Enhanced targeting of mitochondrial peroxide defense by the combined use of thiosemicarbazones and inhibitors of thioredoxin reductase

被引:27
作者
Myers, Charles R. [1 ,2 ]
机构
[1] Med Coll Wisconsin, Dept Pharmacol & Toxicol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA
[2] Med Coll Wisconsin, Free Radical Res Ctr, Milwaukee, WI 53226 USA
关键词
Triapine; Thiosemicarbazones; Peroxiredoxin-3; Thioredoxin reductase; Auranofin; Cisplatin; TRIAPINE 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE; SELECTIVE ANTITUMOR-ACTIVITY; IRON CHELATORS; RIBONUCLEOTIDE REDUCTASE; CANCER-CELLS; MAMMALIAN THIOREDOXIN; PEROXIREDOXIN-III; TRANSFERRIN RECEPTOR; HYDROGEN-PEROXIDE; PROGNOSTIC-SIGNIFICANCE;
D O I
10.1016/j.freeradbiomed.2015.12.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Peroxiredoxin-3 (Prx3) accounts for about 90% of mitochondrial peroxidase activity, and its marked upregulation in many cancers is important for cell survival. Prx3 oxidation can critically alter peroxide signaling and defense and can be a seminal event in promoting cell death. Here it is shown that this mechanism can be exploited pharmacologically by combinations of clinically available drugs that compromise Prx3 function in different ways. Clinically relevant levels of the thiosemicarbazone iron chelators triapine (Tp) and 2,2'-Dipyridyl-N,N-dimethylsemicarbazone (Dp44mT) promote selective oxidation of mitochondrial Prx3, but not cytosolic Prxl, in multiple human lung and ovarian cancer lines. Decreased cell survival closely correlates with Prx3 oxidation. However, Prx3 oxidation is not merely an indicator of cell death as cytotoxic concentrations of cisplatin do not cause Prx3 oxidation. The siRNA-mediated suppression of either Prx3 or thioredoxin-2, which supports Prx3, enhances Tp's cytotoxicity. Tp-mediated Prx3 oxidation is driven by enhanced peroxide generation, but not by nitric oxide. Many tumors overexpress thioredoxin reductase (TrxR) which supports Prx activity. Direct inhibitors of TrxR (e.g. auranofin, cisplatin) markedly enhanced Tp's cytotoxicity, and auranofin enhanced Prx3 oxidation by low dose Tp. Together, these results support an important role for Prx3 oxidation in the cytotoxicity of Tp, and demonstrate that TrxR inhibitors can significantly enhance Tp's cytotoxicity. Thiosemicarbazone-based regimens could prove effective for targeting Prx3 in a variety of cancers. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:81 / 92
页数:12
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