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XB-ART-40788
Mol Cancer 2009 Dec 31;8:133. doi: 10.1186/1476-4598-8-133.
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Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors.

Landais I , Hiddingh S , McCarroll M , Yang C , Sun A , Turker MS , Snyder JP , Hoatlin ME .


Abstract
The Fanconi anemia (FA) pathway is a multigene DNA damage response network implicated in the repair of DNA lesions that arise during replication or after exogenous DNA damage. The FA pathway displays synthetic lethal relationship with certain DNA repair genes such as ATM (Ataxia Telangectasia Mutated) that are frequently mutated in tumors. Thus, inhibition of FANCD2 monoubiquitylation (FANCD2-Ub), a key step in the FA pathway, might target tumor cells defective in ATM through synthetic lethal interaction. Curcumin was previously identified as a weak inhibitor of FANCD2-Ub. The aim of this study is to identify derivatives of curcumin with better activity and specificity. Using a replication-free assay in Xenopus extracts, we screened monoketone analogs of curcumin for inhibition of FANCD2-Ub and identified analog EF24 as a strong inhibitor. Mechanistic studies suggest that EF24 targets the FA pathway through inhibition of the NF-kB pathway kinase IKK. In HeLa cells, nanomolar concentrations of EF24 inhibited hydroxyurea (HU)-induced FANCD2-Ub and foci in a cell-cycle independent manner. Survival assays revealed that EF24 specifically sensitizes FA-competent cells to the DNA crosslinking agent mitomycin C (MMC). In addition, in contrast with curcumin, ATM-deficient cells are twofold more sensitive to EF24 than matched wild-type cells, consistent with a synthetic lethal effect between FA pathway inhibition and ATM deficiency. An independent screen identified 4H-TTD, a compound structurally related to EF24 that displays similar activity in egg extracts and in cells. These results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.

PubMed ID: 20043851
PMC ID: PMC2807854
Article link: Mol Cancer
Grant support: [+]

Species referenced: Xenopus
Genes referenced: apcs atm chuk fanca fancd2 h2ac21 h2ax h2ax
GO keywords: DNA repair

Disease Ontology terms: pancytopenia [+]
OMIMs: FANCONI ANEMIA, COMPLEMENTATION GROUP D2; FANCD2

Article Images: [+] show captions
References [+] :
Adams, Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. 2004, Pubmed