Elsevier

Pharmacological Research

Volume 173, November 2021, 105889
Pharmacological Research

Review
Innovative therapies for neuroblastoma: The surprisingly potent role of iron chelation in up-regulating metastasis and tumor suppressors and down-regulating the key oncogene, N-myc

https://doi.org/10.1016/j.phrs.2021.105889Get rights and content

Abstract

Iron is an indispensable requirement for essential biological processes in cancer cells. Due to the greater proliferation of neoplastic cells, their demand for iron is considerably higher relative to normal cells, making them highly susceptible to iron depletion. Understanding this sensitive relationship led to research exploring the effect of iron chelation therapy for cancer treatment. The classical iron-binding ligand, desferrioxamine (DFO), has demonstrated effective anti-proliferative activity against many cancer-types, particularly neuroblastoma tumors, and has the surprising activity of down-regulating the potent oncogene, N-myc, which is a major oncogenic driver in neuroblastoma. Even more significant is the ability of DFO to simultaneously up-regulate the potent metastasis suppressor, N-myc downstream-regulated gene-1 (NDRG1), which plays a plethora of roles in suppressing a variety of oncogenic signaling pathways. However, DFO suffers the disadvantage of demonstrating poor membrane permeability and short plasma half-life, requiring administration by prolonged subcutaneous or intravenous infusions. Considering this, the specifically designed di-2-pyridylketone thiosemicarbazone (DpT) series of metal-binding ligands was developed in our laboratory. The lead agent from the first generation DpT series, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), showed exceptional anti-cancer properties compared to DFO. However, it exhibited cardiotoxicity in mouse models at higher dosages. Therefore, a second generation of agents was developed with the lead compound being di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) that progressed to Phase I clinical trials. Importantly, DpC showed better anti-proliferative activity than Dp44mT and no cardiotoxicity, demonstrating effective anti-cancer activity against neuroblastoma tumors in vivo.

Section snippets

Prelude

Iron is an indispensable requirement for the activity of many essential metabolic processes as it plays critical roles in the active sites of many proteins involved in DNA synthesis, energy generation, etc. [1]. Neoplastic cells have a far more intense requirement for iron than normal cells, which is related to their rapid rate of proliferation [2]. As such, drugs that bind iron inhibit cancer cell proliferation, including the growth of aggressive tumors, for instance neuroblastoma [3].

Funding sources

D.R.R. thanks the National Health and Medical Research Council of Australia (NHMRC) for a Research Career Award (Senior Principal Research Fellowship; APP1159596).

Author contributions

T.P.W. and D.R.R. conceived and wrote the article with input from M.D. and C.C.D. All authors reviewed, revised and commented on the manuscript prior to submission.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (190)

  • D.R. Richardson et al.

    Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents

    Biochim. Biophys. Acta

    (2009)
  • M.A. Zoroddu et al.

    The essential metals for humans: a brief overview

    J. Inorg. Biochem.

    (2019)
  • M. Kolberg et al.

    Structure, function, and mechanism of ribonucleotide reductases

    Biochim. Biophys. Acta

    (2004)
  • C.C. Philpott et al.

    Special delivery: the role of iron chaperones in the distribution of iron in developing red cells

    Blood

    (2015)
  • I. Yanatori et al.

    The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer

    J. Biol. Chem.

    (2017)
  • P.M. Harrison et al.

    The ferritins: molecular properties, iron storage function and cellular regulation

    Biochim. Biophys. Acta

    (1996)
  • D. Boyd et al.

    Structural and functional relationships of human ferritin H and L chains deduced from cDNA clones

    J. Biol. Chem.

    (1985)
  • D.M. Ward et al.

    Ferroportin-mediated iron transport: expression and regulation

    Biochim. Biophys. Acta

    (2012)
  • I. Yanatori et al.

    Iron export through the transporter ferroportin 1 is modulated by the iron chaperone PCBP2

    J. Biol. Chem.

    (2016)
  • B. Guo et al.

    Iron regulates the intracellular degradation of iron regulatory protein-2 by the proteasome

    J. Biol. Chem.

    (1995)
  • E.S. Gurzau et al.

    Essential metals--case study on iron

    Ecotoxicol. Environ. Saf.

