Linked Life Data

20124459

Source:http://linkedlifedata.com/resource/pubmed/id/20124459

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-2-11
pubmed:abstractText
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1538-8514
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
347-57
pubmed:dateRevised
2011-11-2
pubmed:meshHeading
pubmed-meshheading:20124459-Animals, pubmed-meshheading:20124459-Annexin A5, pubmed-meshheading:20124459-Cell Cycle Proteins, pubmed-meshheading:20124459-Cell Line, Tumor, pubmed-meshheading:20124459-DNA Repair, pubmed-meshheading:20124459-DNA-Binding Proteins, pubmed-meshheading:20124459-Female, pubmed-meshheading:20124459-Humans, pubmed-meshheading:20124459-Lymphoma, Mantle-Cell, pubmed-meshheading:20124459-Mice, pubmed-meshheading:20124459-Neoplasm Transplantation, pubmed-meshheading:20124459-Phosphorylation, pubmed-meshheading:20124459-Phthalazines, pubmed-meshheading:20124459-Piperazines, pubmed-meshheading:20124459-Poly(ADP-ribose) Polymerases, pubmed-meshheading:20124459-Protein-Serine-Threonine Kinases, pubmed-meshheading:20124459-Radiation, Ionizing, pubmed-meshheading:20124459-Trypan Blue, pubmed-meshheading:20124459-Tumor Suppressor Proteins
pubmed:year
2010
pubmed:articleTitle
ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural