SEARCH:   Advanced

Blood, 15 November 2005, Vol. 106, No. 10, pp. 3584-3593. Prepublished online as a Blood First Edition Paper on July 28, 2005; DOI 10.1182/blood-2005-02-0711. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-02-0711v1 106/10/3584    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Walter, R. B. Articles by Banker, D. E. Search for Related Content PubMed PubMed Citation Articles by Walter, R. B. Articles by Banker, D. E. Related Collections Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism Roland B. Walter, Jason L. Pirga, Michelle R. Cronk, Sasha Mayer, Frederick R. Appelbaum, and Deborah E. Banker From the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. The peripheral benzodiazepine receptor (pBR) ligand, PK11195, promotes mitochondrial apoptosis and blocks P-glycoprotein (Pgp)-mediated drug efflux to chemosensitize cancer cells at least as well or better than the Pgp modulator, cyclosporine A (CSA). We now show that PK11195 broadly inhibits adenosine triphosphate (ATP)-binding cassette (ABC) transporters in hematologic cancer cell lines and primary leukemia-cell samples, including multidrug resistance protein (MRP), breast cancer resistance protein (BCRP), and/or Pgp. Ectopic expression models confirmed that pBR can directly mediate chemosensitizing by PK11195, presumably via mitochondrial activities, but showed that pBR expression is unnecessary to PK11195-mediated efflux inhibition. PK11195 binds plasma-membrane sites in Pgp-expressing cells, stimulates Pgp-associated adenosine triphosphatase (ATPase) activity, and causes conformational changes in Pgp, suggesting that PK11195 modulates Pgp-mediated efflux by direct transporter interaction(s). PK11195 and CSA bind noncompetitively in Pgp-expressing cells, indicating that PK11195 interacts with Pgp at sites that are distinct from CSA-binding sites. Importantly, PK11195 concentrations that were effective in these in vitro assays can be safely achieved in patients. Because PK11195 promotes chemotherapy-induced apoptosis by a pBR-dependent mitochondrial mechanism and broadly blocks drug efflux by an apparently pBR-independent, ABC transporter-dependent mechanism, PK11195 may be a useful clinical chemosensitizer in cancer patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Favreau, L. Rossard, K. Zhang, T. Desurmont, E. Manguy, A. Belliard, S. Fabre, J. Liu, Z. Han, R. Thuillier, et al. Expression and modulation of translocator protein and its partners by hypoxia reoxygenation or ischemia and reperfusion in porcine renal models Am J Physiol Renal Physiol, July 1, 2009; 297(1): F177 - F190. [Abstract] [Full Text] [PDF] A. F. Santidrian, A. M. Cosialls, L. Coll-Mulet, D. Iglesias-Serret, M. de Frias, D. M. Gonzalez-Girones, C. Campas, A. Domingo, G. Pons, and J. Gil The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells Haematologica, December 1, 2007; 92(12): 1631 - 1638. [Abstract] [Full Text] [PDF] A. Mookerjee, J. Mookerjee Basu, P. Dutta, S. Majumder, S. Bhattacharyya, J. Biswas, S. Pal, P. Mukherjee, S. Raha, R. N. Baral, et al. Overcoming Drug-Resistant Cancer by a Newly Developed Copper Chelate through Host-Protective Cytokine-Mediated Apoptosis. Clin. Cancer Res., July 15, 2006; 12(14): 4339 - 4349. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020