    (2003)
  • D.R. Richardson et al.

    The uptake of iron and transferrin by the human malignant melanoma cell

    Biochim. Biophys. Acta

    (1990)
  • Y. Wang et al.

    Iron metabolism in cancer

    IJMS

    (2019)
  • B. Zhu et al.

    Reduced expression of ferroportin1 and ceruloplasmin predicts poor prognosis in adrenocortical carcinoma

    J. Trace Elem. Med. Biol.

    (2019)
  • M. Han et al.

    Six-transmembrane epithelial antigen of prostate 3 predicts poor prognosis and promotes glioblastoma growth and invasion

    Neoplasia

    (2018)
  • S. Toyokuni

    Iron-induced carcinogenesis: the role of redox regulation

    Free Radic. Biol. Med.

    (1996)
  • M. Valko et al.

    Free radicals, metals and antioxidants in oxidative stress-induced cancer

    Chem. Biol. Interact.

    (2006)
  • C. Abou Zeid et al.

    Chapter 2 – normal human copper metabolism

  • M.L. Turski et al.

    New roles for copper metabolism in cell proliferation, signaling, and disease

    J. Biol. Chem.

    (2009)
  • R.S. Ohgami et al.

    The steap proteins are metalloreductases

    Blood

    (2006)
  • M. Chojnacka et al.

    Cox17 protein is an auxiliary factor involved in the control of the mitochondrial contact site and cristae organizing system

    J. Biol. Chem.

    (2015)
  • R.A. Festa et al.

    Copper: an essential metal in biology

    Curr. Biol.

    (2011)
  • A. Gupte et al.

    Elevated copper and oxidative stress in cancer cells as a target for cancer treatment

    Cancer Treat. Rev.

    (2009)
  • F. Soncin et al.

    Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells

    Biochem. Biophys. Res. Commun.

    (1997)
  • H.-W.L. Hann et al.

    Serum ferritin as a guide to therapy in neuroblastoma

    Cancer Res.

    (1980)
  • D.S. Kalinowski et al.

    The evolution of iron chelators for the treatment of iron overload disease and cancer

    Pharmacol. Rev.

    (2005)
  • F. Berthold et al.

    Neuroblastoma

    Drugs

    (2000)
  • C.C. Swift et al.

    Updates in diagnosis, management, and treatment of neuroblastoma

    Radiographics

    (2018)
  • J.M. Maris

    Recent advances in neuroblastoma

    N. Engl. J. Med.

    (2010)
  • J.L. Weinstein et al.

    Advances in the diagnosis and treatment of neuroblastoma

    Oncologist

    (2003)
  • S.L. Cohn et al.

    The International Neuroblastoma Risk Group (INRG) classification system: an INRG task force report

    J. Clin. Oncol.

    (2009)
  • N.R. Pinto et al.

    Advances in risk classification and treatment strategies for neuroblastoma

    J. Clin. Oncol.

    (2015)
  • P. Kaczówka et al.

    The role of N-Myc gene amplification in neuroblastoma childhood tumour – single-centre experience

    Contemp. Oncol.

    (2018)
  • R.C. Seeger et al.

    Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas

    N. Engl. J. Med.

    (1985)
  • D. Potaznik et al.

    Ferritin in neuroblastoma: impact of tumor load and blood transfusions

    Cancer Investig.

    (1985)
  • H.-W.L. Hann et al.

    Human ferritins present in the sera of nude mice transplanted with human neuroblastoma or hepatocellular carcinoma

    Cancer Res.

    (1984)
  • H.-W.L. Hann et al.

    Prognostic importance of serum ferritin in patients with stages III and IV neuroblastoma: the Childrens Cancer Study Group experience

    Cancer Res.

    (1985)
  • D.M. Miller et al.

    c-Myc and cancer metabolism

    Clin. Cancer Res.

    (2012)
  • M.W. Zimmerman et al.

    MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification

    Cancer Discov.

    (2018)
  • A. Ushmorov et al.

    Growth inhibition of murine neuroblastoma cells by c-Myc with cell cycle arrest in G2/M

    Cancer Biol. Ther.

    (2005)
  • Cited by (0)

    View full text