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The anticancer natural product chaetocin is a competitive substrate and inhibitor of thioredoxin reductase at achieved intracellular concentrations.

3282 We recently reported that the antineoplastic natural product chaetocin is dramatically accumulated in cancer cells and potently induces cellular ROS, consequently selectively killing cancer cells in vitro and in vivo (Isham et al., Blood 2007;109:2579-2588). However, chaetocin does not deplete intracellular reduced glutathione, leading to uncertainty as to underlying molecular mechanisms. We now report that chaetocin is a competitive and selective substrate for the oxidative stress mitigation enzyme thioredoxin reductase-1 (TrxR1) with lower K m than the TrxR1 native substrate thioredoxin (Trx; chaetocin K m =4.6 ± 0.6 μM, Trx K m =104.7 ± 26 μM), and that chaetocin thereby attenuates TrxR1-reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. Moreover, we determined that intact disulfides are required for TrxR1 inhibition, that chaetocin disulfides are reduced by TrxR1, and that structurally-related thiodioxopiperazines including gliotoxin and chetomin also inhibit TrxR1, albeit less potently than chaetocin. Consistent with a role for TrxR1 targeting in the anticancer effects of chaetocin, overexpression of the TrxR1 downstream effector Trx in HeLa cells conferred resistance to chaetocin-induced - but not to doxorubicin-induced - cytotoxicity. As the TrxR/Trx pathway is of central importance in limiting cellular reactive oxygen species (ROS) - and as chaetocin exerts its selective anti-cancer effects via ROS imposition - the inhibition of TrxR1 by chaetocin has potential to explain its selective anticancer effects. These observations have important implications not just with regard to the mechanism of action and clinical development of chaetocin and related thiodioxopiperazines, but also with regard to the utility of the thioredoxin reductase/thioredoxin pathway as a potential source of promising candidate antineoplastic molecular targets.