Gemcitabine sensitization by Chk1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells

Show simple item record Parsels, LA en Morgan, MA en Tanska, DM en Parsels, JD en Palmer, Brian en Booth, RJ en Denny, William en Canman, CE en Kraker, AJ en Lawrence, TS en Maybaum, J en 2011-11-17T17:21:16Z en 2009 en
dc.identifier.citation Molecular Cancer Therapeutics 8:45-54 2009 en
dc.identifier.issn 1535-7163 en
dc.identifier.uri en
dc.description.abstract The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD- 321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3or M-Panc96 en
dc.language EN en
dc.publisher American Association for Cancer Research en
dc.relation.ispartofseries Molecular Cancer Therapeutics en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.subject S-PHASE CHECKPOINT en
dc.subject CDC25A PHOSPHATASE en
dc.subject CHK1 INHIBITORS en
dc.subject HISTONE H2AX en
dc.subject REPLICATION en
dc.subject ABROGATION en
dc.subject PATHWAY en
dc.title Gemcitabine sensitization by Chk1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells en
dc.type Journal Article en
dc.identifier.doi 10.1158/1535-7163.MCT-08-0662 en
pubs.issue 1 en
pubs.begin-page 45 en
pubs.volume 8 en
dc.rights.holder Copyright: American Association for Cancer Research en
dc.identifier.pmid 19139112 en
pubs.end-page 54 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 88893 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 19139112 en

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