Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/99152
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dc.contributor.authorMerlot, A.en
dc.contributor.authorPantarat, N.en
dc.contributor.authorMenezes, S.en
dc.contributor.authorSahni, S.en
dc.contributor.authorRichardson, D.en
dc.contributor.authorKalinowski, D.en
dc.date.issued2013en
dc.identifier.citationMolecular Pharmacology, 2013; 84(6):911-924en
dc.identifier.issn0026-895Xen
dc.identifier.issn1521-0111en
dc.identifier.urihttp://hdl.handle.net/2440/99152-
dc.description.abstractThe chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) shows potent and selective anticancer and antimetastatic activity. However, the mechanism by which it is initially transported into cells to induce cytotoxicity is unknown. Hence, the current investigation examined the cellular uptake of ¹⁴C-Dp44mT relative to two structurally related ligands, namely the aroylhydrazone ¹⁴C-pyridoxal isonicotinoyl hydrazone (¹⁴C-PIH) and the thiosemicarbazone (¹⁴C-2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (¹⁴C-Bp4eT). In marked contrast to the cellular uptake of ¹⁴C-PIH and ¹⁴C-Bp4eT, which were linear as a function of concentration, ¹⁴C-Dp44mT uptake was saturable using SK-N-MC neuroepithelioma cells (Bmax, 4.28 × 10⁷ molecules of chelator/cell; and Kd, 2.45 μM). Together with the fact that ¹⁴C-Dp44mT uptake was temperature-dependent and significantly (P < 0.01) decreased by competing unlabeled Dp44mT, these observations indicated a saturable transport mechanism consistent with carrier/receptor-mediated transport. Other unlabeled ligands that shared the saturated N4 structural moiety with Dp44mT significantly (P < 0.01) inhibited ¹⁴C-Dp44mT uptake, illustrating its importance for carrier/receptor recognition. Nevertheless, unlabeled Dp44mT most markedly decreased (¹⁴C-Dp44mT uptake, demonstrating that the putative carrier/receptor shows high selectivity for Dp44mT. Interestingly, in contrast to ¹⁴C-Dp44mT, uptake of its Fe complex [Fe(¹⁴C-Dp44mT)₂] was not saturable as a function of concentration and was much greater than the ligand alone, indicating an alternate mode of transport. Studies examining the tissue distribution of ¹⁴C-Dp44mT injected intravenously into a mouse tumor model demonstrated the ¹⁴C label was primarily identified in the excretory system. Collectively, these findings examining the mechanism of Dp44mT uptake and its distribution and excretion have clinical implications for its bioavailability and uptake in vivo.en
dc.description.statementofresponsibilityAngelica M. Merlot, Namfon Pantarat, Sharleen V. Menezes, Sumit Sahni, Des R. Richardson, and Danuta S. Kalinowskien
dc.language.isoenen
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics (ASPET)en
dc.rights© 2013 by The American Society for Pharmacology and Experimental Therapeuticsen
dc.subjectCarbon Radioisotopes; Thiosemicarbazones; Pyridoxal; Antineoplastic Agentsen
dc.titleCellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanismsen
dc.typeJournal articleen
dc.identifier.rmid0030048058en
dc.identifier.doi10.1124/mol.113.088393en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1021607en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1021601en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1048972en
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/571123en
dc.identifier.pubid248153-
pubs.library.collectionMedicine publicationsen
pubs.library.teamDS08en
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Medicine publications

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