The iron-chelating drug triapine causes pronounced mitochondrial thiol redox stress

ArticleinToxicology Letters 201(2):130-6 · March 2011with28 Reads
DOI: 10.1016/j.toxlet.2010.12.017 · Source: PubMed
Triapine (Tp) is an iron chelator with activity against several types of cancer. Iron-Tp [Fe(III)(Tp)(2)] can be redox-cycled to generate reactive oxygen species that may contribute to its cytotoxicity. However, evidence for this mechanism in cells is limited. The cytosolic and mitochondrial thioredoxins (Trx1 and Trx2, respectively) are essential for cell survival. They are normally maintained in the reduced state, and support the function of many intracellular proteins including the peroxiredoxins (Prxs). Their redox status can indicate oxidant stress in their respective subcellular compartments. Tp treatment of human lung A549 cells caused almost complete oxidation of Trx2 and its dependent peroxiredoxin (Prx3), but there was no effect on Trx1 redox status. Significant inhibition of total TrxR activity did not occur until Tp levels were 4-fold above those needed to cause Trx2 oxidation. While Tp caused a 36-45% decline in reduced glutathione (GSH) levels, GSH accounted for >99% of the total glutathione in the absence and presence of Tp. In vitro studies demonstrated that cysteine reduces Fe(III)(Tp)(2) to Fe(II)(Tp)(2), and cysteine was faster and more efficient than reduced glutathione (GSH) in this regard. Fe(III)(Tp)(2) also mediated the oxidation of purified Trx2 in vitro. Thus, Fe(III)(Tp)(2) itself, and/or various reactive species that may result from its redox cycling, could account for Trx2 and Prx3 oxidation in Tp-treated cells. The striking difference between the effects on Trx2 and Trx1 implies a pronounced thiol redox stress that is largely directed at the mitochondria. These previously unrecognized effects of Tp could contribute to its overall cytotoxicity.
    • "Cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins are at the core of cellular thiol redox control and antioxidant defense, making them essential for cellular survival [272]. Thus, the ability of Triapine ® to increase Trx2 oxidation suggests the contributing role of redox cycling and ROS generation in anti-cancer activity [271]. Triapine ® also could increase iron release from cells, prevent Fe uptake from transferrin, and increase IRP-RNA-binding activity like other chelators such as DFO, demonstrating that it was effective at chelating iron present in intracellular iron pools [268]. "
    [Show abstract] [Hide abstract] ABSTRACT: Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metal compared to their normal counterparts. Interestingly, new anti-cancer agents have been developed that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS. These ligands can avidly bind metals ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics.
    Full-text · Article · Feb 2016
    • "The results with multiple cell lines show that mitochondrial Prx3 is distinctly sensitive to the pro-oxidant effects of low micromolar Tp and sub-micromolar Dp44mT, with little to no effect on cytosolic Prx1 (Fig. 3[34], and Tp does not cause TrxR2 inhibition in cells[45]. While nitric oxide is a potential Prx oxidant[64], the inability of the nitric oxide synthase inhibitor L-NAME to protect Prx3 from Tp (Fig. 10) suggests that nitric oxide does not have a major role. "
    [Show abstract] [Hide abstract] ABSTRACT: 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 Prx1, 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.
    Article · Dec 2015
    • "Fe(salen)Cl induces apoptosis in tumor cells cells, though the exact molecular mechanism by which it induces apoptosis is still not entirely clear. However, involvement of iron signaling in the regulation of mitochondrial function and dynamics by altering oxidative stress is possible (Zhu et al., 2010; Huang et al., 2011; Myers et al., 2011; Wang and Pantopoulos, 2011). Our results also agree with the other previously established observations, and that Fe(salen)Cl causes a significant loss of mitochondrial membrane potential in Jurkat cells, but not in human PBMCs. "
    [Show abstract] [Hide abstract] ABSTRACT: Iron-based compounds possess the capability of inducing cell death due to their reactivity with oxidant molecules, but their specificity towards cancer cells and the mechanism of action are hitherto less investigated. A Fe(salen)Cl derivative has been synthesized that remains active in monomer form. The efficacy of this compound as an anti-tumor agent has been investigated in mouse and human leukemia cell lines. Fe(salen)Cl induces cell death specifically in tumor cells and not in primary cells. Mouse and human T-cell leukemia cell lines, EL4 and Jurkat cells are found to be susceptible to Fe(salen)Cl and undergo apoptosis, but normal mouse spleen cells and human peripheral blood mononuclear cells (PBMC) remain largely unaffected by Fe(salen)Cl. Fe(salen)Cl treated tumor cells show significantly higher expression level of cytochrome c that might have triggered the cascade of reactions leading to apoptosis in cancer cells. A significant loss of mitochondrial membrane potential upon Fe(salen)Cl treatment suggests that Fe(salen)Cl induces apoptosis by disrupting mitochondrial membrane potential and homeostasis, leading to cytotoxity. We also established that apoptosis in the Fe(salen)Cl-treated tumor cells is mediated through caspase-dependent pathway. This is the first report demonstrating that Fe(salen)Cl can specifically target the tumor cells, leaving the primary cells least affected, indicating an excellent potential for this compound to emerge as a next-generation anti-tumor drug.
    Full-text · Article · May 2014
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