Cellular uptake mechanisms of an antitumor ruthenium compound: The endosomal/lysosomal system as a target for anticancer metal-based drugs

Leonor Côrte-Real; António P. Matos; Irina Alho; Tânia S. Morais; Ana Isabel Tomaz; Maria Helena Garcia; Isabel Santos; Manuel P. Bicho; Fernanda Marques

doi:10.1017/S143192761300175X

Cellular uptake mechanisms of an antitumor ruthenium compound: The endosomal/lysosomal system as a target for anticancer metal-based drugs

Leonor Côrte-Real, António P. Matos, Irina Alho, Tânia S. Morais, Ana Isabel Tomaz, Maria Helena Garcia, Isabel Santos, Manuel P. Bicho, Fernanda Marques

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

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 Ru^II(η⁵-cyclopentadienyl) complex.

Original language	English
Pages (from-to)	1122-1130
Number of pages	9
Journal	Microscopy and Microanalysis
Volume	19
Issue number	5
DOIs	https://doi.org/10.1017/S143192761300175X
Publication status	Published - Oct 2013
Externally published	Yes

Keywords

Ruthenium(II)
antitumor activity
cellular uptake
cyclopentadienyl
endosomal system
intracellular distribution
lysosomes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1017/S143192761300175X

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title = "Cellular uptake mechanisms of an antitumor ruthenium compound: The endosomal/lysosomal system as a target for anticancer metal-based drugs",

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), antitumor activity, cellular uptake, cyclopentadienyl, endosomal system, intracellular distribution, lysosomes",

author = "Leonor C{\^o}rte-Real and Matos, {Ant{\'o}nio P.} and Irina Alho and Morais, {T{\^a}nia S.} and Tomaz, {Ana Isabel} and Garcia, {Maria Helena} and Isabel Santos and Bicho, {Manuel P.} and Fernanda Marques",

year = "2013",

month = oct,

doi = "10.1017/S143192761300175X",

language = "English",

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TY - JOUR

T1 - Cellular uptake mechanisms of an antitumor ruthenium compound

T2 - The endosomal/lysosomal system as a target for anticancer metal-based drugs

AU - Côrte-Real, Leonor

AU - Matos, António P.

AU - Alho, Irina

AU - Morais, Tânia S.

AU - Tomaz, Ana Isabel

AU - Garcia, Maria Helena

AU - Santos, Isabel

AU - Bicho, Manuel P.

AU - Marques, Fernanda

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Ruthenium(II)

KW - antitumor activity

KW - cellular uptake

KW - cyclopentadienyl

KW - endosomal system

KW - intracellular distribution

KW - lysosomes

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AN - SCOPUS:84884579362

SN - 1431-9276

VL - 19

SP - 1122

EP - 1130

JO - Microscopy and Microanalysis

JF - Microscopy and Microanalysis

IS - 5

ER -

Cellular uptake mechanisms of an antitumor ruthenium compound: The endosomal/lysosomal system as a target for anticancer metal-based drugs

Abstract

Keywords

UN SDGs

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