GenomeRNAi - a database for RNAi phenotypes and reagents
TitleScreen TitleAssayBiomodelSpecies
Small interfering RNA screens reveal enhanced cisplatin cytotoxicity in tumor cells having both BRCA network and TP53 disruptions. Bartz et al. (2006) Combinatorial effect with anticancer drugs (2): gemcitabine Viability (synthetic lethal)HeLaH. sapiens

Abstract

RNA interference technology allows the systematic genetic analysis of the molecular alterations in cancer cells and how these alterations affect response to therapies. Here we used small interfering RNA (siRNA) screens to identify genes that enhance the cytotoxicity (enhancers) of established anticancer chemotherapeutics. Hits identified in drug enhancer screens of cisplatin, gemcitabine, and paclitaxel were largely unique to the drug being tested and could be linked to the drug''s mechanism of action. Hits identified by screening of a genome-scale siRNA library for cisplatin enhancers in TP53-deficient HeLa cells were significantly enriched for genes with annotated functions in DNA damage repair as well as poorly characterized genes likely having novel functions in this process. We followed up on a subset of the hits from the cisplatin enhancer screen and validated a number of enhancers whose products interact with BRCA1 and/or BRCA2. TP53(+/-) matched-pair cell lines were used to determine if knockdown of BRCA1, BRCA2, or validated hits that associate with BRCA1 and BRCA2 selectively enhances cisplatin cytotoxicity in TP53-deficient cells. Silencing of BRCA1, BRCA2, or BRCA1/2-associated genes enhanced cisplatin cytotoxicity approximately 4- to 7-fold more in TP53-deficient cells than in matched TP53 wild-type cells. Thus, tumor cells having disruptions in BRCA1/2 network genes and TP53 together are more sensitive to cisplatin than cells with either disruption alone.

Screen details


Stable Id: GR00101-A-2
Screen title: Combinatorial effect with anticancer drugs (2): gemcitabine
Assay: Viability (synthetic lethal)
Method: Alamar Blue
Scope: Selected genes
Screen type: Cell-based
Species: Homo sapiens
Biosource: Cell line
Biomodel: HeLa
Library: Sigma-Proligo, rp
Reagent type: siRNA
Score type: log2 ratio
Cutoff: 2 standard deviations from mean ratio
Notes: Additional information about the primary genome-wide screen