Competing pathways of iron chelation: Angiogenesis or anti‐tumor activity: Targeting different molecules to induce specific effects

Le, Nghia T.V.; Richardson, Des R.

doi:10.1002/ijc.20161

Cited by 11 publications

(8 citation statements)

References 17 publications

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“…Moreover, we found that gene expression of Ndrg1 increased when LNCaP cells were treated with other prolyl hydroxylase inhibitors, such as DMOG. The effect of L-mimosine on Ndrg1 in our study was mediated by iron depletion, because it was reversed by adding iron, which is in agreement with other studies (16,17). RT-qPCR and immunoblotting assays showed that chetomin suppressed hypoxia-induced Ndrg1 expression.…”

Section: Discussionsupporting

confidence: 94%

l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

Chung

Tsui

Feng

et al. 2012

American Journal of Physiology-Cell Physiology

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L-Mimosine, an iron chelator and a prolyl 4-hydroxylase inhibitor, blocks many cancer cells at the late G1 phase. B-cell translocation gene 2 (Btg2) regulates the G1/S transition phases of the cell cycle. N-myc downstream regulated gene 1 (Ndrg1) is a differentiation-inducing gene upregulated by hypoxia. We evaluated the molecular mechanisms of L-mimosine on cell cycle modulation in PC-3 and LNCaP prostate carcinoma cells. The effect of L-mimosine on cell proliferation of prostate carcinoma cells was determined by the [3H]thymidine incorporation and flow cytometry assays. L-Mimosine arrested the cell cycle at the G1 phase in PC-3 cells and at the S phase in LNCaP cells, thus attenuating cell proliferation. Immunoblot assays indicated that hypoxia and L-mimosine stabilized hypoxia-inducible factor-1α (HIF-1α) and induced Btg2 and Ndrg1 protein expression, but downregulated protein levels of cyclin A in both PC-3 and LNCaP cells. L-Mimosine treatment decreased cyclin D1 protein in PC-3 cells, but not in LNCaP cells. Dimethyloxalylglycine, a pan-prolyl hydroxylase inhibitor, also induced Btg2 and Ndrg1 protein expression in LNCaP cells. The transient gene expression assay revealed that L-mimosine treatment or cotransfection with HIF-1α expression vector enhanced the promoter activities of Btg2 and Ndrg1 genes. Knockdown of HIF-1α attenuated the increasing protein levels of both Btg2 and Ndrg1 by hypoxia or L-mimosine in LNCaP cells. Our results indicated that hypoxia and L-mimosine modulated Btg2 and Ndrg1 at the transcriptional level, which is dependent on HIF-1α. L-Mimosine enhanced expression of Btg2 and Ndrg1, which attenuated cell proliferation of the PC-3 and LNCaP prostate carcinoma cells.

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Section: Discussionsupporting

confidence: 94%

l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

Chung

Tsui

Feng

et al. 2012

American Journal of Physiology-Cell Physiology

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“…Without constant supply of iron, the conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase is inhibited and DNA synthesis is prevented (44). Up-regulation of HIF-1a by anti-TfR or iron chelators may also induce apoptosis via induction of BNIP3 (7,45), a proaptotic Bcl-2 member (46). However, in an in vivo setting, up-regulation of angiogenic factors and CAIX may increase tumor vasculature and resistance to acidic stress (47).…”

Section: Discussionmentioning

confidence: 99%

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

2006

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Cellular iron is needed for cell survival and hydroxylation of hypoxia-inducible factor-1A (HIF-A) by prolyl hydroxylases (PHD). One mechanism of iron uptake is mediated by the cell surface transferrin receptor (TfR). Because iron is required for cell growth and suppression of HIF-A levels, we tested the effects of the two anti-TfR monoclonal antibodies (mAb) E2.3 and A27.15 on growth of breast cancer cells and induction of HIF-A and hypoxia-regulated genes. Treatment with both mAbs together synergistically inhibited cell proliferation in a doseresponsive manner by up to 80% following 8 days of exposure, up-regulated HIF-1A and HIF transcription targets, downregulated TfR expression, and down-regulated cellular labile iron pool by 60%. Because combined treatment with anti-TfR mAbs resulted in the up-regulation of the hypoxia pathway, which may increase tumor angiogenesis, we analyzed the effects of ascorbate on cell viability and HIF-1A levels in cells treated with both anti-TfR mAbs together, as ascorbate has been shown to be required by PHD enzymes for full catalytic activity. Ascorbate at physiologic concentrations (25 Mmol/L) suppressed HIF-1A protein levels and HIF transcriptional targets in anti-TfR mAb-treated cells but did not suppress the antiproliferative effect of the mAbs. These results indicate that the addition of ascorbate increased the activity of the PHD enzymes in down-regulating HIF but not the proliferation of iron-starved anti-TfR mAb-treated cells. The use of anti-TfR mAbs and ascorbate in inhibiting both cell proliferation and HIF-1A and angiogenesis under normoxic conditions may be of therapeutic use. (Cancer Res 2006; 66(5): 2749-56)

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“…Indeed, the chelator-mediated response obtained, that is, either angiogenesis or anti-proliferative activity, may be dependent on the extent of Fe chelation and the intracellular pathways targeted by these ligands [85,175,176]. Indeed, these competing pathways can be induced by Fe chelation and it may be possible to pharmacologically promote either pathway depending upon ligand design [176].…”

Section: Potent Iron Chelators Overwhelm the Pro-angiogenic And Cell mentioning

confidence: 98%

Molecular Mechanisms of Iron Uptake by Cells and the Use of Iron Chelators for the Treatment of Cancer

Richardson

2005

CMC

Self Cite

116

102

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The field of iron (Fe) metabolism has been invigorated in the past 10 years with the discovery of a variety of new molecules involved in the homeostatic control of this critical nutrient. These proteins include the transferrin receptor 2, frataxin, hephaestin, hepcidin, hemojuvelin and others. Basic understanding of the metabolism of Fe in cells is vital in order to develop Fe chelators for the treatment of a variety of disease states. In addition, examination of the role of Fe in the regulation of cell cycle progression and angiogenesis has led to investigations of the use of novel Fe chelators as anti-proliferative agents. These studies have resulted in the identification of new ligands that show selective and potent anti-tumor activity in vitro and in vivo. Moreover, the ability of these chelators to inhibit growth is not only limited to the inhibition of DNA synthesis. In fact, there is a range of targets that are affected by Fe-depletion, such as molecules involved in cell cycle control, angiogenesis and metastasis suppression. These include hypoxia-inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor-1 (VEGF1), p21(CIP1/WAF1), cyclin D1 and the protein product of the N-myc downstream regulated gene-1 (Ndrg1). As such, Fe chelators can now be designed to target molecules to induce specific effects, for instance, angiogenesis or metastasis suppression.

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Competing pathways of iron chelation: Angiogenesis or anti‐tumor activity: Targeting different molecules to induce specific effects

Cited by 11 publications

References 17 publications

l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

l-Mimosine blocks cell proliferation via upregulation of B-cell translocation gene 2 and N-myc downstream regulated gene 1 in prostate carcinoma cells

Effects of Transferrin Receptor Blockade on Cancer Cell Proliferation and Hypoxia-Inducible Factor Function and Their Differential Regulation by Ascorbate

Molecular Mechanisms of Iron Uptake by Cells and the Use of Iron Chelators for the Treatment of Cancer

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