Activation of Caspase Pathways during Iron Chelator-mediated Apoptosis

Greene, Bryan T.; Thorburn, Jackie; Willingham, Mark C.; Thorburn, Andrew; Planalp, Roy P.; Brechbiel, Martin W.; Jennings-Gee, Jamie; Wilkinson, John; Torti, Frank M.; Torti, Suzy V.

doi:10.1074/jbc.m110345200

Cited by 76 publications

(66 citation statements)

References 42 publications

(47 reference statements)

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“…205 Furthermore, apoptosis mediated by Tachpyridine was not prevented by blocking the CD95 death receptor pathway with a Fas-associated death domain protein dominant-negative mutant. 206 In addition, this chelator-mediated cell death was blocked in cells pre-treated with Bcl-XL and a dominant-negative caspase-9 expression vector. 206 Iron and the Cell Cycle Induction of apoptosis by Dp44mT and DFO was accompanied by a decrease in Bcl-2 expression, an increase in Bax and also cytochrome c efflux from the mitochondrion.…”

Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

“…206 In addition, this chelator-mediated cell death was blocked in cells pre-treated with Bcl-XL and a dominant-negative caspase-9 expression vector. 206 Iron and the Cell Cycle Induction of apoptosis by Dp44mT and DFO was accompanied by a decrease in Bcl-2 expression, an increase in Bax and also cytochrome c efflux from the mitochondrion. 93,169 More recently, and similarly, DFO has been shown to induce apoptosis through down-regulation of the Bcl-2 protein and upregulation of Bax in malignant oral keratinocytes.…”

Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

“…For instance, DFO has been demonstrated to induce apoptosis in a number of cancer cell lines including ovarian cancer, 202 neuroblastoma, 203 Kaposi's sarcoma, 122 malignant oral keratinocytes 169 and cervical carcinomas. 204 Other chelators, including Triapine, 205 311, 90 Tachpyridine, 132,206,207 O-Trensox 208 and Dp44mT 93 have also been shown to induce apoptosis in a variety of neoplastic cell types both in vitro and in vivo.…”

Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

See 2 more Smart Citations

Tuning Cell Cycle Regulation with an Iron Key

Yu¹,

Kovačević²,

Richardson³

2007

Cell Cycle

216

190

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Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

Section: The Molecular Targets Of Iron Chelators and Their Effects Onmentioning

confidence: 99%

See 1 more Smart Citation

Tuning Cell Cycle Regulation with an Iron Key

Yu¹,

Kovačević²,

Richardson³

2007

Cell Cycle

216

190

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“…[46][47][48] One mechanism by which chelators and other factors (eg, oxidative stress) cause tumor cell death may be through the induction of apoptosis. 22,24,[49][50][51][52][53][54][55][56] However, the precise mechanisms involved in chelator-mediated apoptosis remain unclear, particularly for aroylhydrazone ligands.The caspase enzymes are common executors of apoptosis. 52,57,58 Two caspase-activating cascades that regulate apoptosis have been described; one is initiated through death receptors (eg, CD95), and the other is triggered by changes in mitochondrial integrity.…”

mentioning

confidence: 99%

Novel di-2-pyridyl–derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment

Yuan

Lovejoy

Richardson

2004

Blood

357

754

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Aroylhydrazone and thiosemicarbazone iron (Fe) chelators have potent antitumor activity. The aim of the current study was to examine the antitumor effects and mechanisms of action of a novel series of Fe chelators, the di-2-pyridyl thiosemicarbazones. Of 7 new chelators synthesized, 4 showed pronounced antiproliferative effects. The most active chelator was Dp44mT, which had marked and selective antitumor activity-for example, an IC 50 of 0.03 M in neuroepithelioma cells compared with more than 25 M in mortal fibroblasts. Indeed, this antiproliferative activity was the greatest yet observed for an Fe chelator. Efficacy was greater than it was for the cytotoxic ligand 311 and comparable to that of the antitumor agent doxorubicin. Strikingly, Dp44mT significantly (P < .01) decreased tumor weight in mice to 47% of the weight in the control after only 5 days, whereas there was no marked change in animal weight or hematologic indices. IntroductionIron (Fe) is essential for proliferation, and many studies have shown that tumor cells are more sensitive to Fe deprivation than normal cells. [1][2][3][4][5][6][7][8][9][10][11] This sensitivity probably exists because cancer cells have greater Fe requirements than their normal counterparts [12][13][14][15] and because cancer cells express higher levels of the Fe-containing enzyme, ribonucleotide reductase (RR), which is the critical rate-limiting step in DNA synthesis. [16][17][18][19][20][21] Many in vitro 2,4,[7][8][9][21][22][23][24][25][26][27][28] and in vivo 6,29,30 studies and clinical trials 3,5,[31][32][33][34][35][36] have demonstrated that chelators are effective antiproliferative agents (for reviews, see Hershko,10 Lovejoy and Richardson, 11 and Richardson 37 ). The most well-studied chelator is desferrioxamine (DFO; Figure 1). 10,11 However, its short half-life and low efficacy at permeating membranes limit its antiproliferative activity. 22,38 Indeed, these factors probably resulted in its failure to inhibit tumor growth in some studies. 39,40 One group of ligands with high Fe chelation efficacy is the pyridoxal isonicotinoyl hydrazone (PIH) class. [41][42][43][44] We characterized PIH analogs that show far greater Fe chelation efficacy and antiproliferative activity than DFO. 23,24,45 Some of these ligands, such as 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311; Figure 1) inhibit RR activity 9 and affect the expression of molecules vital for cell cycle control. [46][47][48] One mechanism by which chelators and other factors (eg, oxidative stress) cause tumor cell death may be through the induction of apoptosis. 22,24,[49][50][51][52][53][54][55][56] However, the precise mechanisms involved in chelator-mediated apoptosis remain unclear, particularly for aroylhydrazone ligands.The caspase enzymes are common executors of apoptosis. 52,57,58 Two caspase-activating cascades that regulate apoptosis have been described; one is initiated through death receptors (eg, CD95), and the other is triggered by changes in mitochondrial integrity. 52,59,60 In the ...

