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PMID: 17003122 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 40 ·2006-10-03 ·Pages 14901-6

Whitnall M, Howard J, Ponka P, Richardson DR

Abstract

Novel chemotherapeutics with marked and selective antitumor activity are essential to develop, particularly those that can overcome resistance to established therapies. Iron (Fe) is critical for cell-cycle progression and DNA synthesis and potentially represents a novel molecular target for the design of new anticancer agents. The aim of this study was to evaluate the antitumor activity and Fe chelation efficacy of a new class of Fe chelators using human tumors. In this investigation, the ligands showed broad antitumor activity and could overcome resistance to established antitumor agents. The in vivo efficacy of the most effective chelator identified, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone (Dp44mT), was assessed by using a panel of human xenografts in nude mice. After 7 weeks, net growth of a melanoma xenograft in Dp44mT-treated mice was only 8% of that in mice treated with vehicle. In addition, no differences in these latter animals were found in hematological indices between Dp44mT-treated mice and controls. No marked systemic Fe depletion was observed comparing Dp44mT- and vehicle-treated mice, probably because of the very low doses required to induce anticancer activity. Dp44mT caused up-regulation of the Fe-responsive tumor growth and metastasis suppressor Ndrg1 in the tumor but not in the liver, indicating a potential mechanism of selective anticancer activity. These results indicate that the novel Fe chelators have potent and broad antitumor activity and can overcome resistance to established chemotherapeutics because of their unique mechanism of action.

MeSH Terms
Animals Antineoplastic Agents/chemistry,therapeutic use Blood Cells/drug effects Cell Line, Tumor Cell Proliferation/drug effects Chelation Therapy Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic/drug effects Humans Iron/metabolism Iron Chelating Agents/chemistry,therapeutic use Liver/cytology,drug effects,pathology Mice Mice, Nude Myocardium/cytology,pathology Neoplasms/drug therapy Organ Size/drug effects Pyridines/pharmacology Spleen/cytology,drug effects,pathology Thiosemicarbazones/pharmacology Transplantation, Heterologous Tumor Stem Cell Assay Tumor Suppressor Protein p53/metabolism
Chemicals
Antineoplastic Agents Iron Chelating Agents Pyridines Thiosemicarbazones Tumor Suppressor Protein p53 3-aminopyridine-2-carboxaldehyde thiosemicarbazone Iron
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Whitnall Megan
Children's Cancer Institute Australia for Medical Research, Sydney, New South Wales 2031, Australia.
Howard Jonathan
Ponka Prem
Richardson Des R
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0604979103
Published
2006-10-03
Epub
2006-00-26
Pages
14901-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1595448
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0604979103 PMC Full Text View journal details
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