The Differential Distribution of RAPTA-T in Non-Invasive and Invasive Breast Cancer Cells Correlates with Its Anti-Invasive and Anti-Metastatic Effects.

Ronald Lee,Anders Meibom,Gianni Sava,Stéphane Escrig,Paul Dyson,Catherine Maclachlan,Graham Knott

doi:10.3390/ijms18091869

Abstract

Nanoscale secondary ion mass spectrometry (NanoSIMS) combined with transmission electron microscopy (TEM) can be a powerful approach to visualize the exact distribution of drugs at the sub-cellular level. In this work, we exploit this approach to identify the distribution and localisation of the organometallic ruthenium(II)-arene drug Ru(η6-C6H5Me)(pta)Cl2, termed RAPTA-T, in MDA-MB-231 and MCF-7 human breast cancer cells. These cell lines have been chosen because the former cell lines are highly invasive and resistant to most chemotherapeutic agents and the latter ones are very sensitive to hormonal-based therapies. In the MDA-MB-231 cells, RAPTA-T was found to predominantly localise on the cell membrane and to a lesser extent in the nucleolus. These findings are consistent with the previously reported anti-metastatic properties of RAPTA-T and the observation that once internalized RAPTA-T is associated with chromatin. RAPTA-T shows a lack of membrane accumulation on the non-invasive MCF-7 cells, which correlates well with its selective anti-metastatic properties on invasive cell lines.

Highlights

Platinum-based drugs are widely used in the clinic [1,2]
Nanoscale secondary ion mass spectrometry (NanoSIMS) combined with transmission electron microscopy (TEM) can be a powerful approach to visualize the exact distribution of drugs at the sub-cellular level
In the MDA-MB-231 cells, RAPTA-T was found to predominantly localise on the cell membrane and to a lesser extent in the nucleolus. These findings are consistent with the previously reported anti-metastatic properties of RAPTA-T and the observation that once internalized RAPTA-T is associated with chromatin

Summary

Introduction

In recent years, an increasing number of ruthenium complexes, with profoundly different properties compared with the currently used platinum drugs, e.g., higher cancer cell selectivity leading to reduced side-effects in vivo [3], have been (pre-)clinically evaluated [4,5,6,7]. All these drugs possess the classical coordination complexes structure, but there is considerable interest in the anticancer properties of organometallic complexes, i.e., those containing direct metal-to-carbon bonds [8,9]. TThheessee ddaattaaememphpahsaissiesethethreoleroolfetaorfgetatirnggetminoglecmuolelesctuoltehsetcoellthmeemcebllramneemfobrrtahneecofnortrothl oef cmoenttarsotlasoisf mofestoalsitdastiusmofosuorlsi.dTthuims aosupresc. tThhaissaaslpreeacdtyhabseaenlresatrdeyssbeedenfosrttrhesesreudthfoerntihuemr(uIItIh)ednriuugm, N(IIAI)MdrI-uAg,, aNnAotMheI-r Apo, taennottahnetri-pmoetteansttaatnictid-mruegt,awsthatiicchdhrausgb,ewenhischhohwans tboebeinndshtoowinntetgorbininsd[2t8o].inIfteitgirsinfosu[n2d8]t.hIaf titRiAs PfoTuAn-dT tihs aatlsRoAaPbTleAt-oT tiasraglestoinabtelegrtionsta, ringetetginritnegmrionds,uilnatteiognrincomuloddubelactoiomnecaouhlidghbleycoamttreacatihvieghalpypartotaracchtifvoer atupmproouarchcofnotrrotluwmiotuhrmceotnatlr-oblaswedithdrmugesta. l-Sbuacsheda dmreucghsa. nSiusmch, wa hmicehchisanpirsomfo, uwnhdilcyhdiisffeprreonftoutondthlye ddiefvfeerloenptmtoentthoefdDeNveAlo-dpammeangtinofgDmNetAal--dbaamseadgdinruggms e[2ta9l]-,bwaoseudlddsrtuimgsul[a2t9e],thweosueladrcshtifmorunlaotveetlh, seesleecatricvhe fdorrungosvtoel,cosenltercotlivtuemdrouugrsmtoalcigonnatrnoclyt.umour malignancy

Materials and Methods

NanoSIMS Analysis

Data Extraction and Image Processing