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Abstract
BackgroundThe 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.ResultsUsing 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.ConclusionsThese results suggest that monoketone analogs of curcumin are potent inhibitors of the FA pathway and constitute a promising new class of targeted anticancer compounds.
Highlights
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
This is due in part to the successful treatment of BRCA-deficient tumors with PARP1 inhibitors [8,9], which demonstrated that taking advantage of the synthetic lethal relationship between two DNA damage genes is a valid approach for the development of novel targeted therapies in oncology
Using curcumin as a lead we identified EF24, a monoketone analog with improved activity and specificity toward the FA pathway
Summary
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. Two genes have a synthetic lethal relationship if mutants for either gene are viable but the double mutation is lethal [7] Targeting this particular type of genetic interaction in tumors is currently the subject of intense development due to the promising results of clinical trials using PARP inhibitors in BRCA1/2-deficient breast tumors [8,9]. ATM is a major kinase involved in the sensing and repair of DNA double-strand breaks by homologous recombination [13] Germline mutations in this gene cause the Ataxia Telangectasia cancer susceptibility syndrome [14], and ATM deficiencies (mutations or lack of expression) are frequent in sporadic hematological malignancies such as chronic lymphocytic leukemia [15] and mantle cell lymphoma [16]. Because deficiency in the FA pathway is not lethal [2], specific inhibitors are expected to display low toxicity toward normal cells but kill tumor cells deficient in ATM or other genes with synthetic lethal relationships to the FA pathway
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