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Cellular Uptake Mechanisms of an Antitumor Ruthenium Compound: The Endosomal/Lysosomal System as a Target for Anticancer Metal-Based Drugs

Published online by Cambridge University Press:  24 June 2013

Leonor Côrte-Real ,
António P. Matos ,
Irina Alho ,
Tânia S. Morais ,
Ana Isabel Tomaz ,
Maria Helena Garcia ,
Isabel Santos ,
Manuel P. Bicho  and
Fernanda Marques
Leonor Côrte-Real
Affiliation:
Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Superior Técnico, Polo de Loures-Campus Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
António P. Matos
Affiliation:
Departamento de Anatomia Patológica Curry Cabral, Centro Hospitalar de Lisboa Central, Rua da Beneficência, 8, 1069-166 Lisboa, Portugal and CESAM, Faculdade de Ciências da Universidade de Lisboa, Portugal
Irina Alho
Affiliation:
Laboratório de Genética, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
Tânia S. Morais
Affiliation:
Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Ana Isabel Tomaz
Affiliation:
Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Maria Helena Garcia
Affiliation:
Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Isabel Santos
Affiliation:
Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Superior Técnico, Polo de Loures-Campus Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal
Manuel P. Bicho
Affiliation:
Laboratório de Genética, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal
Fernanda Marques*
Affiliation:
Unidade de Ciências Químicas e Radiofarmacêuticas, Instituto Superior Técnico, Polo de Loures-Campus Tecnológico e Nuclear, Estrada Nacional 10, 2686-953 Sacavém, Portugal
*
*Corresponding author. E-mail: fmarujo@ctn.ist.utl.pt
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Abstract

Previous studies have described promising antitumor activity of an organometallic Ru(II) complex, η5-Cyclopentadienyl(2,2′-bipyridyl)(triphenylphosphane) Ruthenium(II) triflate ([(η5-C5H5)Ru(2,2′-bipyridyl)(PPh3)][CF3SO3]) herein designated as TM34. Its broad spectrum of activity against a panel of human tumor cell lines and high antiproliferative efficiency prompted us to focus on its mode of action. We present herein results obtained with two human tumor cell lines A2780 and MDAMB231 on the compound distribution within the cell, the mechanism of its activity, and its cellular targets. The prospective metallodrug TM34 revealed: (a) fast antiproliferative effects even at short incubation times for both cell lines; (b) preferential localization at the cell membrane and cytosol; (c) cellular activity by a temperature-dependent process, probably macropinocytosis; (d) inhibition of a lysosomal enzyme, acid phosphatase, in a dose-dependent mode; and (e) disruption and vesiculation of the Golgi apparatus, which suggest the involvement of the endosomal/lysosomal system in its mode of action. These results are essential to elucidate the basis for the cytotoxic activity and mechanism of action of this RuII(η5-cyclopentadienyl) complex.

Keywords

Ruthenium(II)cyclopentadienylantitumor activitycellular uptakeintracellular distributionendosomal systemlysosomes
Type
Portuguese Society for Microscopy
Information
Microscopy and Microanalysis , Volume 19 , Issue 5 , October 2013 , pp. 1122 - 1130
Copyright
Copyright © Microscopy Society of America 2013 

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