA) following 48-72 h exposure to bryostatin 1. For 2-CdA to manifest 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 result of bryostatin 1-induced modulation of nucleoside transporters in WSU-CLL cells. The bi-directional equilibrative NBMPR sensitive transporters in WSU-CLL cells were significantly down-regulated 90 min post-exposure to 1-200 nM bryostatin 1. This down-regulation was evident up to 144 h. In contrast, WSU-CLL cells exhibited a transient increase in Na+-dependent concentrative 2-CdA influx from 48 to 96 h after bryostatin 1 exposure which was evident for a longer duration than that accounted for by the increase in deocycytidine kinase activity. These data may, in part, explain the enhanced efficacy of 2-CdA seen in WSU-CLL cells following 48-72 h exposure to bryostatin 1. It may raise questions as to the importance of the bi-directional transporters in determining the resistance or sensitivity of CLL cells to 2-CdA or other nucleoside analogues.

• Authors: F W Beck, A M Al-Katib, I Ahmad, N R Wall, K Z Liu, H H Mantsch, R M Mohammad
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 5 Issue 4 Pg. 341-7 (Apr 2000) ISSN: 1107-3756 [Print] Greece
• PMID: 10719048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Bryostatins
• Carrier Proteins
• Lactones
• Macrolides
• Membrane Proteins
• Nucleoside Transport Proteins
• bryostatin 1
• Thioinosine
• Cladribine
• Dipyridamole
• Deoxycytidine Kinase
• Vidarabine
• 4-nitrobenzylthioinosine
• fludarabine

Topics

• Aged
• Antineoplastic Agents (pharmacology)
• Biological Transport, Active (drug effects)
• Bryostatins
• Carrier Proteins (metabolism)
• Cladribine (metabolism)
• Deoxycytidine Kinase (metabolism)
• Dipyridamole (pharmacology)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm
• Humans
• Lactones (pharmacology)
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, metabolism)
• Macrolides
• Male
• Membrane Proteins (metabolism)
• Nucleoside Transport Proteins
• Phosphorylation
• Thioinosine (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured
• Vidarabine (analogs & derivatives, pharmacology)