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“…using Western blotting. 9) As shown in Fig. 8, procapase-3 was proteolytically activated after treated with ME 8 mM for 36 h, and cleaved fragments were detected at the same time.…”

Section: Resultsmentioning

confidence: 87%

Cytotoxic Effects of Mansonone E and F Isolated from Ulmus pumila

Wang

Xia

Zheng

et al. 2004

Biological & Pharmaceutical Bulletin

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Ulmus pumila L. is a deciduous tree that is widely distributed in East Asia. The stem and root bark of this species have been used in traditional Chinese medicine (TCM) for edema, mastitis, gastric cancer, and inflammation. 1,2) To search for biologically active substances, we separated the 80% ethanol extract of the root bark of U. pumila, and two sesquiterpene o-naphthoquinones, mansonone E (ME) and F (MF), were isolated from this species for the first time. It has been reported that ME and MF have antioxidant activities, 3) and many recent reports have focused on the apoptosis-inducing effects of antioxidants such as magnolol, ursolic acid, oleanic acid, maslinic acid, and others. [4][5][6] Therefore in this study the cytotoxic effects of ME and MF on the human tumor cell lines A375-S2, HeLa, MCF-7, and U937 were investigated. Both ME and MF showed potent antiproliferative effects, and ME induced apoptosis of HeLa cells by downregulation of Bcl-2 and Bcl-XL and upregulation of Bax, leading to the initiation of mitochondria-apoptosome pathways. The effects of ME on normal human cells, human peripheral blood mononuclear cells (PBMCs) and human embryonic lung (HEL) fibroblast cells were also investigated. MATERIALS AND METHODS General Experimental ProceduresThe NMR spectra were recorded on a Bruker ARX-300 NMR spectrometer ( 1 H, 300 MHz; 13 C, 75 MHz), using TMS as an internal standard. EI-MS were recorded on a GC-MS QP5050 spectrometer (Shimadzu, Kyoto, Japan). Column chromatography was performed on silica gel (100-140 and 200-300 mesh, Qingdao Haiyang Chemical, Shandong, China) and Sephadex LH-20 (bead size 25-100 mm, Sigma-Aldrich Chemical, St. Louis, MO, U.S.A.). Analytical TLC was performed using silica gel 60 F 254 plates (Kieselgel 60 F 254 precoated plates, Merck, Darmstadt, Germany). Hemipreparative HPLC was performed on an ODS C-18 column (9.8 mmϫ250 mm, 5 mm, Phenomenex, Torrance, CA, U.S.A.) using a watermethanol system as a mobile phase, monitored with an RID detector. All solvents were of analytical reagent or chromatographic reagent grade.Plant Material The root barks of U. pumila were collected from Fuxin, Liaoning Province, China, in May 2000 and identified by Prof. Zheng Cui of Shengyang Pharmaceutical University, China. Fresh root barks were dried in a dark, well-ventilated place, and a voucher specimen has been deposited in the Department of Traditional China Materia Medica, Shenyang Pharmaceutical University. Extraction and IsolationThe air-dried root barks of U. pumila (10 kg) were milled and extracted three times with 80% ethanol under reflux. The ethanol extract was filtered and concentrated under reduced pressure. The crude product (1195 g) was successively partitioned with EtOAc and n-butanol. The EtOAc layer was concentrated under reduced pressure, and the residue (111.8 g) was subjected to silica gel column chromatography eluted with c-hexane and a c-hexaneacetone mixture with increasing proportions of acetone. The fractions were collected and combined by monitoring with analytical T...

show abstract

Activation of Caspase Pathways during Iron Chelator-mediated Apoptosis

Cited by 76 publications

References 42 publications

Tuning Cell Cycle Regulation with an Iron Key

Tuning Cell Cycle Regulation with an Iron Key

Novel di-2-pyridyl–derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment

Cytotoxic Effects of Mansonone E and F Isolated from Ulmus pumila

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