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1.
Curr Med Chem ; 19(17): 2689-702, 2012.
Article in English | MEDLINE | ID: mdl-22455580

ABSTRACT

The study of iron chelators as anti-tumor agents is still in its infancy. Iron is important for cellular proliferation and this is demonstrated by observations that iron-depletion results in cell cycle arrest and also apoptosis. In addition, many iron chelators are known to inhibit ribonucleotide reductase, the iron-containing enzyme that is the rate-limiting step for DNA synthesis. Desferrioxamine is a well known chelator used for the treatment of iron-overload disease, but it has also been shown to possess anti-cancer activity. Another class of chelators, namely the thiosemicarbazones, have been shown to possess anti-cancer activity since the 1950's, although their mechanism(s) of action have only recently been more comprehensively elucidated. In fact, the redox activity of thiosemicarbazone iron complexes is thought to be important in mediating their potent cytotoxicity. Moreover, unlike typical iron chelators which simply act to deplete tumors of iron, several thiosemicarbazones (i.e., Bp44mT and Dp44mT) do not induce this effect, their anti-cancer efficacy being due to other mechanisms e.g., redox activity. Other reports have also shown that some thiosemicarbazones inhibit topoisomerase IIα, demonstrating that this class of agents have multiple molecular targets and act by various mechanisms. The most well characterized thiosemicarbazone iron chelator in terms of its assessment in humans is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP). Observations from these clinical trials highlight the less than optimal activity of this ligand and several side effects related to its use, including myelo-suppression, hypoxia and methemoglobinemia. The mechanisms responsible for these latter effects must be elucidated and the design of the ligand altered to minimize these problems and increase efficacy. This review discusses the development of chelators as unique agents for cancer treatment.


Subject(s)
Antineoplastic Agents/therapeutic use , Iron Chelating Agents/therapeutic use , Neoplasms/drug therapy , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Humans , Iron Chelating Agents/adverse effects , Iron Chelating Agents/chemistry , Iron Chelating Agents/pharmacology , Neoplasms/pathology
2.
Br J Pharmacol ; 165(1): 148-66, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21658021

ABSTRACT

BACKGROUND AND PURPOSE: Our previous studies demonstrated that a thiosemicarbazone iron chelator (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; Dp44mT) possesses potent and selective anti-cancer activity but led to cardiotoxicity at non-optimal doses. In this study, we examined the in vivo anti-tumour efficacy and tolerability of a new-generation 2-benzoylpyridine thiosemicarbazone iron chelator (2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes. EXPERIMENTAL APPROACH: BpT chelators were tested in vitro against human lung cancer cells (DMS-53) and in vivo in DMS-53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron-regulated molecules involved in growth and cell cycle control were investigated. KEY RESULTS: Administration of Bp44mT by either route resulted in marked dose-dependent inhibition of tumour growth. When administered at 50 mg·kg(-1) via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle-treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator-treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated. CONCLUSIONS AND IMPLICATIONS: This is the first study to show that Bp44mT can be given orally with potent anti-tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens.


Subject(s)
Antineoplastic Agents/pharmacology , Iron Chelating Agents/pharmacology , Neoplasms, Experimental/drug therapy , Pyridines/pharmacology , Thiosemicarbazones/pharmacology , Administration, Oral , Animals , Carcinoma, Squamous Cell/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Humans , Injections, Intravenous , Lung Neoplasms/drug therapy , Mice , Molecular Structure , Pyridines/classification , Thiosemicarbazones/classification
3.
Oncogene ; 26(42): 6113-24, 2007 Sep 13.
Article in English | MEDLINE | ID: mdl-17452986

ABSTRACT

Melanotransferrin (MTf) or melanoma tumor antigen p97 is a transferrin (Tf) homolog that is found predominantly bound to the cell membrane via a glycosyl phosphatidylinositol anchor. The molecule is a member of the Tf superfamily and binds iron through a single high-affinity iron(III)-binding site. Since its discovery on the plasma membrane of melanoma cells, the function of MTf has remained intriguing, particularly in relation to its role in cancer cell iron transport. In fact, considering the crucial role of iron in many metabolic pathways, e.g., DNA synthesis, it was important to understand the function of MTf in the transport of this vital nutrient. MTf has also been implicated in diverse physiological processes, such as plasminogen activation, angiogenesis and cell migration. However, recent studies using a knockout mouse and post-transcriptional gene silencing have demonstrated that MTf is not involved in iron metabolism, but plays a vital role in melanoma cell proliferation and tumorigenesis. In this review, we discuss the possible biological functions of MTf, particularly in relation to cancer.


