title: 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.affiliation: Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: F W
authors.initials: FW
authors.lastname: Beck
authors.forename: A M
authors.initials: AM
authors.lastname: Al-Katib
authors.forename: I
authors.initials: I
authors.lastname: Ahmad
authors.forename: N R
authors.initials: NR
authors.lastname: Wall
authors.forename: K Z
authors.initials: KZ
authors.lastname: Liu
authors.forename: H H
authors.initials: HH
authors.lastname: Mantsch
authors.forename: R M
authors.initials: RM
authors.lastname: Mohammad
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D054713:Bryostatins; D002352:Carrier Proteins / Q000378:metabolism*; D017338:Cladribine / Q000378:metabolism*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D018942:Macrolides; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D033703:Nucleoside Transport Proteins; D010766:Phosphorylation; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; D002352:Carrier Proteins; D007783:Lactones; D018942:Macrolides; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; C046785:bryostatin 1; D013868:Thioinosine; D017338:Cladribine; D004176:Dipyridamole; D003842:Deoxycytidine Kinase; D014740:Vidarabine; C001789:4-nitrobenzylthioinosine; C024352:fludarabine