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Open Access Research

Monoketone analogs of curcumin, a new class of Fanconi anemia pathway inhibitors

Igor Landais1, Sanne Hiddingh1, Matthew McCarroll1, Chao Yang2, Aiming Sun2, Mitchell S Turker3, James P Snyder2 and Maureen E Hoatlin1*

Author Affiliations

1 Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, USA

2 Chemical Biology Discovery Center, Emory University, Atlanta, USA

3 Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, USA

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Molecular Cancer 2009, 8:133  doi:10.1186/1476-4598-8-133

Published: 31 December 2009

Abstract

Background

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.

Results

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.

Conclusions

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.