Subject(s)
Iron/metabolism , Melanoma/metabolism , Neoplasm Proteins/physiology , Animals , Antigens, Neoplasm , Cell Proliferation , Humans , Melanoma/etiology , Melanoma/genetics , Melanoma-Specific Antigens , Neoplasm Proteins/genetics
4.
Carcinogenesis ; 28(10): 2172-83, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17449903

ABSTRACT

Melanoma tumor antigen p97 or melanotransferrin (MTf) is an iron (Fe)-binding protein with high homology to serum transferrin. MTf is expressed at very low levels in normal tissues and in high amounts in melanoma cells although its function remains elusive. To understand the function of MTf, we utilized whole-genome microarray analysis to examine the gene expression profile of five models after modulating MTf expression. These models included two new stably transfected MTf hyper-expression models (SK-N-MC neuroepithelioma and LMTK- fibroblasts) and one cell type (SK-Mel-28 melanoma) where MTf was down-regulated by post-transcriptional gene silencing. These findings were compared with alterations in gene expression identified using the MTf-/- mice. In addition, the changes identified from the microarray data were also assessed in a new model of MTf down-regulation in SK-Mel-2 melanoma cells. In the cell line models, MTf hyper-expression led to increased proliferation, whereas MTf down-regulation resulted in decreased proliferation. Across all five models of MTf down- and up-regulation, we identified three genes modulated by MTf. These included ATP-binding cassette subfamily B member 5, whose change in expression mirrored MTf down- or up-regulation. In addition, thiamine triphosphatase and transcription factor 4 were inversely expressed relative to MTf levels across all five models. The products of these three genes are involved in membrane transport, thiamine phosphorylation and proliferation/survival, respectively. This study identifies novel molecular targets directly or indirectly regulated by MTf and the potential pathways involved in its function, including modulation of proliferation.


Subject(s)
Gene Expression Regulation, Neoplastic , Melanoma/genetics , Neoplasm Proteins/genetics , Animals , Antigens, Neoplasm , Cell Division , Cell Line, Tumor , Fibroblasts/physiology , Gene Silencing , Genetic Vectors , Humans , Melanoma-Specific Antigens , Mice , Mice, Knockout , Neoplasm Proteins/deficiency , Neuroectodermal Tumors, Primitive, Peripheral , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transfection
5.
Carcinogenesis ; 27(11): 2157-69, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16704991

ABSTRACT

Melanotransferrin (MTf) or melanoma tumor antigen p97 is an iron (Fe) binding transferrin homolog expressed highly on melanomas and at lower levels on normal tissues. It has been suggested that MTf is involved in a variety of processes such as Fe metabolism and cellular differentiation. Considering the crucial role of Fe in many metabolic pathways, for example, DNA synthesis, it is important to understand the function of MTf. To define the roles of MTf, two models were developed: (i) an MTf knockout (MTf-/-) mouse and (ii) downregulation of MTf expression in melanoma cells by post-transcriptional gene silencing (PTGS). Examination of the MTf-/- mice demonstrated no differences compared with wild-type littermates. However, microarray analysis showed differential expression of molecules involved in proliferation such as Mef2a, Tcf4, Gls and Apod in MTf-/- mice compared with MTf+/+ littermates. Considering the role of MTf in melanoma cells, PTGS was used to downregulate MTf mRNA and protein levels by >90 and >80%, respectively. This resulted in inhibition of proliferation and migration. As found in MTf-/- mice, in melanoma cells with suppressed MTf expression, hMEF2A and hTCF4 were upregulated compared with parental cells. Furthermore, when melanoma cells with decreased MTf expression were injected into nude mice, tumor growth was markedly reduced, suggesting a role for MTf in proliferation and tumorigenesis.


Subject(s)
Cell Transformation, Neoplastic , Gene Expression Regulation, Neoplastic , Melanoma/pathology , Neoplasm Proteins/physiology , Animals , Antigens, Neoplasm , Cell Proliferation , Copper/chemistry , Female , Humans , Iron/chemistry , Iron/metabolism , Male , Melanoma-Specific Antigens , Mice , Mice, Inbred C57BL , Neoplasm Proteins/metabolism , Neoplasm Transplantation , RNA Processing, Post-Transcriptional , Zinc/chemistry
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