Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/99152
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Type: Journal article
Title: Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanisms
Author: Merlot, A.
Pantarat, N.
Menezes, S.
Sahni, S.
Richardson, D.
Kalinowski, D.
Citation: Molecular Pharmacology, 2013; 84(6):911-924
Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Issue Date: 2013
ISSN: 0026-895X
1521-0111
Statement of
Responsibility: 
Angelica M. Merlot, Namfon Pantarat, Sharleen V. Menezes, Sumit Sahni, Des R. Richardson, and Danuta S. Kalinowski
Abstract: The 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.
Keywords: Carbon Radioisotopes; Thiosemicarbazones; Pyridoxal; Antineoplastic Agents
Rights: © 2013 by The American Society for Pharmacology and Experimental Therapeutics
RMID: 0030048058
DOI: 10.1124/mol.113.088393
Grant ID: http://purl.org/au-research/grants/nhmrc/1021607
http://purl.org/au-research/grants/nhmrc/1021601
http://purl.org/au-research/grants/nhmrc/1048972
http://purl.org/au-research/grants/nhmrc/571123
Appears in Collections:Medicine publications

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