Naphthalene (1) and para-dichlorobenzene (PDCB, 2), which are widely used as moth repellents and air fresheners, cause cancer in rodents and are potential human carcinogens. However, their mechanisms of action remain unclear. Here we describe a novel method for delivering and screening hydrophobic chemicals in C. elegans and apply this technique to investigate the ways in which naphthalene and PDCB may promote tumorigenesis in mammals. We show that naphthalene and PDCB inhibit apoptosis in C. elegans, a result that suggests a cellular mechanism by which these chemicals may promote the survival and proliferation of latent tumor cells. In addition, we find that a naphthalene metabolite directly inactivates caspases by oxidizing the active site cysteine residue; this suggests a molecular mechanism by which these chemicals suppress apoptosis. Naphthalene and PDCB are the first small-molecule apoptosis inhibitors identified in C. elegans. The power of C. elegans molecular genetics, in combination with the possibility of carrying out large-scale chemical screens in this organism, makes C. elegans an attractive and economic animal model for both toxicological studies and drug screens.
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We thank T. Blumenthal, M. Han, M. Stowell, S. Copley and members of the Xue lab for comments and discussions and H.R. Horvitz and P. Sternberg for strains. This work was supported by the US National Institutes of Health R01 grants (GM59083 and GM66262) and a Burroughs Wellcome Fund Career Award (D.X.).
The authors declare no competing financial interests.
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Kokel, D., Li, Y., Qin, J. et al. The nongenotoxic carcinogens naphthalene and para-dichlorobenzene suppress apoptosis in Caenorhabditis elegans. Nat Chem Biol 2, 338–345 (2006). https://doi.org/10.1038/nchembio791
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