TY - JOUR
T1 - The anticancer agent chaetocin is a competitive substrate and inhibitor of thioredoxin reductase
AU - Tibodeau, Jennifer D.
AU - Benson, Linda M.
AU - Isham, Crescent R.
AU - Owen, Whyte G.
AU - Bible, Keith C.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of 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±0.6μM, Trx K m=104.7±26μM), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. 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 anticancer 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 molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents. Antioxid. Redox Signal. 11, 1097-1106.
AB - We recently reported that the antineoplastic thiodioxopiperazine natural product chaetocin potently induces cellular oxidative stress, thus selectively killing cancer cells. In pursuit of 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±0.6μM, Trx K m=104.7±26μM), thereby attenuating reduction of the critical downstream ROS remediation substrate Trx at achieved intracellular concentrations. 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 anticancer 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 molecular targets within the thioredoxin reductase/thioredoxin pathway in the development of novel candidate antineoplastic agents. Antioxid. Redox Signal. 11, 1097-1106.
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U2 - 10.1089/ars.2008.2318
DO - 10.1089/ars.2008.2318
M3 - Article
C2 - 18999987
AN - SCOPUS:64549104648
SN - 1523-0864
VL - 11
SP - 1097
EP - 1106
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 5
ER -