Cytotoxic and DNA‐inhibitory effects of iron chelators on human leukaemic cell lines

Kontoghiorghes, George J.; Piga, Andrea; Av, Hoffbrand

doi:10.1002/hon.2900040303

Cited by 61 publications

(44 citation statements)

References 25 publications

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“…The antiproliferative activity of iron chelators was first demonstrated on leukemia in cell cultures and clinical trials [24, 25]. Then, the antiproliferative activity of iron chelators was demonstrated in solid tumors, including pancreatic cancer tumors, and in cell culture in recent studies [15, 26, 27].…”

Section: Discussionmentioning

confidence: 99%

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

et al. 2016

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BackgroundIron is essential for cell replication, metabolism and growth. Because neoplastic cells have high iron requirements due to their rapid proliferation, iron depletion may be a novel therapeutic strategy for cancer. Deferasirox (DFX), a novel oral iron chelator, has been successful in clinical trials in iron-overload patients and has been expected to become an anticancer agent. However, no studies have investigated the effects of DFX on pancreatic cancer. This study aimed to elucidate the effects of DFX against pancreatic cancer.MethodsThe effects of DFX on cell cycle, proliferation, and apoptosis were examined in three human pancreatic cancer cell lines: BxPC-3, HPAF-II, and Panc 10.05. The effect of orally administered DFX on the growth of BxPC-3 pancreatic cancer xenografts was also examined in nude mice. Additionally, microarray analysis was performed using tumors excised from xenografts.ResultsDFX inhibited pancreatic cancer cell proliferation in a dose-dependent manner. A concentration of 10 μM DFX arrested the cell cycle in S phase, whereas 50 and 100 μM DFX induced apoptosis. In nude mice, orally administered DFX at 160 and 200 mg/kg suppressed xenograft tumor growth with no serious side effects (n = 5; average tumor volumes of 674 mm3 for controls vs. 327 mm3 for 160 mg/kg DFX, p <0.05; average tumor volumes of 674 mm3 for controls vs. 274 mm3 for 200 mg/kg DFX, p <0.05). Importantly, serum biochemistry analysis indicated that serum levels of ferritin were significantly decreased by the oral administration of 160 or 200 mg/kg DFX (n = 5; average serum ferritin of 18 ng/ml for controls vs. 9 ng/ml for 160 mg/kg DFX, p <0.05; average serum ferritin of 18 ng/ml for controls vs. 10 ng/ml for 200 mg/kg DFX, p <0.05). Gene expression analysis revealed that most genes in pancreatic adenocarcinoma signaling, especially transforming growth factor-ß1 (TGF-ß1), were downregulated by DFX.ConclusionsDFX has potential as a therapeutic agent for pancreatic cancer. Iron depletion was essential for the antiproliferative effect of DFX in a preclinical model, and DFX acted through the suppression of TGF-ß signaling.

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Section: Discussionmentioning

confidence: 99%

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

et al. 2016

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“…Deferoxamine (DFO), which is produced by Streptomyces pilosus, binds to iron and acts as an iron chelator in cells [Keberle, 1964]. DFO has been shown to exert an anti-proliferative effect on certain cancer cell lines, including hepatoma, leukemia, and neuroblastoma cells [Lederman et al, 1984;Kontoghiorghes et al, 1986;Brodie et al, 1993;Fan et al, 2001]. Also, DFO regulates the expression of many genes such as cytochrome c oxidases and ubiquinone oxidoreductase involving in ATP synthesis [Ye and Connor, 1999].…”

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confidence: 99%

Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor‐associated protein 1 (TRAP1) regulates production of reactive oxygen species

Lee

Zheng

et al. 2006

J of Cellular Biochemistry

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Iron is an essential component of many proteins, and has crucial roles in the proper functioning of proteins involved in cellular respiration, proliferation, and differentiation. It has been recently reported that the deferoxamine (DFO), an iron chelator, induces mitochondrial dysfunction, characterized by an attenuation of oxidative phosphorylation, as well as senescence-like cellular morphology. However, the effects of DFO on mitochondrial heat shock proteins (HSPs) remain poorly understood. In this study, we examined the effect of DFO on tumor necrosis factor receptor-associated protein 1 (TRAP1), a representative mitochondrial HSP, in a normal human hepatocyte cell line, Chang cells. DFO specifically decreased TRAP1 levels, increasing reactive oxygen species (ROS) and caveolin-1 (Cav-1), a marker protein of senescence. To examine whether these effects of DFO are reversed, we established TRAP1-overexpressing Chang cells. DFO treatment to TRAP1-overexpressing cells resulted in decreases in levels of ROS, Cav-1, glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD) levels as well as senescence-associated beta-galactosidase (SA beta-gal) activity. These results suggest that TRAP1 might play a role in protecting mitochondria against damaging stimuli via decrease of ROS generation.

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“…Further experiments with omadine showed that this compound was almost immediately cytotoxic to NB cells, since if the ligand was removed from cells within 3 h, the cells continued to die (Blatt et al 1989). Addition of Fe to omadine did not prevent or enhance the ability of this chelator to inhibit NB growth (Blatt et al 1989), which is in contrast with other work with leukemic cells, which showed that the addition of Fe to this ligand enhanced its cytotoxicity (Kontoghiorghes et al 1986a(Kontoghiorghes et al , 1986b. This latter investigation suggested that the ability of omadine to inhibit proliferation was probably not by the same mechanism as that found for DFO.…”

Section: (A) Effect Of Dfo On Human Tumor Growthmentioning

confidence: 71%

Potential of iron chelators as effective antiproliferative agents

Richardson¹

1997

Can. J. Physiol. Pharmacol.

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Initially the impetus to develop iron (Fe) chelators for clinical use was based upon the need for a drug to treat Fe-overload diseases such as beta-thalassemia. However, it has become clear that Fe chelators may be useful for the treatment of a wide variety of disease states, including cancer, malaria, and free radical mediated injury. In particular, over the last 10 years a number of studies have shown that Fe chelators may be of use in the treatment of a number of aggressive human cancers, including neuroblastoma and leukemia, and several clinical trials have substantiated their potential. In the current review the role of Fe in cellular proliferation will be discussed, followed by the possible sites and mechanism of action of some of the most effective ligands. Attention will then be turned to examine the Fe chelators shown to possess antiproliferative activity and the clinical trials performed to assess their efficacy.

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Cytotoxic and DNA‐inhibitory effects of iron chelators on human leukaemic cell lines

Cited by 61 publications

References 25 publications

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo

Iron chelation study in a normal human hepatocyte cell line suggests that tumor necrosis factor receptor‐associated protein 1 (TRAP1) regulates production of reactive oxygen species

Potential of iron chelators as effective antiproliferative agents

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