Cell Permeable Iron Chelators as Potential Cancer Chemotherapeutic Agents

Pahl, Paula M. B.; Horwitz, Lawrence D.

doi:10.1080/07357900500359976

Cited by 38 publications

(34 citation statements)

References 95 publications

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“…The basis for this relates, in part, to the greater uptake and metabolism of Cu and Fe for essential processes in cancer cells relative to normal cells (5). Under such conditions, the lysosome could be more active in terms of its metal metabolism, and hence, more susceptible to Dp44mT.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Rao and colleagues reported topoisomerase IIa inhibition (10) and broad and specific antitumor activity (12). Additional modes of anticancer activity reported for Dp44mT include inhibition of the metastasis suppressor protein, Ndrg-1 (1), and modulation of the cell-cycle control proteins of the cyclin family (A, B, D1, D2, and D3) as well as cyclin-dependent kinase 2 (1,5).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the crucial roles of these metals, development of novel Fe and Cu chelators has become a promising anticancer strategy (1,5). Indeed, the chelator, Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; Fig.…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes

et al. 2011

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The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer. Cancer Res; 71(17);

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes

et al. 2011

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“…Our data indicate that this oxidative stress might be more harmful to cancer cells because they generally show higher basic levels of ROS due to high energy demand and fast proliferation (40,41). Slow and mild down-regulation of FHC is less toxic to cells but will deplete intracellular iron stores, thus decreasing proliferation rates (42). To investigate whether depletion of intracellular iron stores decreases tumor growth, we analyzed the effects of NF-nB inhibition in vivo.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Constitutively Activated Nuclear Factor-κB Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma

et al. 2009

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Aberrant signaling of the nuclear facotr (NF-KB) pathway has been identified as a mediator of survival and apoptosis resistance in leukemias and lymphomas. Here, we report that cell death of cutaneous T-cell lymphoma cell lines induced by inhibition of the NF-KB pathway is independent of caspases or classic death receptors. We found that free intracellular iron and reactive oxygen species (ROS) are the main mediators of this cell death. Antioxidants such as N-Acetyl-L-cysteine and glutathione or the iron chelator desferrioxamine effectively block cell death in cutaneous T-cell lymphoma cell lines or primary T cells from Sézary patients. We show that inhibition of constitutively active NF-KB causes down-regulation of ferritin heavy chain (FHC) that leads to an increase of free intracellular iron, which, in turn, induces massive generation of ROS. Furthermore, direct down-regulation of FHC by siRNA caused a ROS-dependent cell death. Finally, high concentrations of ROS induce cell death of malignant T cells. In contrast, T cells isolated from healthy donors do not display down-regulation of FHC and, therefore, do not show an increase in iron and cell death upon NF-KB inhibition. In addition, in a murine T-cell lymphoma model, we show that inhibition of NF-KB and subsequent down-regulation of FHC significantly delays tumor growth in vivo. Thus, our results promote FHC as a potential target for effective therapy in lymphomas with aberrant NF-KB signaling. [Cancer Res 2009;69(6):2365-74]

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“…These observations are similar to and consistent with prior studies describing the antileukemic effects of known iron chelators and differentiating agents. [20][21][22][23][24][25][26] Studies show that iron chelators have anticancer effects in a variety of malignancies, including breast cancer and melanoma, as shown in patients and solid tumor xenograft models. 25,27,28 It is unclear which exact molecular pathways mediate the antileukemic effects of EPinduced reduction of intracellular iron.…”

mentioning

confidence: 99%

Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

Roth

Will

Simkin

et al. 2012

Blood

146

123

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Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G 1 phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia. (Blood. 2012;120(2):386-394) IntroductionSurvival in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) has remained poor despite recent efforts to treat patients with novel therapeutic regimens. [1][2][3][4] In addition, complications secondary to thrombocytopenia and bleeding occur frequently in AML and MDS, leading to significant morbidity and mortality. 5,6 Given that the median age of patients with AML is close to 70 years, novel antileukemia agents with limited BM toxicity are needed to improve outcomes.Eltrombopag (EP) is an oral, nonpeptide, small-molecule thrombopoietin receptor (TPO-R) agonist that has proven efficacy in treating chronic immune thrombocytopenic purpura (ITP) and hepatitis C-related thrombocytopenia. 7,8 Despite concerns that some leukemia blast cells express TPO-R, we and others have reported previously that EP does not stimulate leukemia or MDS cell growth, but may rather lead to a modest inhibition while continuing to stimulate normal megakaryopoiesis in BM samples of patients with AML or MDS. 9,10 One study using a close chemical derivative of EP found a toxic effect on myeloid leukemia cells, suggesting that the entire substance class, including EP itself, may possess antileukemic activity. 11 Studies using cell lines further suggested that the growth-inhibitory effect of EP is not related to expression levels of However, this hypothesis has not yet been formally tested, and the mechanism through which EP exerts its potential antileukemic effect is not known. The concentrations at which EP inhibits leukemia cell proliferation in vitro are clinically achievable with few side effects and hav...

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Cell Permeable Iron Chelators as Potential Cancer Chemotherapeutic Agents

Cited by 38 publications

References 95 publications

Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes

Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes

Inhibition of Constitutively Activated Nuclear Factor-κB Induces Reactive Oxygen Species- and Iron-Dependent Cell Death in Cutaneous T-Cell Lymphoma

Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

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